Febrile Seizures Case File

Febrile Seizures Case File

Eugene C. Toy, MD, Ericka Simpson, MD, Pedro Mancias, MD, Erin E. Furr-Stimming, MD

CASE 45

A 22-month-old girl is brought to the emergency room (ER) after a 5-minute seizure at home witnessed by her parents. The child was well until 1 day ago when she developed rhinorrhea, cough, decreased appetite, and increased fussiness. This morning, the patient’s mother took the child’s tympanic membrane temperature and found it to be 39.3°C (102.7°F). Fifteen minutes later, the patient’s father heard a “gurgling” noise coming from the child’s room and found the child unresponsive, foaming at the mouth, with “jerking movements” of all four extremities. Both parents estimate that the motor activity persisted for approximately 5 minutes although both report that it “seemed much longer.” On examination, the patient is sleepy but can be aroused. Her examination is significant only for crusting of the nares and an erythematous oropharynx without exudate. There is no nuchal rigidity or focal findings on her neurologic examination. Her rectal temperature is now 39.5°C (103.2°F), her pulse is 110 beats/min, with unlabored breathing at 16 breaths/min and an oxygen saturation of 99%. The child is the product of a full-term uncomplicated pregnancy and went home on day 2 of life. She has had no other significant medical problems. Her parents state she is developmentally on track with an eight-word vocabulary, a normal toddler gait, appropriate fine motor skills, and no hint of developmental regression. There is no history of seizures in the family nor neurologic events except for a stroke in the patient’s maternal grandmother at age 78.

▶ What is the most likely diagnosis?

▶ What is the next diagnostic step?

▶ What is the next step in therapy?

ANSWERS TO CASE 45:

Febrile Seizures                                                      

Summary: A 22-month-old previously healthy, developmentally normal girl with a 1-day history of upper respiratory symptoms developed a fever this morning followed by a 5-minute generalized convulsion. Now in the ER, she is febrile and somewhat obtunded but without other significant physical findings.

• Most likely diagnosis: Simple febrile seizure
• Next diagnostic step: Evaluation for fever source (such as a nasal wash for viral studies and a complete blood count [CBC])
• Next step in therapy: Symptomatic treatment of fever (antipyretics)

ANALYSIS

Objectives

1. Understand the difference between provoked and unprovoked seizures as well as between a seizure and epilepsy.
2. Know the criteria for a simple febrile seizure versus a complex febrile seizure.
3. Be aware of the relationship between febrile seizures and the development of epilepsy.
4. Know when a seizure in the context of a fever necessitates further workup or treatment and when reassurance is all that is needed.

Considerations

This 22-month-old girl developed a generalized convulsion in association with a fever and is now postictally obtunded without any focal findings on neurologic examination. Since the seizure is now over, attention should first be directed to find a source for the child’s fever. Given the patient’s nasal discharge and lack of other symptoms, it is most likely caused by a viral upper respiratory infection. If the patient was tachypneic, consideration should be given to pneumonia. There is no evidence to suggest a central nervous system (CNS) infection, by history or on examination. Clearly, seizures can occur in association with meningoencephalitis but are rarely the sole manifestation of such a serious infection. Of course, if any clinical suspicion for CNS infection exists, a lumbar puncture (LP) must be performed to obtain cerebrospinal fluid (CSF) for analysis. In particular, infants younger than 12 months presenting with fever and a seizure can have only minimal additional signs of meningitis, and an LP should be performed. After 18 months, however, an LP can safely be reserved for patients with nuchal rigidity or other suggestive findings on history and examination.

APPROACH TO:

Seizures With Fever                                                     

DEFINITIONS

FEBRILE SEIZURES: Generalized seizure associated with a fever usually exceeding 38.5°C (101°F), typically occurring in children between age 6 months and 5 years.

SIMPLE FEBRILE SEIZURE: A single generalized clonic or tonic-clonic seizure lasting less than 15 minutes, in a child between ages 6 months and 5 years, in an otherwise neurologically healthy child, and not caused by meningitis, encephalitis, or other brain process.

COMPLEX FEBRILE SEIZURE: Age and fever the same as in febrile seizure definition, but the seizure is either prolonged (lasting >15 minutes) or there are multiple seizures in close succession.

SYMPTOMATIC FEBRILE SEIZURE: Meeting the age and fever parameters of a febrile seizure, but having a preexisting neurologic abnormality or acute illness.

CLINICAL APPROACH

Febrile seizures are common, most are simple, and they usually have a benign course; these are, however, a diagnosis of exclusion. In order to be considered a simple febrile seizure, a convulsive event must meet certain criteria:

1. Patient’s age between 3 months and 6 years
2. A generalized seizure without focal elements
3. A seizure lasting less than 15 minutes
4. Associated with a fever (38.5°C [101°F]) that is not caused by a CNS infection
5. Occurs only once in a 24-hour period

If the seizure is focal in nature, lasts longer than 15 minutes, or recurs within 24 hours, then it is considered to be a complex febrile seizure. Febrile seizures, either simple or complex, are a type of acute symptomatic or provoked seizure, just like acute traumatic seizures or alcohol withdrawal convulsions. In fact, febrile seizures are the most common type of provoked seizure—occurring in up to 5% of all children in the United States. It is important to understand the difference between epilepsy and an acute symptomatic (provoked) seizure. The former indicates that a patient has had two or more unprovoked seizures separated by at least 24 hours. The latter refers to convulsions that occur immediately in response to a precipitating event (such as fever, ischemia, anoxia, or trauma).

Febrile seizures most commonly occur within the first 24 hours of an illness with fever, and it is not at all unusual for them to be the first manifestation of illness. The underlying illness is more commonly viral than bacterial and may be due to a large number of different causative agents. However, certain viral agents—commonly human herpesvirus 6 (HHV-6) (35%), adenovirus, influenza, parainfluenza virus (14%), respiratory syncytial virus (11%), herpes simplex virus (9%), cytomegalovirus (3%), and HHV-7 (2%)—are associated with febrile convulsions for unknown reasons.

There are also familial genetic syndromes that can include febrile seizures as part of the phenotype—particularly the generalized epilepsy with febrile seizures plus (GEFS+) syndromes. In this heterogeneous disorder, patients in a given family can have typical febrile seizures or febrile seizures persisting beyond age 5, as well as various forms of generalized epilepsy typically beginning in childhood. Significant phenotypic variability is the rule in GEFS+. Mutations in the gene coding for voltage-gated sodium channel subunits (alpha-1, alpha-2, and beta-1) as well as the gamma-2 subunit of the gamma-aminobutyric acid (GABA)(A) receptor have been found to underlie some of these cases. Furthermore, several genetic loci have been identified that appear to increase the likelihood of febrile seizures without leading to subsequent epilepsy.

For patients who have experienced a single simple febrile seizure, the overall risk of at least one recurrence is approximately 30%. If the seizure occurred prior to 12 months, the risk increases to 50%, and if the seizure occurred after age 3, the risk is closer to 20%. This might be caused, in part, by the fact that febrile seizures are an age-dependent phenomenon occurring before the age of 5. In addition to the age at which the first seizure occurred, the duration and degree of fever appear to be related to recurrence risk. The longer the duration of the fever and the higher the degree of the fever associated with the first febrile convulsion, the lower the risk of recurrence. As might be expected, a family history of febrile seizures also increases the risk of recurrence. Half of all recurrences occur within 6 months, and 90% will occur within 24 months.

The relationship between febrile seizures and the subsequent development of afebrile unprovoked seizures (epilepsy) is somewhat complicated. Examined retrospectively, approximately 15% of children with epilepsy have a history of febrile seizures earlier in life. However, of all children who experience febrile seizures, only 2% to 4% will develop epilepsy—a two- to fourfold increase over the baseline incidence of epilepsy (~ 1% in the United States). Stated conversely, 96% to 98% of patients with febrile seizures will not develop epilepsy—which is one reason that physicians generally can be quite reassuring in talking to the parents of a child who experiences a simple febrile seizure.

Factors that are known to increase the risk of later epilepsy include (1) preexistent neurodevelopmental problems (such as cerebral palsy or developmental delay), (2) complex febrile seizures, (3) family history of epilepsy, and (4) febrile seizures early in life or associated with mild fevers. Temporal lobe epilepsy (TLE) is the most common type of epilepsy in adults, and there has been significant debate regarding the role that febrile seizures might play in the etiology of TLE. On the one hand, it could be that frequent febrile seizures damage the temporal lobe and lead to epilepsy. On the other hand, the temporal lobe might already be abnormal, thereby increasing the patient’s susceptibility to febrile seizures. There are data from clinical and animal research to support both of these contentions.

TREATMENT AND PROPHYLAXIS

Although the vast majority of febrile seizures last less than 15 minutes, approximately 5% will last 30 minutes or more (febrile status epilepticus). Management of such patients is a medical emergency because prolonged seizures can cause significant neurologic injury. As with any acute life-threatening emergency, initial attention must be paid to the patient’s airway, breathing, and circulation. Subsequent management proceeds as with status epilepticus of any cause: parenteral benzodiazepines followed by phenobarbital. Attention should also be paid to controlling the patient’s fever by removing clothing, using a cooling blanket, and administering antipyretics.

The majority of febrile seizures do not recur, and the vast majority of cases are not associated with development of epilepsy. In other words, most simple febrile seizures can safely be seen as a benign age-limited event. However, they are truly terrifying events for the patient and the patient’s family, and a small percentage of patients do develop afebrile seizures. Given these factors, it is not surprising that prophylaxis of febrile seizures has been a long-standing controversy in pediatric neurology. There have been two approaches to prevention: daily medication regimens and intermittent prophylaxis. Although the daily administration of phenobarbital and valproic acid is effective in reducing the occurrence of febrile seizures, their frequent side effects makes their use in this context difficult to justify. Intermittent prophylaxis, giving antipyretics or anticonvulsants only during a febrile illness, decreases the frequency of such side effects. Parents are generally able to anticipate the onset of a febrile illness, although at times the seizure can seem to be the first manifestation. The simplest approach is to treat children with antipyretics during an illness, yet this does not seem to reduce the risk of seizures. Treatment with rectal or oral preparations of diazepam during a febrile illness, however, does reduce the risk of recurrence in children who have already had a febrile seizure. Additionally, a rectal diazepam gel (Diastat) can be used to abort a convulsion at home once it has begun. It is not clear, however, whether prevention of febrile seizures has any long-term impact on neurodevelopmental outcome.

CASE CORRELATION

• See also Case 44 (New-Onset Seizure, Child) and Case 49 (Benign Epilepsy with Centrotemporal Spikes)

COMPREHENSION QUESTIONS

45.1 A toddler is brought into the emergency department (ED) with what is diagnosed as a febrile seizure. The physician is diagnosing the child as having a complex febrile seizure. Which of the following findings would support the diagnosis?

A. Loss of consciousness

B. Duration of 14 minutes

C. Focal onset

D. Association with a fever of 38.6°C (101.5°F)

E. Age of 4 years

45.2 Which of the following has been shown to be effective in preventing the recurrence of febrile seizures with an acceptable side effect profile?

A. Daily oral phenobarbital

B. Oral valproic acid during febrile illnesses

C. Fever reduction with antipyretics

D. Rectal diazepam during febrile illness

E. Daily phenytoin

45.3 Which of the following is true regarding the relationship between febrile seizures and the development of subsequent epilepsy?

A. Patients who experience a febrile convulsion are at a high risk of developing epilepsy.

B. Patients who have their first febrile seizure older than 3 are at greater risk of epilepsy than those with a first event younger than 12 months.

C. Preventing febrile seizures clearly reduces the risk of epilepsy.

D. Of patients with a febrile seizure, 96% to 98% will not develop epilepsy.

E. Only patients with a complex febrile seizure develop epilepsy.

45.4 Most patients with febrile seizures can be observed carefully without the need for LP. Which of the following patients should have an LP?

A. A 3-year-old previously healthy boy now in the ER after a 10-minute generalized seizure in association with a 39.1°C (102.5°F) temperature caused by a viral respiratory illness

B. A 9-month-old girl presenting after a 5-minute generalized seizure in association with a 38.6°C (101.5°F) fever

C. A 7-year-old boy with known epilepsy who has a typical seizure while ill with gastroenteritis

D. A 30-month-old boy now in the ER with his third simple febrile seizure in 6 months

ANSWERS

45.1 C. The focal nature of the seizure in this case is concerning. A febrile seizure is considered complex if it lasts longer that 15 minutes, is focal, or recurs within 24 hours.

45.2 D. Although daily treatment with phenobarbital or valproic acid reduces recurrence of seizures, these agents are associated with significant side effects. Treatment with oral or rectal diazepam during febrile illness is both effective and better tolerated.

45.3 D. Although the risk of epilepsy can double from 1% (population baseline incidence) to 2% or even quadruple to 4%, that still means that 96% to 98% of patients will never develop epilepsy. Rarely, patients with simple febrile seizures may develop epilepsy in the future.

45.4 B. The main reason to perform an LP is to assess for meningitis. Children younger than 12 months can present with minimal or only subtle signs of CNS infections. Of course, an LP should be performed in any patient in whom a CNS infection is clinically suspected.

    CLINICAL PEARLS    

▶ It is critical to differentiate simple from complex febrile seizures—duration greater than 15 minutes, focal, or recurrence in 24 hours are complex. ▶ Treating children with daily phenobarbital to prevent febrile seizures is associated with poorer performance on cognitive tests. ▶ An electroencephalogram (EEG) is not useful in the acute evaluation of simple febrile seizures because epileptiform abnormalities are present for up to 2 weeks after a seizure, regardless of cause. ▶ The peak age of incidence for febrile seizures is approximately 18 months. ▶ The overall risk of recurrence of a simple febrile seizure is 30%.

REFERENCES

Audenaert D, Van Broeckhoven C, De Jonghe P. Genes and loci involved in febrile seizures and related epilepsy syndromes. Human Mutat. 2006;27(5):391-401. 

Hancili S, Önal ZE, Ata P, et al. The GABAA receptor γ2 subunit (R43Q) mutation in febrile seizures. Pediatr Neurol. 2014;50:353-356. 

Nakayama J, Aranami T. Molecular genetics of febrile seizures. Epilepsy Res. 2006;70(suppl 1):S190-S198. 

Oluwabusi T, Sood SK. Update on the management of simple febrile seizures: emphasis on minimal intervention. Curr Opin Pediatr. 2012;24:259-265. 

Rosman NP. Febrile seizures. In: Pellock J, Dodson W, Bourgeois B, eds. Pediatric Epilepsy: Diagnosis and Therapy. New York, NY: Demos Medical Publishing; 2001:163-175. 

Zerr DM, Meier AS, Selke SS, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. 2005;352:768-776.

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