Febrile Seizure

Etiology

Febrile seizures are generalized seizures, typically in children between the ages of 6 months and 5 years, that occur with a fever greater than 100.4 °F (38 °C) not associated with a central nervous system (CNS) infection, a known seizure-provoking etiology (eg, electrolyte imbalance, hypoglycemia, or substance abuse), or history of an afebrile seizure.[1] No defined fever threshold is required to precipitate febrile seizures, as each patient's convulsive temperature threshold varies.[2][3] The primary febrile seizure risk factors appear to include existing neurologic impairment, the presence of a viral infection, a family history of seizure, developmental delay, decreased serum zinc and iron levels, and maternal smoking and stress.[1]

An estimated 10% to 33% of patients have a first-degree relative with a positive seizure history, along with a concordance rate of approximately 35% to 69% in monozygotic twins and 14% to 20% in dizygotic twins, which suggests that the cause of febrile seizures may have a genetic component.[5][6] An autosomal dominant mode of inheritance with reduced penetrance and a polygenic or multifactorial mode of inheritance may be present in addition to specific genes that increase the risk of febrile seizures and are found on the following loci of chromosomes: 1q31, 2q23*34, 3p24.2*23, 3q26.2*26.33, 5q14*15, 5q34, 6q22*24, 8q13*21, 18p11*2, 19p13*3, 19q, and 21q22.[5]

Another factor determining the risk of febrile seizures may be the highest temperature reached during a fever rather than the speed at which the temperature rises.[7][8][9] A contributing factor that can also affect fever's impact is the seizure threshold, which varies among individuals and changes with age and development. Infants have a higher risk of febrile seizures, but premature infants are at an even higher risk, especially those receiving postnatal corticosteroids.[10] Furthermore, infants generally have a lower seizure threshold, which may be modified by certain medications and water and electrolyte imbalances (eg, hyponatremia). Iron, zinc, vitamin B12, folic acid, selenium, calcium, and magnesium deficiencies increase the risk of febrile seizures.[5]

No specific fever etiology is more likely to cause febrile seizures; however, 80% of viral infections rather than bacterial infections are commonly associated with febrile seizures.[11] Roseolovirus is the most common virus associated with febrile seizures in the US and European countries and is observed in up to one-third of patients younger than 2 years.[12] Other studies have found that febrile seizures secondary to Roseolovirus are associated with a higher incidence of complex features, recurrence, and febrile status epilepticus.[13][14] In Asian countries, however, influenza A has been frequently associated with febrile seizures. Other commonly associated viral infections include human herpesvirus 7 (HHV-7), human coronavirus HKU1, adenovirus, RSV, cytomegalovirus, shigella, and herpes simplex virus (HSV). 

Vaccines have also been shown to temporarily increase the risk of febrile seizures a few days postinoculation. These include the DTaP-IPV-Hib, MMRV, conjugated pneumococcal vaccine, and some formulations of inactivated influenza vaccines. The risk, although low, is also slightly higher in those getting more than one vaccination at a time. One study found the maximum estimated absolute excess risk due to concomitant administration of IIV3, PCV, and DTaP-containing vaccines was 30 febrile seizures per 100,000 persons vaccinated compared with administration on separate days.[15]

Epidemiology

Febrile seizures are the most common type of seizure in children between the ages of 6 months to 5 years. Febrile seizures are the most common type of seizures in childhood, with a slight male predominance of 1.6:1. Febrile seizures have an incidence of 2% to 5% of US and European children, which peaks between 12 to 18 months of age. A seasonal and diurnal association has also been observed in Japan, Finland, and the US, with more episodes occurring in the afternoon and winter months.[16] Some children have a single febrile seizure event, while 30% of children have multiple seizures during early childhood.

Pathophysiology

The exact pathophysiology of febrile seizures is not understood fully, but there is a recognized complex genetic predisposition, immaturity and vulnerability of the central nervous system, and various environmental factors. As a result of these various risk factors, the immature brain, with fever-enhanced neuronal excitation, is more susceptible to seizures and is one explanation as to why they occur more commonly in those younger than 3.[17]

History and Physical

Clinical History

A comprehensive medical history and detailed description of the seizure event are essential for the evaluation of a possible febrile seizure. Because febrile seizures most commonly occur in children, a parent or caregiver is critical to help provide the patient's history, including vaccination history, immunization status, family history of seizure activity, any recent illness, development, exposure to toxins, and personal medical history. Historical information regarding the interval between fever onset and seizure activity, seizure appearance, length, and postictal symptoms should also be obtained, as this can help differentiate simple febrile seizures from complex types.[5][4]

Simple febrile seizures usually have a single episode of generalized tonic-clonic movements, often involving facial and respiratory muscles, lasting less than 15 minutes with a short period of postictal drowsiness. Conversely, complex febrile seizures are characterized by focal seizures, usually limited to one side of the body, lasting 15 minutes or more, that can recur within 24 hours. Complex febrile seizures are frequently followed by postictal weakness or paralysis on one side of the body (ie, Todd paralysis). Other associated symptoms for both febrile seizure types include loss of consciousness, foaming at the mouth, shortness of breath, and cyanosis. Additionally, clinicians should inquire about possible central nervous system (CNS) infection and underlying structural abnormalities to determine whether an event of concern constitutes a febrile seizure or a more severe illness presenting with a seizure.[5][4]

Clinical Examination

Following seizure activity, patients must undergo a general physical and a neurologic exam to ensure that the patient has had a neurologic return to their baseline state. However, differential diagnoses should be considered if a patient continues to have acute neurologic impairment or symptoms (eg, headaches, cognitive dysfunction, or weakness) on an exam. During the physical exam, serial vital signs should be obtained, and findings that may suggest the underlying etiology of the fever should be noted (eg, erythematous bulging eardrums, a red pharynx, enlarged and inflamed tonsils, nuchal rigidity, bulging or tense fontanels, and Brudzinski sign). Clinicians should also perform a complete neurological examination, including a fundus examination, to assess increased intracranial pressure. Dermatologic signs that may indicate an underlying etiology should also be evaluated, such as the unilateral port-wine stain associated with Sturge–Weber syndrome, hypopigmented macules indicative of tuberous sclerosis, or café au lait spots and Lisch nodules suggestive of neurofibromatosis.[5][4]

Evaluation

Patients who have a presentation and clinical features consistent with simple febrile seizures do not need further diagnostic studies due to the benign nature of this type of febrile seizure. However, if a patient's history is consistent with a complex febrile seizure, a thorough evaluation is recommended, which usually involves ruling out any structural or infectious causes and obtaining an electroencephalogram (EEG). Laboratory studies (eg, complete blood count, complete metabolic profile, and urinalysis) should also be performed if a patient has signs of dehydration, poor fluid intake, vomiting, or diarrhea.[4] Some cases of complex febrile seizures may require hospital admission for observation and further studies.[3][18]

A lumbar puncture is not necessary for a patient with simple febrile seizures and a rapid return to baseline; however, the study is recommended when there are signs or concerns of a CNS infection. A lumbar puncture should also be considered in infants presenting after a febrile seizure who are younger than12 months, not adequately immunized against Streptococcus pneumoniae or Haemophilus influenza type B, had seizure 2 days after fever onset, or taking antibiotics which may mask meningitis or other CNS infection.[5]

Magnetic resonance imaging or computer tomography studies of the head for febrile seizures are not typically considered unless any of the following are present:[5]

• Increased intracranial pressure
• Focal neurologic abnormality
• Suspected structural defect in the brain
• Enlarged head
• Severe head injury

Treatment / Management

No specific treatment for simple or complex febrile seizures is indicated other than supportive care and evaluation for possible underlying conditions causing the fever. Antipyretics have not been shown to prevent a recurrence of febrile seizures. In those who have recurrent febrile seizures, prevention is challenging. A few studies have examined the treatment with benzodiazepines as a bridging measure for a few days during subsequent febrile events; however, the adverse effects outweighed the potential benefits. Therefore, benzodiazepines are not a recommended preventative measure.[19][20][21] 

Although most febrile seizures are a single occurrence and spontaneously resolve, febrile status epilepticus does occasionally occur in <10% of children during the first febrile seizure. In patients with febrile status epilepticus or seizures lasting longer than 5 minutes, intravenous benzodiazepines (eg, lorazepam), rectal diazepam, or intranasal midazolam can be used.[21][22] Furthermore, nonpharmacological methods (eg, removing clothing, directly fanning the child, and tepid sponging) to reduce a fever have not prevented fever recurrence.[23](A1)

Differential Diagnosis

The differential diagnosis of febrile seizures includes:

• Breath-holding spells
• CNS infections (eg, aseptic meningitis, viral or bacterial meningitis, and encephalitis)
• Drug-induced
• Febrile delirium
• Febrile myoclonus
• Febrile infection-related epilepsy syndrome (FIRES)
• Generalized/genetic epilepsy with febrile seizures plus (GEFS+)
• Metabolic disturbances such as hyponatremia
• Shaking chills or rigors
• Simple febrile seizure
• Tonic-clonic seizures

Prognosis

Febrile seizures are typically harmless and do not cause long-term neurological or cognitive problems. The majority of children who experience febrile seizures have normal developmental outcomes. Studies suggest that around 30% of children with a history of febrile seizures are at an increased risk of having recurrent episodes. Children younger than 12 months at the time of their first febrile seizure have a 50% chance of experiencing a second seizure within the first year. However, this risk decreased to 30% in the following year. Factors such as young age during the initial seizure, a family history of febrile seizures, low fever intensity during the seizure, and a short interval between fever onset and the seizure may indicate a higher likelihood of recurrent febrile seizures. On the other hand, features associated with complex febrile seizures do not necessarily increase the risk of recurrence.

Approximately 1% to 2% of children with simple febrile seizures, which is only slightly higher than the general population of .5% to .9%, may develop epilepsy later on. However, children with a history of complex febrile seizure, febrile seizure at an earlier age, prolonged febrile seizure, abnormal neurodevelopment, abnormal EEG, and a family history of epilepsy have an estimated 2% to 10% risk of developing epilepsy, depending now how many risk factors are present.[24] Notably, a single febrile seizure episode does not appear to be linked to learning disabilities, lower intelligence, behavioral problems, or executive functioning. However, in those with recurrent febrile seizures, an increased risk of delayed vocabulary development may be present.[5]

Complications

Although most febrile seizures are self-limited and have an excellent prognosis, rare complications may occur, including the following:

• Unexpected death
• Subsequent epilepsy
• Encephalopathy 
• Autism spectrum disorder
• Intellectual disability
• Attention-deficit/hyperactivity disorder
• Tourette syndrome
• Allergic rhinitis
• Asthma