Background

Febrile seizures are the most common type of seizures observed in the pediatric age group. Although described by the ancient Greeks, it was not until this century that febrile seizures were recognized as a distinct syndrome separate from epilepsy. In 1980, a consensus conference held by the National Institutes of Health described a febrile seizure as, "An event in infancy or childhood usually occurring between three months and five years of age, associated with fever, but without evidence of intracranial infection or defined cause."[1] It does not exclude children with prior neurological impairment and neither provides specific temperature criteria nor defines a "seizure." Another definition from the International League Against Epilepsy (ILAE) is "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 (CNS), without previous neonatal seizures or a previous unprovoked seizure, and not meeting the criteria for other acute symptomatic seizures".[2] For other information, see Medscape's Pediatrics Specialty page.

Pathophysiology
Febrile seizures occur in young children at a time in their development when the seizure threshold is low. This is a time when young children are susceptible to frequent childhood infections such as upper respiratory infection, otitis media, viral syndrome, and they respond with comparably higher temperatures. Animal studies suggest a possible role of endogenous pyrogens, such as interleukin 1beta, that, by increasing neuronal excitability, may link fever and seizure activity.[3] Preliminary studies in children appear to support the hypothesis that the cytokine network is activated and may have a role in the pathogenesis of febrile seizures, but the precise clinical and pathological significance of these observations is not yet clear.[4, 5] Febrile seizures are divided into 2 types: simple febrile seizures (which are generalized, last < 15 min and do not recur within 24 h) and complex febrile seizures (which are prolonged, recur more than once in 24 h, or are focal).[6] Complex febrile seizures may indicate a more serious disease process, such as meningitis, abscess, or encephalitis. Viral illnesses are the predominant cause of febrile seizures. Recent literature documented the presence of human herpes simplex virus 6 (HHSV-6) as the etiologic agent in roseola in about 20% of a group of patients presenting with their first febrile seizures. Shigella gastroenteritis also has been associated with febrile seizures. One study suggests a relationship between recurrent febrile seizures and influenza A.[7, 8] Febrile seizures tend to occur in families. In a child with febrile seizure, the risk of febrile seizure is 10% for the sibling and almost 50% for the sibling if a parent has febrile seizures as well. Although clear evidence exists for a genetic basis of febrile seizures, the mode of inheritance is unclear.[9] While polygenic inheritance is likely, a small number of families are identified with an autosomal dominant pattern of inheritance of febrile seizures, leading to the description of a "febrile seizure susceptibility trait" with an autosomal dominant pattern of inheritance with reduced penetrance. Although the exact molecular mechanisms of febrile seizures are yet to be understood, underlying mutations have been found in genes encoding the sodium channel and the gamma amino-butyric acid A receptor.[10, 11, 12]

Epidemiology
Frequency United States

Between 2% and 5% of children have febrile seizures by their fifth birthday.[13]

International

A similar rate of febrile seizures is found in Western Europe. The incidence elsewhere in the world varies between 5% and 10% for India, 8.8% for Japan, 14% for Guam,[14] 0.35% for Hong Kong, and 0.5-1.5% for China.[15]
Mortality/Morbidity

Children with simple febrile seizures do not have increased mortality risk. However, seizures that were complex, occurred before 1 year of age, or were triggered by a temperature < 39C were associated with a 2-fold increased mortality rate during the first 2 years after seizure occurrence.[16] Children with febrile seizures have a slightly higher incidence of epilepsy compared with the general population (2% vs 1%). Risk factors for epilepsy later in life include complex febrile seizure, family history of epilepsy or neurologic abnormality, and developmental delay. Patients with 2 risk factors have up to a 10% chance of developing afebrile seizures.[17, 18]

Race

Febrile seizures occur in all races.

Sex

Some studies demonstrate a slight male predominance.

Age

By definition, febrile seizures occur in children aged 3 months to 5 years

History

The type of seizure (generalized or focal) and its duration should be described to help differentiate between simple and complex febrile seizures. Focus on the history of fever, duration of fever, and potential exposures to illness. A history of the cause of fever (eg, viral illnesses, gastroenteritis) should be elucidated. Recent antibiotic use is particularly important because partially treated meningitis must be considered. A history of seizures, neurologic problems, developmental delay, or other potential causes of seizure (eg, trauma, ingestion) should be sought.

Physical

The underlying cause for the fever should be sought. A careful physical examination often reveals otitis media, pharyngitis, or a viral exanthem.

Serial evaluations of the patient's neurologic status are essential. Check for meningeal signs as well as for signs of trauma or toxic ingestion.

Causes

Risk factors for developing febrile seizures[13, 19, 20, 21] o Family history of febrile seizures o High temperature o Parental report of developmental delay o Neonatal discharge at an age greater than 28 days (suggesting perinatal illness requiring hospitalization) o Daycare attendance o Presence of 2 of these risk factors increases the probability of a first febrile seizure to about 30%. o Maternal alcohol intake and smoking during pregnancy has a 2-fold increased risk. o Interestingly, no data support the theory that a rapid rise in temperature is a cause of febrile seizures. About one third of all children with a first febrile seizure experience recurrent seizures.[22] o Risk factors for recurrent febrile seizures include the following:[23, 24] Young age at time of first febrile seizure Relatively low fever at time of first seizure Family history of a febrile seizure in a first-degree relative Brief duration between fever onset and initial seizure Multiple initial febrile seizures during same episode o Patients with all 4 risk factors have greater than 70% chance of recurrence. Patients with no risk factors have less than a 20% chance of recurrence

Differentials

Epidural and Subdural Infections Epidural Hematoma Meningitis Pediatrics, Bacteremia and Sepsis Pediatrics, Fever Pediatrics, Meningitis and Encephalitis Pediatrics, Status Epilepticus

Laboratory Studies
In children under the age of 5 with complex febrile seizures, over one-third of experienced pediatric emergency physicians would do extensive workup, nearly half would admit, but variability exists in the approach to optimal management of patients with CFS. Past studies support more aggressive workup for patients under the age of 18 months, but future prospective studies on this subject are warranted.[25]

Routine laboratory studies usually are not indicated for febrile seizure unless they are performed as part of a search for the source of a fever. Electrolytes assessments are rarely helpful in the evaluation of febrile seizures.[6] Patients with febrile seizures have an incidence of bacteremia similar to patients with fever alone.[26]

Imaging Studies

A CT scan usually is not necessary in the evaluation of a child with a first simple febrile seizure. A CT scan should be considered in patients with complex febrile seizures. However, a study by Teng et al analyzed data in 71 children with first complex febrile seizure.[27] Fifty-one (72%) had a single complex feature (20 focal, 22 multiple, and 9 prolonged), and 20 (28%) had multiple complex features. None of the 71 patients (1sided 95% confidence interval, 4%) had intracranial pathologic conditions that required emergency neurosurgical or medical intervention. Forty-six had normal acute scans; the rest were normal on clinical follow up without a scan. The confidence interval means that this study cannot exclude a risk of intracranial pathology of 4% or less.

Other Tests

An electroencephalogram (EEG) usually is not necessary in the routine evaluation of a child with a first simple febrile seizure.

Procedures

Lumbar puncture o Controversy exists regarding the need for a lumbar puncture in a child presenting with a simple febrile seizure. o Lumbar puncture is not needed for young children with first simple febrile seizure.[28] o Certainly, meningitis can present with a seizure, although the seizure usually is not the only sign of meningitis. Patients who have a first-time febrile seizure and do not have a rapidly improving mental status (short postictal period) should be evaluated for meningitis. o Several reviews of the medical literature report less than 5% incidence of meningitis in children presenting with seizures and fever. o Risk factors for meningitis in patients presenting with seizure and fever include the following: A visit to a healthcare setting within the previous 48 hours Seizure activity at the time of arrival in the ED Focal seizure, suspicious physical examination findings (eg, rash, petechiae) cyanosis, hypotension, or grunting Abnormal neurologic examination o In 1996, the American Academy of Pediatrics (AAP) recommended that a lumbar puncture be strongly considered in patients younger than 12 months presenting with fever and seizure.[2] The AAP also recommended that a lumbar

puncture be considered in patients aged 12-18 months. A lumber puncture is not routinely necessary in patients older than 18 months. This recommendation is conservative, but it takes into account the difficulty in recognizing meningitis in infants and young children and the range of experience in the evaluation of pediatric patients among healthcare providers

Prehospital Care

Patients with active seizures should be treated with airway management, high-flow oxygen, supportive care, and anticonvulsants as necessary. Acute treatment such as rectal diazepam (0.5 mg/kg) and buccal 0.4-0.5 mg/kg) or intranasal (0.2 mg/kg) are effective and can be given at home for a seizure lasting longer than 5 minutes.[29, 30, 31] Patients who are postictal should receive supportive care and antipyretics as appropriate.

Emergency Department Care

Patients presenting with status epilepticus should be treated with airway management and anticonvulsants as necessary. Patients presenting with history and physical examination findings consistent with a simple febrile seizure should have frequent neurologic examinations to monitor mental status. Other causes of seizure should be ruled out. The cause of the febrile illness should be sought and treated. Antipyretics should be considered. Acetaminophen (Tylenol) and ibuprofen (Motrin) are often used. Parental anxiety and fear that their child may die or will develop brain damage needs to be addressed with reassurance and education

Medication Summary
Patients presenting in status epilepticus can be treated with routine seizure medications, including benzodiazepines, phenytoin, and phenobarbital. For further discussion on the treatment of seizures, see Pediatrics, Status Epilepticus.

Antipyretics
Class Summary

Antipyretics should be used in patients who appear uncomfortable secondary to fever. Antipyretics do not appear to prevent recurrence of febrile seizures.
View full drug information Acetaminophen (Tylenol)

Reduces fever by acting directly on hypothalamic heat-regulating centers, which increases dissipation of body heat via vasodilation and sweating.
View full drug information

Ibuprofen (Advil, Motrin)

One of the few NSAIDs indicated for reduction of fever. Inhibits the formation of prostaglandins.

Anticonvulsant agents
Class Summary

Prophylactic treatment with an anticonvulsant agent may be considered for subsequent fever episodes.
View full drug information Diazepam (Valium, Diastat)

Can decrease number of subsequent febrile seizures when given with each febrile episode. Modulates postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. Appears to act on part of the limbic system, the thalamus, and hypothalamus, to induce a calming effect. Also has been found to be an effective adjunct for the relief of skeletal muscle spasm caused by upper motor neuron disorders. Rapidly distributes to other body fat stores. Twenty minutes after initial IV infusion, serum concentration drops to 20% of Cmax. Individualize dosage and increase cautiously to avoid adverse effects. Available as IV, PO, and PR dosage forms.
View full drug information Lorazepam (Ativan)

Sedative hypnotic with short onset of effects and relatively long half-life. By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation. Important to monitor patient's blood pressure after administering dose. Adjust as necessary.

Further Inpatient Care

The decision to admit should be individualized, but admission usually is not necessary for patients with febrile seizure. Most patients should be observed in the ED until awake and alert. Conditions requiring admission of the patient include the following: o More than 1 seizure within 24 hours o Unstable clinical status o Lethargy beyond the postictal period o Uncertain home situation o Unclear follow-up care

Further Outpatient Care

Arrange for medical reevaluation of discharged patients and parental education in a follow-up appointment within 24-48 hours.

Inpatient & Outpatient Medications

Discharge medications include antipyretics and, if indicated, antibiotics (eg, otitis media, pneumonia). Prophylactic use of antipyretics and sedatives/anticonvulsants for possible recurrence of febrile seizure has not shown to be effective. o Regular or sporadic administration of antipyretics during febrile illness is generally safe, but no study has shown them to be effective in reducing recurrence of febrile seizures.[32, 33] Acetaminophen and ibuprofen are no better than placebo for preventing recurrences of febrile seizures .[34] o Phenobarbital and valproic acid can be given daily and are effective, but they are associated with multiple adverse effects. Carbamazepine and phenytoin are not effective in preventing recurrent febrile seizures. Citing a preponderance of harm over benefit, the 2008 Clinical Practice Guideline for the Long-Term Management of the Child with Simple Febrile Seizures recommends neither continuous nor intermittent use of anticonvulsants for children with one or more simple febrile seizures.[33] o Some studies report that diazepam, given orally or rectally every 8 hours during febrile illnesses, is effective in preventing recurrence of febrile seizures.[35, 36] . However, these benzodiazepines can cause lethargy, drowsiness, and ataxia, and sedation could mask an evolving central nervous system infection. The AAP guideline released in 2008 does not recommend prophylactic use of diazepam as the risk outweighs the benefits.[33]

Deterrence/Prevention

Given a more established role of influenza A in the etiology of febrile seizure, both acute and recurrent, vaccination against influenza A in the flu season may have a role in preventing development of both acute and recurrent febrile seizures.[8]

Prognosis

Simple febrile seizures may slightly increase the risk of developing epilepsy,[37] but they have no adverse effects on behavior, scholastic performance, or neurocognition. The risk of developing epilepsy is increased further in children with a history of complex febrile seizures.[13, 38, 39, 40] A strong association exists between febrile status epilepticus or febrile seizures characterized by focal symptoms and later development of temporal lobe epilepsy.[37,
41]

o o

Children with febrile seizures have a slightly higher incidence of epilepsy compared with the general population (2% vs 1%). Risk factors for epilepsy later in life include complex febrile seizure, family history of epilepsy or neurologic abnormality, and developmental delay. Patients with 2 risk factors have up to a 10% chance of developing afebrile seizures.[42]

Patient Education

Parents should be taught what to do if their child has another seizure. The parent should be advised to call for assistance if the seizure lasts longer than 10 minutes or if the postictal period lasts longer than 30 minutes. Parents should be counseled on the benign nature of febrile seizures. Parents should be reassured that simple febrile seizures do not lead to neurologic problems or developmental delay. For excellent patient education resources, visit eMedicine's Brain and Nervous System Center. Also, see eMedicine's patient education articles Seizures and Fever and Seizures in Children.

Drugs

acetaminophen (OTC) - Tylenol, Tylenol Arthritis Pain

Pediatric Dosing & Uses

Dosing Forms & Strengths

oral solution/suspension

160mg/5mL 80mg/0.8mL (discontinued; phased out from market mid-2011) 80mg

oral concentrated solution - infant drops (discontinued) tablet, chewable (tablet, oral-disintegrating)
80mg 160mg Pain/Fever Relief

40-60 mg/kg/day PO divided q6hr PRN; not to exceed 5 doses/24 hours Neonates: 10-15 mg/kg PO q6-8hr PRN Potential toxic dose <6 years old: 200 mg/kg
Contraindications

Hypersensitivity Hepatitis or hepatic/renal dysfunction, alcoholism Repeated administration in patients with anemia or cardiac, pulmonary, or renal disease
Cautions

Acetaminophen in many other dosage forms and products, check label carefully to avoid overdose Risk of hepatotoxicity is higher in alcoholics or with use of more than one acetaminophencontaining product G6PD deficiency Phenylketonuria Ibuprofen more effective than acetaminophen for pain from musculoskeletal injuries in children
Mechanism of Action

Acts on hypothalamus to produce antipyresis May work peripherally to pain impulse generation; may also inhibit prostaglandin synthesis in CNS
Absorption

Peak Plasma Time: 10-60 min (PO immediate-release); 60-120 min (PO extended-release); 6 hr (PO 500 mg, conventional tablet); 8 hr (PO 650 mg, extended-release tablet)

Peak Plasma Concentration: 2.1 mcg/mL (PO 500 mg, conventional tablet); 1.8 mcg/mL (PO 650 mg, extended-release tablet)
Distribution

Distribution: rapid & uniform Protein Bound: 25%

Metabolism

Metabolism: liver (microsomal enzyme systems); conjugation (glucuronic/sulfuric acid) Metabolites: N-acetyl-p-benzoquinoneimine, N-acetylimidoquinone, NAPQI; further metabolized via conjugation with glutathione
Elimination

Half-life: 1.25-3 hr Excretion: urine (principally as acetaminophen glucuronide with acetaminophen sulfate/mercaptate)

ibuprofen (Rx) - Advil, Motrin

Dosing Forms & Strengths

tablets

100mg 200mg 300mg 400mg 600mg 800mg 100mg 100mg/5mL 40mg/mL

tablet, chewable oral suspension injection solution

10mg/mL Pain/Fever

5-10 mg/kg PO q6-8hr; not to exceed 40 mg/kg/day

Juvenile Idiopathic Arthritis

7.5-12.5 mg/kg PO q8hr

PDA Closure in Premature Neonates (NeoProfen)

Initial: 10 mg/kg IV, THEN 2 doses of 5 mg/kg each, after 24 & 48 hr If renal dysfunction, withhold 2nd/3rd dose until renal function normal Repeat course may be needed if PDA
Cystic Fibrosis (Off-label)

<4 years old: Safety & efficacy not established >4 years old: Oral administration BID adjusted to maintain serum levels of 50-100 mcg/mL may slow disease progression in younger patients with mild lung disease
Administration

Take with food or 8-12 oz water to avoid GI effects

Other Information

Potential toxic dose <6 years old: 200 mg/kg

Mechanism of Action

Inhibits synthesis of prostaglandins in body tissues by inhibiting cyclooxygenase; at least 2 isoenzymes, cyclooxygenase-1 (COX-1) & -2 (COX-2)
Absorption

Bioavailability: 80-100%

Onset: 30-60 min Duration: 4-6 hr Peak Plasma Concentration: (chewable tabs) 15 mcg/mL, (susp) 19 mcg/mL, (conventional tabs) 20 mcg/mL, (IV, 400 mg dose) 39 mcg/mL Peak plasma time
Adults: (conventional tabs) 120 min, (chewable tabs) 62 min, (susp) 47 min, (IV) 2.2 min Febrile children: (chewable tabs) 86 min, (suspension (58 min) Distribution

Protein Bound: 90-99%; concentrations >20 mcg/mL Vd: Adults (0.12 L/kg), febrile children <11 yo (0.2 L/kg)
Metabolism

Rapid hepatic oxidation to inactive metabolites Hepatic CYP2C9; CYP2C19 substrate Metabolites: (+)-2-[4'-(2-hydroxy-2-methylpropyl) phenyl] propionic acid (metabolite A), (+)-2-[4'-(2-carboxypropyl) phenyl] propionic acid (metabolite B) Enzymes inhibited: cyclooxygenase enzymes
Elimination

Half-life: 2-4 hr Excretion (within 24 hr): Urine 50-60% (<10% unchanged); remainder in feces

diazepam (Rx) - Valium, Diastat

Pediatric Dosing & Uses

Dosing Forms & Strengths

tablet: Schedule IV

2mg 5mg 10mg 5mg/5mL 5mg/mL 5mg/mL

oral solution: Schedule IV rectal solution: Schedule IV injectable solution: Schedule IV

5mg/mL Sedative/Muscle Relaxant

<6 months old: PO not recommended 0.04-0.2 mg/kg IV/IM q2-4hr; no more than 0.6 mg/kg within 8 hours, OR 0.12-0.8 mg/kg/day divided TID/QID PO
Status Epilepticus

IV

Neonate (<28 days old): 0.3-0.75 mg/kg IV q15-30min x2-3 doses (not first-line treatment because of benzyl alcohol content) >1 month old: 0.2-0.5 mg/kg IV q15-30min x2-3 doses No more than <5 years old: 5 mg; >5 years old: 10 mg 2-5 years old: 0.5 mg/kg; repeat in 4-12 hours PRN 6-11 years old: 0.3 mg/kg; repeat in 4-12 hours PRN >12 years old: 0.2 mg/kg; repeat in 4-12 hours PR PR (using IV form): As adult

PR

Administration

PO: Dilute oral concentrate with water/juice/carbonated beverages or mix with semisolid foods PR: Place patient on side facing you with upper leg bent forward, lubricate rectal applicator tip, gently instert syringe tip in rectum and slowly push plunger
Other Information

Potential toxic dose <6 years old: 0.5 mg/kg

Pharmacology
Half-Life: 20-70 hr (active metabolite) Onset: 15-45 min (PO, hypnotic action); 1-5 min (IV sedative action) Duration: PO (hypnotic action):7-8 hr; IV (sedative action); 15-60 min
Peak Plasma

Time: 30-90 min (PO), 5-90 min (PR) Concentration: 373 ng/mL (initial at 45 min); 447 ng/mL (second peak at 70 min)
Other Information

Bioavailability: 90% (PR) Protein Bound: 98% Vd: 0.8-1 L/kg Metabolism: hepatic P450 enzyme CYP2C19, CYP3A4 Metabolites: N-desmethyldiazepam, 3-hydroxdiazepam, oxazepam Renal Clearance: 20-30 mL/min Excretion: urine
Mechanism of Action

Modulates postsynaptic effects of GABA-A transmission, resulting in an increase in presynaptic inhibition. Appears to act on part of the limbic system, the thalamus, and hypothalamus, to induce a calming effect.

lorazepam (Rx) - Ativan

Pediatric Dosing & Uses

Dosing Forms & Strengths

tablet: Schedule IV

0.5mg 1mg 2mg 2mg/mL

oral concentrate: Schedule IV injectable solution: Schedule IV

2mg/mL 4mg/mL Status Epilepticus (Off-label)

Infants and children: 0.05-0.1 mg/kg IV over 2-5 minutes; not to exceed 4 mg/dose; may repeat q10-15min PRN Adolescents: 4 mg slow IV; if seizure persists after 10-15 minutes, administer 4 mg IV again
Anxiolytic/Sedation/Agitation (Off-label)

Children: 0.05 mg/kg/dose PO q4-8hr; not to exceed 2 mg/dose

Chemotherapy-Induced Nausea/Vomiting (Off-label)

Children: 0.05 mg/kg IV q6hr PRN; not to exceed 2 mg/dose

Other Information

Monitor: Respirations q5-15min & before each repeated IV dose

Pharmacology

Mechanism of Action

Sedative hypnotic with short onset of effects and relatively long half-life By increasing the action of gamma-aminobutyric acid (GABA), which is a major inhibitory neurotransmitter in the brain, may depress all levels of CNS, including limbic and reticular formation
Absorption

Bioavailability: 90% Onset: IV 1-5 min; IM 15-30 min Peak plasma time: 2 hr Peak plasma concentration: 20 ng/mL Duration: 12-24 hr (IV/IM)
Distribution

Protein Bound: 85%

Metabolism

Glucuronic acid conjugation Metabolites: inactive

Elimination

Half-Life: unconjugated lorazepam, 12hr; major metabolite lorazepam glucuronide, 18hr Excretion: Urine
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