FULL-LENGTH ORIGINAL RESEARCH
Prognostic factors for subsequent epilepsy in children with febrile seizures *Efterpi Pavlidou and †Christos Panteliadis Epilepsia, 54(12):2101–2107, 2013 doi: 10.1111/epi.12429
SUMMARY
Dr Efterpi Pavlidou is a Consultant Pediatrician working in the field of Pediatric Neurology at a tertiary hospital since 2011. She has finished her dissertation in pediatric neurology in 2007.
Objective: Epilepsy following febrile seizures (FS) has been estimated between 2% and 7%. It concerns a prospective study in a large sample of children with a long-term follow-up. The aim of this study is to identify the prognostic factors that can lead children with FS to epilepsy. Methods: Children with a first episode of FS were included. We gathered information about prenatal and perinatal history, family history of FS and epilepsy in first- and second degree relatives, age at the time of the initial FS, dates of FS recurrences, focality, duration of the FS and recurrent episodes within the same febrile illness, height and duration of fever prior to the seizure, cause of the fever, and frequency of febrile illnesses. Patients were seen every 4–6 months and also at each recurrence. Key Findings: A group of 560 children with a first FS met all entry criteria. Epilepsy was recorded at 5.4%. Statistical analysis was performed between children with epilepsy and those with no afebrile seizure. We analyzed FS recurrences in accordance with the occurrence of epilepsy. From the third FS recurrence and beyond, only focality continued to have prognostic value. Significance: Main prognostic factors for the development of epilepsy after FS are: (1) complex FS that increased the risk for epilepsy 3.6 times, (2) age at onset of FS beyond the third year of life that raised the risk 3.8 times, (3) positive family history of epilepsy 7.3 times, and (4) multiple episodes of FS about 10 times. Focality at the first and the second FS recurrence increased the risk of epilepsy about 9.7 and 11.7 times, respectively. Focality was the only factor that continued to be significant in further FS recurrences. A prognostic profile of each child with FS would be very useful for the follow-up of these children. KEY WORDS: Prognosis, Fever, Afebrile convulsions.
Frequency of febrile seizures (FS) in general pediatric population ranges between 2% and 5% and concerns mainly children from 6 months to 5 years of age (Berg et al., 1997; AAP, 2011). Epidemiologic studies have shown that the recurrence risk of FS depends on genetic Accepted September 20, 2013; Early View publication November 8, 2013. *Pediatric Neurology Department, A.H.E.P.A Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; and †Pediatric Neurology Department, Ippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece Address correspondence to Efterpi Pavlidou, Pediatric Neurology Department, A.H.E.P.A Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1 St., 54636 Thessaloniki, Greece. E-mail: [email protected] Wiley Periodicals, Inc. © 2013 International League Against Epilepsy
background. Gene analyses have located the responsible genes on chromosomes 2, 5, 8, 19p, and 19q (Winawer & Shinnar, 2005; Kang et al., 2006). However, the mechanisms underlying the genesis of FS are still unknown. The risk of having a first recurrence is estimated between 23% and 42%. Approximately one third to one half of those children with a first FS recurrence, will have a second recurrence, and only 10% will have three or more recurrences (Pavlidou et al., 2008). Epilepsy after FS has been investigated for many years, with conflicted results. Epilepsy following FS has been estimated between 2% and 7%, and is four to five times greater than that of the general pediatric population (Neligan et al., 2012). However, all children with a history of FS do not have the same risk of subsequent epilepsy. This is a prospective study in a large sample of children with a long-term follow-up.
2101
2102 E. Pavlidou and C. Panteliadis The aim of this study is to identify those prognostic factors that can lead children with FS to epilepsy. This knowledge could be very useful for the management and follow-up of these children.
Patients and Methods Children with a first episode of FS were included. The children were seen either at the outpatient pediatric neurology clinic or were hospitalized for their first episode of FS. In our area, all children with FS (simple or complex) almost are either referred to a pediatric neurology outpatient clinic or hospitalized. Epilepsy was defined as the occurrence of at least two episodes of afebrile seizures in two different days. The types of epilepsy that occurred after FS were designated according to the latest classification of epilepsies and epileptic syndromes (Berg et al., 2010). Eligibility Criteria for eligibility were the following: no previous personal history of afebrile or neonatal seizures; no evidence of intracranial infections or head trauma; no previous anticonvulsant medication; and age between 3 months and 6 years. None of the children received any antiepileptic treatment, including intermittent diazepam prophylaxis, during the study period. The parents of the children were interviewed by a research assistant. The interviewer elicited a complete description of the seizure. Descriptions of the seizures were compiled from the medical records and the interview, and each seizure was classified on the basis of this information by an expert in pediatric neurology. According to the protocol, we gathered information about prenatal and perinatal history of each child, age at the time of the initial FS, dates of FS recurrences, presence of focal features (including Todd’s paresis), duration of the FS episode and recurrent episodes within the same febrile illness, height of temperature and duration of fever prior to the seizure, cause of the fever and frequency of febrile illnesses during the follow-up period, and family history of FS and epilepsy in first- and second-degree relatives. We specifically analyzed the data from the children with a history of maternal epilepsy and children with no history of maternal epilepsy regarding the subsequent development or not of epilepsy. All of the above factors were evaluated regarding their prognostic value for subsequent epilepsy in children with FS. Body temperature (axillary) was recorded in degrees of Celsius. Temperature up to 38.5°C was defined as low, whereas greater than 38.5°C as high. At the time of the first FS a detailed neurologic examination was conducted by a pediatric neurologist. Parents were fully informed about the nature and management of FS. All children had electroencephalography (EEG) 7–10 days after the FS episode and while the child was afebrile. Lumbar puncture was performed only in cases that were indicative of meningitis or encephalitis, whereas neuEpilepsia, 54(12):2101–2107, 2013 doi: 10.1111/epi.12429
roimaging (computerized tomography [CT] or mainly magnetic resonance imaging [MRI]) was performed on children with focal seizures, febrile status epilepticus, or abnormal neurologic examination. Follow-up The median time of follow up was 5.3 years (range 2.5– 8.5 years, standard deviation [SD] 1.3 years). During the follow-up period, at every recurrence clinical reevaluation and a new EEG were performed. The patients’ parents were fully informed about the nature and management of FS. Parents and patients were seen every 4–6 months, in order to reinforce the study program, and also at each recurrence they called the study staff and provided all the necessary information about the FS recurrence or the occurrence of an afebrile seizure. Statistical analysis A univariate analysis was performed between the examined factors at the total episodes of FS and also to each recurrence separately in correlation to the occurrence or not of subsequent epilepsy. We investigated several factors on whether they can predict subsequent epilepsy, with the Pearson chi-square test (p-value < 0.05). We identified index “c”, which showed how powerful the connection was between the variables that we examined. Finally, we proceeded to a multivariate analysis (Cox regression-survival analysis), in order to identify the factors that contribute to the prognosis of epilepsy. The relative risk (RR) was calculated, which showed how many times a certain factor increase the risk for subsequent epilepsy. Statistical analysis was performed using SPSS 17.0 software (IBM Corp., Armonk, NY, U.S.A.).
Results A group of 560 children with a first episode of FS met all entry criteria. However, 59 children were excluded because no follow-up information could be obtained after the initial evaluation. This report is, therefore, based on the remaining 501 children. The age at onset of FS ranged between 3 months and 5 years old (median age at onset 23 months 12 months). Four hundred sixty-three (92.4%) of 501 children had normal perinatal history, 3 (0.6%) of 501 had twin pregnancy, 11 (2.2%) of 501 had prematurity (3 years 15 min and recurrence within the same febrile illness) are prognostic markers for the development of afebrile seizures (Sfaihi et al., 2012; Wo et al., 2013). Few studies have analyzed separately the prognostic value of each of the three features of complex FS. Annegers et al. (1987) reported that the risk of subsequent epilepsy in children with one of the three characteristics
of complex FS is about 6–8%, with two 17–22%, and with three up to 49%. Late age at onset of FS Our study showed that late age at onset of FS (>3 years old), as an isolated factor, has no influence at the occurrence of epilepsy, but only when it is taken into account with other prognostic markers, plays an important role in epileptogenesis. Specifically, late age at onset of FS increased the risk of subsequent epilepsy about four times. A retrospective study found that children who had their first FS at an age 3 years had epilepsy more often in the first 2 years after the FS episode (Vestergaard et al., 2007). Other authors found that children with a first FS at an age younger than 12 months old had a higher incidence of epilepsy (Nelson & Ellenberg, 1976; Annegers et al., 1987).The interpretation of this finding is that severe episodes of FS tend to occur at a younger age. The present study showed that focality, not only at the first FS but mostly at recurrences, is a reliable prognostic factor for subsequent epilepsy. Indeed, the prognostic power of focality was increased at each recurrence. Therefore, children with focal seizures at the fourth recurrence (i.e., more close timely to the occurrence of epilepsy) had an increased risk of epilepsy of up to 30 times. Other authors also supported that the most powerful prognostic factor between the three characteristics of complex FS for subsequent epilepsy was focality (Verity & Golding, 1991). Our results have shown that FS recurrence within the same febrile illness cannot predict subsequent epilepsy. In addition, the number of febrile status epilepticus in our study was restricted and children with so we could not reach to statistical significant results. Sapir et al. (2000), reported that none of their patients with prolonged FS developed later epilepsy. The same conclusion is reached also by other authors, as they noted that febrile status epilepticus does not increase the risk either of FS or afebrile seizures (Maytal & Shinnar, 1990). A recent study concluded that prolonged FS is the result of a previous insult of the hippocampus and not the cause of it (Scott et al., 2006). Different results are published by Verity et al. (1993), who reported that the incidence of subsequent epilepsy was higher in children with febrile status epilepticus. Saltik et al. (2003) found that 13.7% of their patients with epilepsy had a history of febrile status epilepticus. However, most of the studies differ from ours, since they concern patients hospitalized at reference centers and therefore involved a select group of severe cases, who possibly had a preexisting brain injury. It has been proven that prolonged seizures can harm the neurons. The question that arises is how often such an injury can occur and why it happens to certain children. It seems that the neuronal insult is connected with the cause of the seizures and not with the seizures per se (Verity, 1998). Most of the studies in the literature have examined various prognostic factors for subsequent epilepsy, either the Epilepsia, 54(12):2101–2107, 2013 doi: 10.1111/epi.12429
2106 E. Pavlidou and C. Panteliadis total of FS episodes (i.e., first FS and recurrences) or only the first episode of FS. We analyzed each recurrence, since we hypothesized that recurrences could change the prognostic profile for the child regarding the development of epilepsy. Our findings suggest that focality and short duration of fever (
Prognostic factors for subsequent epilepsy in children with febrile seizures *Efterpi Pavlidou and †Christos Panteliadis Epilepsia, 54(12):2101–2107, 2013 doi: 10.1111/epi.12429
SUMMARY
Dr Efterpi Pavlidou is a Consultant Pediatrician working in the field of Pediatric Neurology at a tertiary hospital since 2011. She has finished her dissertation in pediatric neurology in 2007.
Objective: Epilepsy following febrile seizures (FS) has been estimated between 2% and 7%. It concerns a prospective study in a large sample of children with a long-term follow-up. The aim of this study is to identify the prognostic factors that can lead children with FS to epilepsy. Methods: Children with a first episode of FS were included. We gathered information about prenatal and perinatal history, family history of FS and epilepsy in first- and second degree relatives, age at the time of the initial FS, dates of FS recurrences, focality, duration of the FS and recurrent episodes within the same febrile illness, height and duration of fever prior to the seizure, cause of the fever, and frequency of febrile illnesses. Patients were seen every 4–6 months and also at each recurrence. Key Findings: A group of 560 children with a first FS met all entry criteria. Epilepsy was recorded at 5.4%. Statistical analysis was performed between children with epilepsy and those with no afebrile seizure. We analyzed FS recurrences in accordance with the occurrence of epilepsy. From the third FS recurrence and beyond, only focality continued to have prognostic value. Significance: Main prognostic factors for the development of epilepsy after FS are: (1) complex FS that increased the risk for epilepsy 3.6 times, (2) age at onset of FS beyond the third year of life that raised the risk 3.8 times, (3) positive family history of epilepsy 7.3 times, and (4) multiple episodes of FS about 10 times. Focality at the first and the second FS recurrence increased the risk of epilepsy about 9.7 and 11.7 times, respectively. Focality was the only factor that continued to be significant in further FS recurrences. A prognostic profile of each child with FS would be very useful for the follow-up of these children. KEY WORDS: Prognosis, Fever, Afebrile convulsions.
Frequency of febrile seizures (FS) in general pediatric population ranges between 2% and 5% and concerns mainly children from 6 months to 5 years of age (Berg et al., 1997; AAP, 2011). Epidemiologic studies have shown that the recurrence risk of FS depends on genetic Accepted September 20, 2013; Early View publication November 8, 2013. *Pediatric Neurology Department, A.H.E.P.A Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece; and †Pediatric Neurology Department, Ippokratio Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece Address correspondence to Efterpi Pavlidou, Pediatric Neurology Department, A.H.E.P.A Hospital, Aristotle University of Thessaloniki, St. Kiriakidi 1 St., 54636 Thessaloniki, Greece. E-mail: [email protected] Wiley Periodicals, Inc. © 2013 International League Against Epilepsy
background. Gene analyses have located the responsible genes on chromosomes 2, 5, 8, 19p, and 19q (Winawer & Shinnar, 2005; Kang et al., 2006). However, the mechanisms underlying the genesis of FS are still unknown. The risk of having a first recurrence is estimated between 23% and 42%. Approximately one third to one half of those children with a first FS recurrence, will have a second recurrence, and only 10% will have three or more recurrences (Pavlidou et al., 2008). Epilepsy after FS has been investigated for many years, with conflicted results. Epilepsy following FS has been estimated between 2% and 7%, and is four to five times greater than that of the general pediatric population (Neligan et al., 2012). However, all children with a history of FS do not have the same risk of subsequent epilepsy. This is a prospective study in a large sample of children with a long-term follow-up.
2101
2102 E. Pavlidou and C. Panteliadis The aim of this study is to identify those prognostic factors that can lead children with FS to epilepsy. This knowledge could be very useful for the management and follow-up of these children.
Patients and Methods Children with a first episode of FS were included. The children were seen either at the outpatient pediatric neurology clinic or were hospitalized for their first episode of FS. In our area, all children with FS (simple or complex) almost are either referred to a pediatric neurology outpatient clinic or hospitalized. Epilepsy was defined as the occurrence of at least two episodes of afebrile seizures in two different days. The types of epilepsy that occurred after FS were designated according to the latest classification of epilepsies and epileptic syndromes (Berg et al., 2010). Eligibility Criteria for eligibility were the following: no previous personal history of afebrile or neonatal seizures; no evidence of intracranial infections or head trauma; no previous anticonvulsant medication; and age between 3 months and 6 years. None of the children received any antiepileptic treatment, including intermittent diazepam prophylaxis, during the study period. The parents of the children were interviewed by a research assistant. The interviewer elicited a complete description of the seizure. Descriptions of the seizures were compiled from the medical records and the interview, and each seizure was classified on the basis of this information by an expert in pediatric neurology. According to the protocol, we gathered information about prenatal and perinatal history of each child, age at the time of the initial FS, dates of FS recurrences, presence of focal features (including Todd’s paresis), duration of the FS episode and recurrent episodes within the same febrile illness, height of temperature and duration of fever prior to the seizure, cause of the fever and frequency of febrile illnesses during the follow-up period, and family history of FS and epilepsy in first- and second-degree relatives. We specifically analyzed the data from the children with a history of maternal epilepsy and children with no history of maternal epilepsy regarding the subsequent development or not of epilepsy. All of the above factors were evaluated regarding their prognostic value for subsequent epilepsy in children with FS. Body temperature (axillary) was recorded in degrees of Celsius. Temperature up to 38.5°C was defined as low, whereas greater than 38.5°C as high. At the time of the first FS a detailed neurologic examination was conducted by a pediatric neurologist. Parents were fully informed about the nature and management of FS. All children had electroencephalography (EEG) 7–10 days after the FS episode and while the child was afebrile. Lumbar puncture was performed only in cases that were indicative of meningitis or encephalitis, whereas neuEpilepsia, 54(12):2101–2107, 2013 doi: 10.1111/epi.12429
roimaging (computerized tomography [CT] or mainly magnetic resonance imaging [MRI]) was performed on children with focal seizures, febrile status epilepticus, or abnormal neurologic examination. Follow-up The median time of follow up was 5.3 years (range 2.5– 8.5 years, standard deviation [SD] 1.3 years). During the follow-up period, at every recurrence clinical reevaluation and a new EEG were performed. The patients’ parents were fully informed about the nature and management of FS. Parents and patients were seen every 4–6 months, in order to reinforce the study program, and also at each recurrence they called the study staff and provided all the necessary information about the FS recurrence or the occurrence of an afebrile seizure. Statistical analysis A univariate analysis was performed between the examined factors at the total episodes of FS and also to each recurrence separately in correlation to the occurrence or not of subsequent epilepsy. We investigated several factors on whether they can predict subsequent epilepsy, with the Pearson chi-square test (p-value < 0.05). We identified index “c”, which showed how powerful the connection was between the variables that we examined. Finally, we proceeded to a multivariate analysis (Cox regression-survival analysis), in order to identify the factors that contribute to the prognosis of epilepsy. The relative risk (RR) was calculated, which showed how many times a certain factor increase the risk for subsequent epilepsy. Statistical analysis was performed using SPSS 17.0 software (IBM Corp., Armonk, NY, U.S.A.).
Results A group of 560 children with a first episode of FS met all entry criteria. However, 59 children were excluded because no follow-up information could be obtained after the initial evaluation. This report is, therefore, based on the remaining 501 children. The age at onset of FS ranged between 3 months and 5 years old (median age at onset 23 months 12 months). Four hundred sixty-three (92.4%) of 501 children had normal perinatal history, 3 (0.6%) of 501 had twin pregnancy, 11 (2.2%) of 501 had prematurity (3 years 15 min and recurrence within the same febrile illness) are prognostic markers for the development of afebrile seizures (Sfaihi et al., 2012; Wo et al., 2013). Few studies have analyzed separately the prognostic value of each of the three features of complex FS. Annegers et al. (1987) reported that the risk of subsequent epilepsy in children with one of the three characteristics
of complex FS is about 6–8%, with two 17–22%, and with three up to 49%. Late age at onset of FS Our study showed that late age at onset of FS (>3 years old), as an isolated factor, has no influence at the occurrence of epilepsy, but only when it is taken into account with other prognostic markers, plays an important role in epileptogenesis. Specifically, late age at onset of FS increased the risk of subsequent epilepsy about four times. A retrospective study found that children who had their first FS at an age 3 years had epilepsy more often in the first 2 years after the FS episode (Vestergaard et al., 2007). Other authors found that children with a first FS at an age younger than 12 months old had a higher incidence of epilepsy (Nelson & Ellenberg, 1976; Annegers et al., 1987).The interpretation of this finding is that severe episodes of FS tend to occur at a younger age. The present study showed that focality, not only at the first FS but mostly at recurrences, is a reliable prognostic factor for subsequent epilepsy. Indeed, the prognostic power of focality was increased at each recurrence. Therefore, children with focal seizures at the fourth recurrence (i.e., more close timely to the occurrence of epilepsy) had an increased risk of epilepsy of up to 30 times. Other authors also supported that the most powerful prognostic factor between the three characteristics of complex FS for subsequent epilepsy was focality (Verity & Golding, 1991). Our results have shown that FS recurrence within the same febrile illness cannot predict subsequent epilepsy. In addition, the number of febrile status epilepticus in our study was restricted and children with so we could not reach to statistical significant results. Sapir et al. (2000), reported that none of their patients with prolonged FS developed later epilepsy. The same conclusion is reached also by other authors, as they noted that febrile status epilepticus does not increase the risk either of FS or afebrile seizures (Maytal & Shinnar, 1990). A recent study concluded that prolonged FS is the result of a previous insult of the hippocampus and not the cause of it (Scott et al., 2006). Different results are published by Verity et al. (1993), who reported that the incidence of subsequent epilepsy was higher in children with febrile status epilepticus. Saltik et al. (2003) found that 13.7% of their patients with epilepsy had a history of febrile status epilepticus. However, most of the studies differ from ours, since they concern patients hospitalized at reference centers and therefore involved a select group of severe cases, who possibly had a preexisting brain injury. It has been proven that prolonged seizures can harm the neurons. The question that arises is how often such an injury can occur and why it happens to certain children. It seems that the neuronal insult is connected with the cause of the seizures and not with the seizures per se (Verity, 1998). Most of the studies in the literature have examined various prognostic factors for subsequent epilepsy, either the Epilepsia, 54(12):2101–2107, 2013 doi: 10.1111/epi.12429
2106 E. Pavlidou and C. Panteliadis total of FS episodes (i.e., first FS and recurrences) or only the first episode of FS. We analyzed each recurrence, since we hypothesized that recurrences could change the prognostic profile for the child regarding the development of epilepsy. Our findings suggest that focality and short duration of fever (
