24.1 Introduction

Febrile seizures are the most common seizure disorder in childhood, affecting 2–5% of children. They are a major cause of emergency facility visits and a source of family distress and anxiety. While they recur in approximately one-third of children during early childhood, they are an otherwise benign phenomenon and are associated with a risk of future epilepsy that is slightly higher than the general population.

Febrile seizure is a clinical diagnosis, defined by the following features:

  • A convulsion associated with an elevated temperature greater than 38 °C.

  • A child older than 6 months and younger than 60 months of age.

  • Absence of central nervous system infection or inflammation.

  • Absence of acute systemic metabolic abnormality that may produce convulsions.

  • No history of previous afebrile seizures.

The distinction between simple and complex febrile seizures has prognostic implications, with most studies indicating that patients with complex features have a higher risk of recurrent febrile seizures and a slightly higher risk of future non-febrile seizures.

24.2 Definitions

Febrile seizures are further divided into two categories, simple or complex febrile seizures, based on clinical features [1,2,3].

Simple febrile seizures : These are the most common type. They are characterized by seizures that are generalized, have duration of less than 15 min, and do not recur in a 24-h period, in a child aged 6–60 months, with no neurologic deficits (i.e., with no pre- or postnatal brain damage, with normal psychomotor development, and with no previous afebrile seizure).

A child with a known neurological condition may be more likely to experience a seizure with fever, which would not be classified as a simple febrile seizure.

Complex febrile seizures : These are defined as a focal, or generalized, and prolonged seizure, with a duration greater than 15 min, recurring more than once in 24 h, and/or associated with post-ictal palsy (Todd’s palsy), or with previous neurologic deficits.

Should the complex febrile seizure be characterized by a duration of more than 30 min, or by shorter serial seizures, without consciousness being regained during the interictal state, the disorder is named febrile status epilepticus (FSE) .

24.3 Epidemiology

Simple febrile seizures have an age range classically described as 6 months to 6 years. The peak incidence is usually in the second year of life. Febrile seizures are prevalent in up to 5% of children, with the overall incidence estimated to be 460/100,000 in the age group of 0–4 years. Most are simple febrile seizures, and up to 30% might have some complex features [4].

Risk factors: Aside from age, the most identified risk factors include high fever, viral infection, recent immunization, and a family history of febrile seizures.

24.3.1 High Fever [5]

The majority have febrile seizures on the first day of illness, and in some cases, it is the first manifestation that the child is ill. The degree of fever associated with febrile seizures is variable and is dependent on the child’s threshold convulsive temperature. While measured fever is most often at or above 39 °C, approximately 25% of events occur when temperature is between 38 and 39 °C. Seizures are often seen as the temperature is increasing rapidly, but the degree of fever, not the rate of temperature rise, is the precipitating stimulus.

24.3.2 Vaccination-Related Febrile Seizures

The febrile seizures after vaccination are no different from febrile seizures of other causes, and the risk of hospitalization and illness course are also not differentiated. Such precipitated events are quite rare and often occur on the first 3 days after administration of live-attenuated vaccines [6]. There is no current evidence of any increased risk of either subsequent seizures or neurodevelopmental delay after the initial seizure. It is crucial to alert the families that none of the standard vaccinations are currently contraindicated in children with febrile seizures. Currently there is not enough evidence to suggest usage of rescue medication as a febrile seizure preventative measure after vaccination for at-risk children [7].

24.3.3 Family History

There is a positive family history in first-degree relatives in up to 40% of patients.

24.4 Risk of Recurrence of Febrile Seizures

The risk of recurrence is related to various factors [8,9,10]:

  • Younger age group: Overall recurrence rate is approximately 30–35%; this is higher (50–56%) in children younger than 1 year at the time of first febrile seizure.

  • Prolonged seizure duration.

  • Positive personal and family history of seizures.

  • Brief duration (<1 h) between onset of fever and the initial seizure.

  • Low temperature at the onset of the febrile seizure.

Recurrence frequency is 10% in patients with no risk factors, 25–50% in the presence of 1–2 risk factors, and 50–100% in the presence of 3 or more risk factors.

The longer the seizure continues, the less likely it is to spontaneously stop. The FEBSTAT study group also identified that FSE is associated with an increased risk of subsequent FSE. Any baseline MRI abnormality also increases recurrence risk three- to fourfold [11]. FSE has been associated with hippocampal injury and possibly subsequent mesial temporal sclerosis and temporal lobe epilepsy. HHV-6B and HHV-7 account for one-third of FSE; HHV-6B is more commonly associated [12]. Focal electroencephalogram (EEG) slowing/attenuation is present in EEGs obtained within 72 h of FSE in a substantial proportion of children and is highly associated with MRI evidence of acute hippocampal injury [13, 14]. The EEG is however not useful in determining the risk of recurrent FS but can be performed in outpatient setting, to identify children at increased risk for future epilepsy, in combination with other risk factors [15, 16]. Risk factors for epilepsy among children with FS include abnormal neurological development (e.g., cerebral palsy), first seizure being CFS (focal, multiple within 24 h during same illness, or longer than 15 min), or family history of epilepsy [17,18,19]. The risk of subsequent epilepsy in CFS is closer to 5–10%, compared to a normal child with SFS whose risk is approximately 1–2%, only slightly above incidence in the general population (0.5%).

24.5 Differential Diagnosis

  1. 1.

    This should include various non-epileptic paroxysmal disorders [20]:

    • Syncope during febrile state.

    • Abnormal motor manifestations: Shaking chills or rigors are involuntary movements characterized by fine oscillatory movements about a joint. These usually involve both sides of the body simultaneously and are not associated with loss of consciousness, in contrast to generalized seizures. Any repetitive movements of concern should be evaluated by touch, since seizures should not be suppressible.

  2. 2.

    Central nervous system infection: Provoked seizures from meningitis/encephalitis are the main concerns in a child presenting with fever and seizures. Diagnosis is made by clinical features, although 40%, particularly younger infants, who have seizures as an initial manifestation of meningitis do not have meningeal signs (altered consciousness, nuchal rigidity, petechial rash) [21].

  3. 3.

    Genetic epilepsies with febrile seizures: In some patients, the propensity for febrile seizures is an early manifestation of epilepsy with febrile seizures plus (EFS+), a genetic epilepsy for which a variety of causative mutations have been identified. The phenotype consists of patients who had seizures with fever in early childhood that, unlike typical febrile seizures, continue beyond 6 years of age or are associated with afebrile tonic-clonic seizures as well as other seizure types.

    Dravet syndrome is a rare genetic epilepsy that can resemble complex febrile seizures in the first year. It typically presents in the first year of life (around 6 months of age) in a normal child with prolonged, febrile and afebrile, and focal (usually hemiclonic) or generalized convulsive seizures. Other seizure types including myoclonic and atypical absence seizures appear between the age of 2 and 4 years. Seizures are usually intractable and from the second year of life children demonstrate cognitive and behavioral impairments. The clinical diagnosis is supported by the presence of abnormalities in the sodium channel gene SCN1A (found in 75% of cases). Antecedent, birth, and neonatal history is normal. The first seizure is associated with a fever in about 60% of cases, and sensitivity of seizures to fever may persist throughout life. Development is typically normal in the first year of life, with plateauing or regression in later years [22].

    Febrile infection-related epilepsy syndrome (FIRES) is a severe post-infectious neurological disorder that presents with intractable status epilepticus in a previously normal child (or less commonly adult) after a febrile illness. If the patient survives, they have intellectual and motor impairment and ongoing intractable seizures.

    The pathogenesis of this condition is unknown. Despite extensive investigation for an immune mechanism, anti-neuronal antibody testing on CSF and blood has shown inconsistent findings or been negative. There is no consistent response to immunotherapies such as high-dose steroids, immunoglobulin, or plasma exchange. Metabolic testing has also been unrevealing. This syndrome presents with onset of seizures between 2 and 17 years of age (median 8 years). A febrile upper respiratory or gastrointestinal illness precedes the onset of seizures by 1–14 days (median 4 days). Seizures rapidly progress to refractory status epilepticus. The condition has a high mortality; surviving patients require prolonged ventilator support and have cognitive and neurological impairment and ongoing seizures. There are limited responses to specific therapies such as the early use of the ketogenic diet.

24.6 Diagnostic Evaluation

The initial evaluation of children with seizures in the setting of fever must distinguish febrile seizures from alternative and more serious etiologies, e.g., history and physical examination, with neuroimaging and lumbar puncture in selected circumstances. Children with focal or prolonged febrile seizures require more extensive evaluation than those with simple febrile seizures, particularly at the time of the first seizure.

24.6.1 History

  • The key elements of the seizure history in a child presenting with a febrile seizure include seizure characteristics, duration of seizures, and presence of focal features (e.g., shaking limited to one limb or one side of the body). Children with simple febrile seizures are neurologically and developmentally healthy before and after the seizure. The seizures are described as either generalized clonic or generalized tonic-clonic. Any signs of focal seizures would rule out a simple febrile seizure.

  • Careful history must also identify any underlying medical or neurological condition that increases the child’s risk of serious infection or underlying structural abnormality.

  • History of personal or family history of seizures and history of neurological problems or developmental delay.

24.6.2 Physical Examination

A general physical and neurological examination should include attention to vital signs, level of consciousness, presence or absence of meningism, a tense/bulging fontanelle, and focal differences in muscle tone, strength, or spontaneous movements. The presence of any of these signs should prompt consideration of an alternative etiology, e.g., meningitis or an underlying structural abnormality.

Children with febrile seizures are typically well appearing; post-ictal drowsiness usually resolves within 5–10 min, depending upon the duration and type of seizures. Encephalopathy beyond this time period should prompt increased suspicion for possible central nervous system infection or severe systemic infection.

24.7 Diagnostic Recommendations

The American Academy of Pediatrics (AAP) and the Task Force of Italian League Against Epilepsy Guidelines Commission have developed recommendations depending on the child’s age and the type of seizures [20].

24.8 Simple Febrile Seizures

  • Routine laboratory tests are not recommended. These are performed exclusively to identify the cause of the fever.

  • Routine electroencephalogram (EEG) is not recommended because of limited diagnostic value in a child with a first simple febrile seizure.

  • Routine neuroimaging is not recommended.

  • Lumbar puncture is recommended in the following:

    1. 1.

      In the presence of meningeal signs.

    2. 2.

      In patients under antibiotic treatment during the days before the seizure, owing to the possible masking of meningitis signs and symptoms.

    3. 3.

      In patients younger than 18 months; careful observation of patients for at least 24 h is necessary.

    4. 4.

      In children above 18 months if clinical signs of meningitis present.

24.9 Complex Febrile Seizures

  • Search for fever etiology.

  • Perform blood chemical tests in relation to the clinical condition, i.e., complete blood count, electrolytes, blood sugar (glucose), and blood culture.

  • EEG is recommended as early as possible, within 72 h, to exclude subclinical status or frank interictal activity suggestive of underlying epilepsy.

  • Neuroimaging is highly recommended (CT scan or MRI scan) to exclude a possible underlying brain lesion.

  • Lumbar puncture is considered for all patients with a suspected CNS infection. LP is however contraindicated if the following are present:

  • Signs of raised intracranial pressure

  • Signs of impending herniation

  • Focal neurological signs

  • Critically ill patients at risk for cardio-respiratory arrest

  • Area of sepsis over potential puncture site

  • Bleeding diathesis or low platelet count

24.10 Management of Febrile Seizures

24.10.1 Emergency Rescue Treatment

Most febrile seizures end spontaneously by the time the child is first evaluated and the child is rapidly returned to baseline. Most simple febrile seizures cease within 2–3 min and do not require treatment. Occasionally they may last more than 5 min (up to 15 min); pharmacologic treatment, as with afebrile seizures, is recommended. Intravenous benzodiazepines, diazepam 0.1–0.2 mg/kg or lorazepam 0.05–0.1 mg/kg, are effective in aborting seizures in many cases. If intravenous is unavailable or cannot be achieved, per rectal diazepam, buccal midazolam, and intranasal midazolam are effective alternatives [20, 23,24,25]. The child’s respiratory and circulatory status should be monitored carefully and an advanced airway intervention undertaken if ventilation status becomes inadequate. This acute intervention at the time of a febrile seizure does not alter the risk for subsequent epilepsy [26] but is important to reduce the patient’s discomfort.

24.10.2 Febrile Status Epilepticus

Prolonged/repetitive seizures despite initial benzodiazepine administration should be treated promptly with additional antiepileptic drugs (phenytoin or phenobarbitone). If the child has persistently open and deviated eyes, the child may be seizing even if convulsive motor activity has stopped. Management of status epilepticus is discussed under the pediatric status epilepticus chapter. Efforts should be made to lower fever with antipyretic medication. Paracetamol is more widely used than ibuprofen, whereas aspirin is avoided because it has been associated with the development of Reye syndrome. The use of antipyretic agents does not alter the recurrence rate of febrile seizures [26].

24.10.3 Treatment of a Prolonged Seizure in a Home Setting

Advise the family to remain calm and not to panic and to loosen the child’s clothing, especially around the neck. If the child is unconscious, they should place the child in the lateral decubitus position (on their side), to avoid inhalation of saliva or vomitus, and they should not force the mouth open. They should observe the type and duration of the seizure.

Children with a history of prolonged FS lasting more than 10 min, patients who belong to anxious parents, and patients with logistic difficulties accessing the health care are ideal candidates for rescue FS medication [27]. Administration of rectal diazepam 0.5 mg/kg should be administered in case of prolonged seizure lasting over 2–3 min. Diazepam with rectal administration takes approximately 3 min to reach an efficacious concentration in the brain. Buccal midazolam 0.5 mg/kg can also be used [28,29,30]. Typically, diazepam administration should be limited to two doses, although specific clinical conditions may require a third dose after at least 24 h from the first administration. It should be noted that febrile seizures occur, in 98% of cases, within the first 24 h from the onset of fever; it is, therefore, not justified to extend therapy administration after this period. Parents should be trained about the administration of these rescue medication at home and clear advice given of what to look for and when to come to hospital. Medical intervention in hospital is necessary if seizures are of a duration >10 min or not remitting after treatment and are recurrent and focal or there is the presence of prolonged loss of consciousness and/or post-ictal palsy.

24.10.4 Criteria for Hospital Admission [20]

  1. 1.

    Simple Febrile Seizures

    1. (a)

      First Episode

      Age >18 months: If the patient is clinically stable, with no signs or symptoms requiring diagnostic investigations, admission is unnecessary and parents should be adequately educated.

      Age <18 months: Admission should be envisaged, and observation is recommended for the possible performance of lumbar puncture.

    2. (b)

      Already Diagnosed Simple Febrile Seizures

      Admission is unnecessary; parents’ education must be verified. It should be underscored, however, that a history of simple febrile seizure (SFS) does not exclude that the ongoing seizure may be the symptom of another disease, such as an infectious disease of the central nervous system (CNS).

      It is recommended to give parents information, including instructions on diazepam administration in the event of prolonged seizures in patients with repeated episodes of SFS. It is also recommended to monitor the natural evolution of the seizures.

  2. 2.

    Complex Febrile Seizures

    Admission is recommended for observation because of the wide variability of conditions underlying this event. A febrile seizure stopped with pharmacologic therapy within the first 15 min should be considered, in terms of admission indications, as a complex febrile seizure. As a complex febrile seizure indicates entities with variable etiology, semiology, and prognosis, it may result from an acute disorder of the CNS, be the onset of specific epileptic syndromes (e.g., Dravet syndrome), or simply be a prolonged febrile seizure, with the same prognosis as simple febrile seizure. Therefore, treatment depends upon the etiologic and nosographic picture.

    In patients with either frequent seizures in a short period of time (three or more in 6 months or four or more in 1 year) or history of prolonged seizures >15 min or requiring pharmacologic treatment to be stopped, then intermittent treatment is considered (i.e., rescue medication) as an emergency measure.

24.11 Prevention of Febrile Seizures

The best treatment for children with a first febrile seizure is education and reassurance for the parents. This will allow parents to accept not to treat. There is no evidence for therapies to prevent subsequent epilepsy. There are potential side effects of antiepileptic drug therapy, and there is a benign prognosis of simple febrile seizures, which does not cause brain damage and spontaneously remits with age. There is universal agreement that daily prophylaxis with antiepileptic agents should not be used routinely in SFS.