Febrile seizures are defined as seizures which occur in childhood that are accompanied by a temperature of 38℃ or higher without evidence of an intracranial infection or defined seizure cause. The International League Against Epilepsy defines a febrile seizure as "a seizure occurring in childhood after 1 month of age, associated with a febrile illness not caused by an infection of the central nervous system, without previous neonatal seizures or a previous unprovoked seizure, and not meeting criteria for other acute symptomatic seizures"1). Epilepsy is defined as the occurrence of at least 2 episodes of unprovoked seizures on 2 different days23). Febrile seizures are common and have a good prognosis, except for the risk of subsequent occurrence of epilepsy.

Association studies between febrile seizures and epilepsy have largely focused on the link between prolonged febrile seizures and the subsequent development of temporal lobe epilepsy, using epidemiological studies and investigations of the underlying mechanisms of epileptogenesis with animal models4). However, epilepsy may be considered to be febrile seizures when the first attack occurs in a state of systemic febrile illness. Also, a number of patients who experience febrile seizures may develop epilepsy. In this study, we analyzed the demographic, clinical, and electroencephalographic data of children with febrile seizures to determine any prognostic factors that can predispose children with febrile seizures to epilepsy5678).

The present study sought to determine the prognostic factors in children with febrile seizures for risk of subsequent epilepsy. Our results demonstrate that the frequency of febrile seizures during the first 2 years after initial seizure onset was associated with subsequent occurrence of epilepsy. Other factors predictive of a subsequent occurrence of epilepsy were developmental delay, history of preterm birth, several seizure attacks during one febrile illness, and EEG epileptiform discharges.

Febrile seizures are the most common form of childhood seizure. Over the past 25 years, as more information on febrile seizures has accumulated, the prognosis for febrile seizures is generally found to be good. However, the first seizure in patients with epilepsy can be accompanied by fever. The overall risk of epilepsy following febrile seizures is 2%–5%, which is double the risk for the general child population579). Approximately 15%–20% of children who develop epilepsy have previously had febrile seizures101112).

Our study revealed that the incidence of subsequent epilepsy after febrile seizures was 10% in individuals that had febrile seizures. This is similar to the results in a prospective cohort study by Neligan et al.13), which demonstrated that the risk of developing epilepsy following febrile seizures was 2%–10%.

Previous studies have shown that the risk factors for unprovoked seizures after febrile seizures include the onset of febrile seizures at an early age, complex febrile seizures, neurodevelopmental abnormalities, abnormal EEG, and a family history of epilepsy56781415). The risk factor for epilepsy in patients with no previous risk factors is only 0.9%. With 2 or more risk factors, that incidence increases to 2%516). If febrile seizures are prolonged, approximately 9.4% of children may develop epilepsy717). However, all children with a history of febrile seizures do not have the same risk for developing subsequent epilepsy.

Generally, childhood febrile seizures are benign and self-limiting. In most cases, it is recommended that health care providers should have reduced anxiety through decreasing uncertainty18). However, complex febrile seizures, particularly prolonged febrile seizures or febrile status epilepticus (defined as seizures lasting more than 30 minutes), have been associated with subsequent limbic epilepsy in both prospective and retrospective clinical studies19). In particular, prolonged or focal febrile seizures have been associated with a significantly increased risk for temporal lobe epilepsy2021).

In this study, the prognostic factors associated with later epilepsy included total relapse number of seizures, developmental delay, preterm birth, multiple seizures per febrile seizure attack, and abnormal EEG findings. However, gender, seizure duration, peak temperature, focal seizures, family history of febrile seizures, and family history of epilepsy were not associated with subsequent epilepsy.

Different results were reported by Kanemura et al.22), such that fever duration increased the risk of unprovoked seizures. However, most studies differ from ours in that fever duration and peak temperature had no relationship with subsequent epilepsy14). Most data demonstrate that persistent febrile seizures were related to hippocampal damage, which developed into temporal lobe epilepsy2324). However, in this study, fever and seizure duration were not related to a later presentation of recurrent unprovoked seizures. Brief, recurrent and frequent febrile seizures during the first 2 years after seizure onset were related to later epilepsy in this study, which differs from previous studies. Most of later diagnoses of epilepsy were not temporal lobe epilepsy. Moreover, patients diagnosed with symptomatic frontal epilepsy with cortical dysplasia during adolescence only presented with recurrent, febrile, and generalized tonic-clonic seizures, without definitive focal symptoms during childhood. Therefore, we hypothesize that fever in those patients may be a provocative factor for a first presentation of seizure in patients with epileptic potential.

Focal semiology of febrile seizures increases the risk for subsequent epilepsy1525). Ictal motor manifestations, such as version, clonic and tonic activity, unilateral epileptic spasms, dystonic posturing and unilateral automatisms, automatisms with preserved responsiveness, ictal spitting and vomiting, unilateral eye blinking, ictal nystagmus, and akinesia, have lateralizing value. Ictal language manifestations and postictal features, such as Todd's paralysis, postictal aphasia, postictal nose wiping, postictal memory dysfunction, as well as peri-ictal water drinking, peri-ictal headache, and ipsilateral tongue biting, are semiological lateralizing signs26). In this study, unilateral clonic seizures, asymmetric tonic seizures, or atonic seizures were not related to later epilepsy, while patients with head version were later diagnosed with epilepsy.

For seizure semiology, this study was limited because it relied on parent recall. Parents with anxiety could not recall the exact description of focal signs and seizure shape27). Therefore, there should be allowances made for any discrepancies regarding their observations of video EEG monitoring for seizure semiology. This may be one of the reasons why the number of patients who showed obvious focal signs was relatively small, and why this was not a significant association factor for later epilepsy.

The role of EEG in the work-up of febrile seizures is controversial. However, recent studies show the localizations of EEG paroxysmal discharges, such as spikes, sharp waves, or spike-wave complexes, are predictors for subsequent epilepsy28). In particular, frontal paroxysmal EEG abnormalities are related to subsequent diagnoses of epilepsy. In this study, abnormal EEG findings were seen in 39 patients (24.7%) in the febrile seizures-only group and 13 patients (52.0%) in the subsequent epilepsy group. However, not all the patients who experienced febrile seizures had EEG. Abnormal EEG findings were significant in our data set. Therefore, serial EEG in patients with localized paroxysmal discharges during the first EEG should be performed, even though it may not contribute to treatment.

In conclusion, prognostic factors, such as total relapse number of seizures, developmental delay, preterm birth, multiple seizures per febrile seizure, and abnormal EEG findings, can assist with the early recognition of increased risk for developing epilepsy after febrile seizures. Prospective studies are recommended, with particular attention to seizure semiology, peak fever temperature, fever onset, and family history of epilepsy.