Epilepsy

When a child has one or more paroxysmal events involving episodic alteration of neurologic function, a critical question is whether the event may have been a seizure. The diagnosis of seizure is often made based on careful history. By convention, the diagnosis of epilepsy is made after the occurrence of two unprovoked seizures. As the scientific understanding of epilepsy has expanded, the systems that neurologists use to formally classify types of epilepsy have also evolved. However, for the purposes of front-line recognition of seizures and medical decision-making about diagnosis and management, the straightforward framework below suffices.

The topics in this section are organized as follows:

• Types of Seizures

• Febrile Seizures

• Evaluation of First Unprovoked (Nonfebrile) Seizure

• Classification of Seizures Based on Appearance (Ictal Semiology)

• Epilepsy Syndromes

  • Benign Epilepsy with Centrotemporal Spikes

  • Childhood Absence Epilepsy

  • Juvenile Myoclonic Epilepsy

  • Infantile Spasms

• Status Epilepticus

Types of Seizures

• Provoked seizures are believed to have been caused by a proximate event or induced by a state that is external to the brain and may not recur (e.g., febrile illness, electrolyte disturbance, encephalitis, acute intracerebral hemorrhage). In such cases, diagnosing the provoking factor is the focus and the diagnosis of epilepsy is not appropriate.

• Unprovoked seizures refer to seizures with no identifiable proximate cause that are often associated with one of the following two scenarios:

  • The event is a single lifetime seizure in a person without epilepsy, with no proximate cause identified, and no factors suggesting a high risk of recurrence.

  • The event is a seizure in a person with epilepsy. The diagnosis of epilepsy means the brain tends to have seizures, and that seizures are expected to recur unless the patient is treated. At the time of a first seizure, there is often uncertainty about which of these two scenarios apply. In an otherwise healthy child whose development is on track, clinicians can err on the side of predicting the first scenario and take a clinical watch-and-wait approach.

Febrile Seizures

A febrile seizure is the most common form of provoked seizure in childhood, occurring in 2% to 5% of all children. Febrile seizure is accompanied by fever (100.4°F or 38°C or higher by any method) without central nervous system (CNS) infection in infants and children aged 6 months through 60 months (5 years) with no history of afebrile seizure. Febrile seizures are classified as simple or complex:

• Simple febrile seizures meet all three of the following clinical criteria:

  • at the onset of the seizure, both sides of the body stiffen, jerk, or both (i.e., a generalized, nonfocal seizure has occurred)

  • duration is <15 minutes

  • does not recur within 24 hours

• Complex febrile seizures meet one or more of the following clinical criteria:

  • at the onset of the seizure, only one side of the body jerks or the seizure starts with unresponsive staring, followed by jerking on one or both sides of the body (i.e., a focal-onset seizure has occurred)

  • duration >15 minutes

  • recurs within 24 hours

Diagnostic evaluation of febrile seizures: Most children who present with febrile seizures have viral infections that cause the fever. The rate of serious bacterial infections in children presenting with febrile seizures is similar to that of children presenting with fever without seizure. However, clinicians should use their clinical judgment regarding the likelihood of CNS infection, particularly in children who have not received recommended routine vaccinations.

Lumbar puncture (LP) is almost never indicated in a child with a simple febrile seizure and is seldom necessary in a child with a complex febrile seizure. However, LP should be performed in any child in whom the clinician directly examining the child has reason to suspect meningitis or encephalitis. Such indications are not always precisely definable or based on strong evidence. For example, sustained alteration of mental status after the seizure, a possible indicator of CNS infection, can be challenging to assess in a young child or one who already has developmental delays.

Examples of reasons to strongly consider LP in a child who presents with a seizure and fever include:

• the presence of meningeal signs and symptoms (e.g., neck stiffness, Kernig sign, Brudzinski sign, or both)

• persistent high-pitched cry and excessive irritability or persistent delirium

• infants aged 6 months to 12 months who have not received recommended vaccinations, particularly against Haemophilus influenzae or Streptococcus pneumoniae

Evaluation of simple febrile seizures:

• The primary focus of the evaluation should be to identify the cause of the fever.

• No evidence supports the need for routine laboratory testing (e.g., serum electrolytes, complete blood count [CBC]), electroencephalogram (EEG), or neuroimaging in children who present with simple febrile seizures.

Evaluation of complex febrile seizures:

• The primary focus of the evaluation should be on the cause of the fever. However, given the nature of the seizure, the clinician should also consider the possibility of an intrinsic brain problem.

• Prolonged altered mental status (fluctuating confusion, arousal, and attention for more than an hour after the seizure) or prolonged focal weakness should raise concerns for an ongoing process such as CNS infection or ongoing subclinical seizures. These cases require urgent, comprehensive evaluation possibly including lumbar puncture, neuroimaging, and EEG. Neurology consultation is advised.

• If the child returns to baseline after a complex febrile seizure, a nonurgent outpatient brain MRI is recommended if the seizure had a focal onset or asymmetric features.

• No evidence supports the widespread practice of obtaining EEGs in children with complex febrile seizures that resolved without sequelae.

Recurrence of febrile seizures: Approximately one-third of children with a first febrile seizure will have a recurrence. Most studies indicate that the characteristics of the first febrile seizure (simple versus complex) do not influence recurrence risk.

The following factors are strong independent predictors of recurrent febrile seizures:

• young age at onset (between the ages of about 6 months and 12 months)

• history of febrile seizure in a first-degree relative

• low degree of fever at the onset of the seizure

• brief duration (less than one hour) between the onset of fever and the initial seizure

Prognosis: The vast majority (>90%) of children with febrile seizures do not develop epilepsy. The risk of developing epilepsy in a child with simple febrile seizures is only slightly higher than the risk in the general population (2%). The risk of developing epilepsy in children with complex febrile seizures is higher (5%-8%). Abnormalities on EEG do not predict epilepsy risk.

Evaluation of First Unprovoked (Nonfebrile) Seizure

When a child’s presentation raises concern for a first seizure, the following fundamental questions should be considered:

• Was the event a seizure?

• Was this truly the first event?

• Was the seizure provoked or unprovoked?

• What is the risk of recurrence?

• Does the child have epilepsy?

Was the event a seizure?

When a child presents with a paroxysmal event that suggests a possible seizure, a detailed history is important to obtain from a reliable adult (ideally someone who witnessed the event). This is often the most accurate way to differentiate between seizure and nonseizure spells.

Detailed history: The history is best accomplished by asking the observer to visualize themselves at the location where the event occurred and to report a sequential, detailed description of what occurred (if obtained, smartphone videos of the event can also be helpful) with a focus on the following:

• first observation (ideally including a description of what the child was doing immediately prior to the onset of the spell)

• precipitating events or warning symptoms, if any

• the onset of the altered behavior, with particular attention to the first body movements that occurred

• all body movements during the spell

• the level of awareness during the spell

• the resolution of the spell

• what occurred afterward, particularly confusion or somnolence and the duration of that state

Differential diagnosis: The differential for nonseizure spells includes the following:

• syncope

• breath-holding spells

• sleep paroxysms

• stereotypies with dissociation

• migraines

• paroxysmal nonepileptic events (previously named “pseudoseizures”)

• tics

• behavioral disturbances (e.g., tantrums)

• daydreaming or other dissociative events

Was this truly the first event?

The provider should attempt to elicit information about whether the child has had other events in the past that might have been seizures. Parents may not recognize brief or nonconvulsive events (e.g., staring spells or jerks) that in the right context could raise suspicion for certain epilepsy syndromes.

Was the seizure provoked or unprovoked?

The list of possible causes of a seizure is enormous. Careful consideration of potential causes is critical. Note that febrile seizures, the most common single cause of a provoked single seizure in childhood, are discussed separately above.

Diagnostic workup: The diagnostic workup is aimed at identifying whether there is an external or internal cause for this seizure. That, in turn, helps with assessing recurrence risk and deciding on treatment.

• Laboratory tests: In most cases, blood and cerebrospinal fluid (CSF) laboratory tests are not needed. The yield of testing for electrolytes and other measures in otherwise healthy children is very low. However, depending on the setting (e.g., prolonged diarrhea, young infants fed free water, or suspected toxic ingestion), some blood tests are appropriate. A fingerstick test for glucose measurement is almost universally performed and is reasonable, despite the low yield.

• Imaging:

  • MRI: The International League Against Epilepsy recommends MRI in all children with epilepsy who do not have an identified idiopathic epilepsy syndrome. However, there are no guidelines recommending neuroimaging as a standard of care for all children after a first seizure.

    • In a prospective observational series of 411 children with a first unprovoked seizure, neuroimaging was performed in 218, and 45 of those children (21%) had abnormal imaging findings, most commonly focal findings such as encephalomalacia and cerebral dysgenesis. Nearly all of these findings were not actionable or did not guide any urgent treatment. In addition, many young children need anesthesia to obtain an MRI.

    • A nonemergency MRI is therefore a reasonable diagnostic test in children with a first unprovoked seizure, particularly if sedation is not required. If a temporal lobe lesion is suspected, use of an MRI protocol in which thin cuts are made through the temporal lobes is helpful. Neurologists can provide guidance on whether imaging should be obtained and what type is most valuable.

  • EEG: Neurologists do not universally order EEGs after a first unprovoked seizure because the diagnosis of seizure is usually clinical and because EEG will not influence management in most children with a single unprovoked seizure.

    • In children with certain clinical presentations or multiple seizures, EEG is helpful in diagnosing epilepsy syndromes and selecting medications. For example, if a child has a single seizure involving one side of the face or body that begins during sleep, an EEG showing increased centrotemporal epileptiform discharges during sleep supports a diagnosis of benign epilepsy with centrotemporal spikes (BECTS). This allows for clinical counseling and often a decision to defer antiepileptic medication treatment.

    • In an adolescent with a history of early-morning rapid muscle jerks or an early-morning generalized tonic-clonic seizure (particularly after sleep deprivation), findings of generalized epileptiform discharges on EEG support a diagnosis of juvenile myoclonic epilepsy.

What is the risk of recurrence?

Many children have a single unprovoked seizure as a single lifetime event (i.e., they never develop epilepsy). Overall, 30% to 50% of typically developing children who have a first unprovoked seizure go on to have a second seizure.

• Most recurrences occur in the first 2 years after a first seizure, and half of those occur within the first 6 months. Once a child with typical neurodevelopment has had two unprovoked seizures, the overall risk of having a third seizure is ≥70%.

• Etiology is an important risk factor for recurrence. The biggest predictor of recurrence risk after a first seizure is a structural brain lesion (nonincidental). For example, 5-year recurrence risk after a first focal seizure in a child with a remote traumatic brain injury, prior stroke, or cerebral palsy is >70%.

• In the absence of any known structural brain abnormality, EEG is the most informative test for predicting recurrence risk after a first seizure. However, the sensitivity of epileptiform discharges on EEG for predicting seizures is at best 60% and the specificity is at best 70%. Thus, negative EEGs are not reassuring, and positive EEGs often occur in children who do not have another seizure. The positive predictive value is often below the treatment threshold.

Does the child have epilepsy?

Diagnosis: Epilepsy is defined by any of the following conditions:

• Diagnosis of an epilepsy syndrome (e.g., benign rolandic epilepsy).

• The standard, historical definition of epilepsy — at least two unprovoked seizures occurring more than 24 hours apart — accounts for most clinical presentations.

• One unprovoked seizure and a probability of further seizures similar to the general recurrence risk after two unprovoked seizures (at least 60%). This definition reflects emerging knowledge about seizure pathophysiology, imaging findings, neurophysiology, and genetics. In most cases, use of this definition requires specialty knowledge (e.g., of particular epilepsy syndromes or the implications of any identified structural abnormalities in the brain).

Treatment: After a first unprovoked seizure in children, anti-seizure medication is not usually prescribed. After a second unprovoked seizure in children, particularly if the second seizure has occurred within one year of the first, anti-seizure medication usually is prescribed. The decision to prescribe anti-seizure medication depends on the balance between the benefits of preventing seizure recurrence and the risk of adverse effects of medication.

The decision about which medication to prescribe depends on multiple factors, including but not limited to:

• type of seizure

• EEG findings

• imaging findings

• epilepsy syndrome diagnosis

• genetic test results

• other general health considerations

• family preference when weighing side effect risks

Classification of Seizures Based on Appearance (Ictal Semiology)

Ictal semiology is the study and description of the clinical signs and symptoms exhibited by individuals during seizures. It provides valuable information for diagnosing the type and origin of seizures, guiding treatment decisions, and improving the overall management of epilepsy and related disorders. Ictal semiology of generalized and focal seizures is described below:

• Generalized seizures affect both cerebral hemispheres from onset and are characterized as:

  • tonic-clonic: generalized stiffening, jerking, and shaking, sometimes with tongue biting and incontinence, often lasting 1-3 minutes

  • clonic: sustained rhythmic jerking

  • tonic: sudden stiffening of muscles, which may cause the patient to fall, lasting seconds

  • myoclonic: brief muscle jerks, usually of bilateral upper extremities, lasting a fraction of a second

  • atonic: sudden loss of muscle tone, often causing falls, often lasting seconds

  • epileptic spasms: sudden flexion, extension, or mixed flexion-extension of proximal and truncal muscles; lasting 1-2 seconds; may be focal or generalized

  • absence:

    • typical absence: sudden onset of staring and unresponsiveness lasting a few seconds with abrupt return to baseline

    • atypical absence: start and end more slowly than typical absence seizures

• Focal seizures start from one area of the brain, may later secondarily generalize, and are characterized as:

  • focal seizures with impaired awareness (also referred to as complex partial seizures): may have motor or nonmotor onset; motor symptoms may include automatisms or shaking on one side; nonmotor symptoms may include autonomic symptoms (e.g., heart rate increase) or sensory symptoms (e.g., unusual smell); consciousness is affected

  • focal aware seizures (also referred to as simple partial seizures): may have motor or nonmotor onset; motor symptoms may include automatisms or shaking on one side; nonmotor symptoms may include autonomic symptoms (e.g., heart rate increase) or sensory symptoms (e.g., unusual smell)

  • epileptic spasms: sudden flexion, extension, or mixed flexion-extension of proximal and truncal muscles, lasting 1−2 seconds; may be focal or generalized; person is conscious and aware

Note: A seizure may be unclassified due to inadequate information or inability to place the type in other categories.

Epilepsy Syndromes

Benign Epilepsy with Centrotemporal Spikes

Benign epilepsy with centrotemporal spikes (BECTS), also known as benign rolandic epilepsy (BRE), is the most common focal epilepsy of childhood and accounts for approximately 15% of epilepsy with onset before the age of 13 years. Seizure onset is usually between ages 3 and 10 years, and peak frequency of onset is between ages 5 and 8 years.

Seizure characteristics: Simple motor seizures are the exclusive or dominant seizure type in most cases. Most seizures in BECTS (70%-80%) are focal, although generalized seizures can also occur. Focal seizures in BECTS preferentially involve one side of the face (with contraction of one side of the face, jerking of the cheek and eyelid, or both); the oropharyngeal muscles (leading to guttural sounds, mouth movements, and excessive salivation and drooling); and less often, the upper extremity. Lower extremities are rarely involved. In younger children, seizures tend to be less localized and may involve the complete hemibody. Longer seizures may be followed by postictal hemiplegia (Todd paralysis). Consciousness is typically preserved, and if the seizure occurs during the awake state or awakens the child, he or she may walk to the caregiver during the seizure.

In BECTS, seizures are usually, but not always, nocturnal. In more than half of patients, seizures only occur during sleep. Seizure frequency is low in BECTS (approximately 25% of patients have only one seizure and 50% have fewer than five seizures). BECTS remits spontaneously after a few years, with a mean duration of less than 3 years. Remission occurs in 60% of patients by age 6 years and peaks by age 13 years. On neurologic examination, there are no associated focal signs. Cognitive impairment is not present in most cases. However, formal neuropsychological testing may demonstrate mild impairments, such as reading difficulties, in some children.

Diagnosis: BECTS is characterized by a typical EEG pattern. The EEG background activity is normal. The abnormalities include high-amplitude sharp waves in the centrotemporal head regions, which enhance with sleep. EEG usually normalizes later than clinical remission. BECTS is an idiopathic epilepsy that is not caused by structural brain abnormalities; therefore, MRI is not indicated. Clinical studies and family-based studies suggest a genetic component to the condition, although no single-gene mutations causing the disorder have been identified.

(Source: Benign Childhood Focal Epilepsies. Epilepsia 2012.)

Treatment: Because seizures are infrequent in BECTS, occur primarily at night, and remit within a few years, antiepileptic medication is typically not recommended. However, clinicians may choose to treat children with more-frequent seizures, daytime seizures, or generalized tonic-clonic seizures. In cases where clinicians and parents agree that treatment is the best strategy for a particular child, carbamazepine or oxcarbazepine is the treatment of choice.

Childhood Absence Epilepsy

Childhood absence epilepsy (CAE) is the most common type of childhood epilepsy and accounts for 10% to 17% of cases. Seizure onset is typically between ages 4 and 8 years. Children with CAE are usually developmentally typical with normal cognition at the time of diagnosis. However, formal neurocognitive testing can detect mild impairment in a variety of domains, particularly executive function. Psychiatric comorbidities are common, including attention deficit-hyperactivity disorder (ADHD) and anxiety.

Etiology: CAE is classified by the International League Against Epilepsy as an epilepsy syndrome with a presumed genetic cause. Genetic etiology is suggested by family and twin studies, although single-gene mutations causing CAE have not been identified.

Seizure characteristics: CAE is characterized by typical absence seizures, which are brief spells of loss of consciousness, without loss of tone, that typically last less than 10 seconds. These seizures have an abrupt onset and offset with no postictal period and typically begin with behavioral arrest and staring. Some seizures include blinking or lip-smacking automatisms, which are semi-coordinated repetitive movements associated with impaired consciousness. Seizures occur frequently, typically many times per day. However, they are often subtle and may go unnoticed for long periods by caregivers. Most children with CAE have only typical absence seizures, although, rarely, some may have generalized tonic-clonic seizures. The prevalence of generalized tonic-clonic seizures in CAE is highly variable in studies.

Diagnosis: A diagnosis of CAE is based on history, examination, and EEG findings. The typical EEG pattern in CAE is a normal background with 2.5-5.0 (classically 3.0) Hz spike and wave discharges during a seizure. Absence seizures are easily provoked by hyperventilation, a maneuver which can be performed at bedside as well as during the EEG. MRI is not indicated for diagnosis of CAE and is by definition normal in children with CAE.

(Source: Electroencephalography (EEG): An Introductory Text and Atlas of Normal and Abnormal Findings in Adults, Children, and Infants. American Epilepsy Society 2016.)

Treatment: Once absence epilepsy is recognized, it should be treated to improve quality of life, school performance, and social acceptance.

• Ethosuximide is the first-line treatment for most children with CAE. In a randomized, controlled trial of ethosuximide, valproic acid, and lamotrigine in children with CAE, ethosuximide and valproate were significantly more effective than lamotrigine. Valproate was as effective as ethosuximide but was associated with more-frequent side effects.

• Valproate is a good second-line treatment choice in children who do not respond to ethosuximide or who develop generalized tonic-clonic seizures, for which ethosuximide is not effective.

Prognosis: In most cases of CAE, first-line therapy is effective and seizures remit prior to puberty. However, some children may continue to experience absence seizures and, rarely, generalized tonic-clonic seizures, while others initially diagnosed with absence epilepsy whose seizures do not remit may eventually be diagnosed with juvenile myoclonic epilepsy (JME).

Juvenile Myoclonic Epilepsy

Seizure characteristics: Juvenile myoclonic epilepsy (JME) is characterized by myoclonic seizures that are bilateral, single, or repetitive jerks predominantly in the upper extremities, without loss of consciousness. Often, brief myoclonic jerks may cause some patients to fall suddenly or drop objects they are holding. Provoking factors include transition from sleep to wake, particularly after insufficient sleep. These may also occur in relaxation periods later in the day. Onset of seizures can occur between ages 10 and 25 years in stricter definitions, or between ages 6 and 25 years in less-strict definitions. In most patients, JME begins around puberty.

Etiology: JME, like CAE, is thought to be genetic in origin, although no single genes have been identified. Also like CAE, comorbid behavioral disturbances and psychiatric disorders are common and present in 30% to 40% of patients with JME.

Diagnosis: Myoclonic jerks are the only obligatory symptoms required to make a diagnosis of JME, although patients may also have generalized tonic-clonic seizures and, less commonly, absence seizures. The first myoclonic jerks typically precede the first generalized tonic-clonic seizure by a mean period of 3 years, although generalized tonic-clonic seizures may precede myoclonic seizures in up to 25% of patients who are ultimately diagnosed with JME. Patients may not come to medical attention until the first generalized tonic-clonic seizure occurs.

The most common EEG finding in JME is generalized bursts of rapid 4-6 Hz spike and wave discharges, and the most specific EEG finding is polyspike-wave complexes with frontocentral predominance. During a myoclonic seizure, the EEG shows a burst of spikes followed by slow waves. Photoconvulsive responses (bursts of epileptiform discharges induced by exposure to a strobe light) are common. The likelihood of positive findings on EEG is greater after sleep deprivation.

(Source: Electroencephalography (EEG): An Introductory Text and Atlas of Normal and Abnormal Findings in Adults, Children, and Infants. American Epilepsy Society 2016.)

Treatment: First-line treatment for JME in boys is valproic acid, with a response rate of up to 80%. Valproic acid should be avoided in female patients of child-bearing age because of increased risk of fetal neurologic malformations. Treatment options for women of child-bearing age with JME include levetiracetam and lamotrigine. JME is generally responsive to treatment and is traditionally considered a lifelong epilepsy condition requiring continued treatment. However, more-recent data suggest that remission is more common than previously thought, with one long-term follow-up series indicating that approximately 25% of patients were seizure-free without medications.

Infantile Spasms

Infantile spasms are a unique, age-specific, epileptic encephalopathy of early infancy. The onset of spasms is frequently associated with neurodevelopmental regression, but infants may rebound between spells. The incidence of infantile spasms is approximately 0.25 to 0.60 per 1000 live births. Peak age of presentation is 4-6 months. Early diagnosis is vital for best outcomes.

Clinical characteristics: Spasms consist of an initial contraction phase followed by a tonic phase and may be characterized as “flexor,” “extensor,” and “mixed flexor-extensor” spasms. Spasms may be symmetric or asymmetric, occur in clusters, and tend to occur around sleep-wake transitions. Initial appearance can be subtle.

Electrographic characteristics: The pathognomonic EEG pattern is hypsarrhythmia (i.e., a chaotic, high-amplitude EEG background without normal background electrical activity). Variations include modified hypsarrhythmia, in which amplitude criteria are not met. At clinical onset, EEG may be normal or demonstrate multifocal epileptiform discharges.

Etiology is the most important predictor of outcome. Infantile spasms are classified into the following two etiologic groups:

• Known (symptomatic): associated with developmental delay preceding development of spasms, prior diagnosis of epilepsy, abnormal neurologic examination, genetic/chromosomal abnormality, abnormal brain MRI

• Unknown (cryptogenic): associated with normal prior development, symmetric/ typical spasms, and normal MRI

Evaluation:

• EEG: All infants with suspected infantile spasms should receive an EEG to look for hypsarrhythmia.

• MRI: Once a diagnosis of infantile spasms is confirmed by EEG, an MRI should be performed. If neuroimaging shows a structural cause for spasms, such as lissencephaly or tuberous sclerosis, no additional workup is needed other than specific genetic testing.

• Additional testing: If MRI is normal, additional workup to identify the etiology depends on the clinical context and may include testing for infectious, metabolic, and genetic causes. Genetic causes are increasingly being identified through chromosomal microarrays and next-generation sequencing.

(Source: Electroencephalography (EEG): An Introductory Text and Atlas of Normal and Abnormal Findings in Adults, Children, and Infants. American Epilepsy Society 2016.)

Treatment: Typically, treatment depends on the etiology of infantile spasms. There is a high degree of consensus that early diagnosis and treatment improves outcomes; however, the choice of first-line agents is more controversial.

• In a recent meta-analysis of clinical trials, high-dose adrenocorticotropic hormone (ACTH, repository natural corticotropin is commonly used in the United States and synthetic tetracosactide or corticotropin carboxymethyl cellulose is used elsewhere) yielded the most favorable electroclinical outcome and likelihood of clinical remission, and statistically, oral high-dose prednisolone was as effective. The choice between these options may be guided by cost, availability, resources to monitor for adverse events, and local experience.

Treatment of infantile spasms associated with tuberous sclerosis complex (TSC) is a special case discussed below.

• ACTH: High-dose intramuscular (IM) ACTH is administered for 2 weeks, followed by a taper.

  • ACTH is a glucocorticoid hormone, and adverse effects include hypertension, irritability, increased appetite and weight gain, hyperglycemia, immunosuppression, and transient cortical atrophy.

    • Echocardiogram is recommended prior to starting ACTH because left ventricular hypertrophy may occur.

    • Adverse effects should resolve within 1-4 months after discontinuation of therapy.

    • In randomized, controlled trials, 42% to 87% of patients treated with ACTH experienced cessation of spasms. The low end of treatment response was reported in a study of low-dose ACTH, and the high end was reported in a study of high-dose ACTH. Time from initiation to cessation of spasms is typically 7 to 12 days.

  • ACTH is a very expensive medication that is administered intramuscularly. Caregivers must be trained in administration. Therefore, infants with newly diagnosed infantile spasms treated with ACTH may be hospitalized until caregivers are trained to administer it, the insurance company approves it, and delivery to the patient’s home is confirmed.

• Prednisolone: High-dose oral prednisolone is administered for 2 weeks, followed by a taper.

  • Some clinicians treat patients with infantile spasms with high-dose prednisolone, given the apparent noninferiority of prednisolone to ACTH and the significant logistic and financial issues involved in utilizing ACTH.

  • Adverse events of prednisolone are similar to those of ACTH.

• Vigabatrin is an irreversible inhibitor of gamma-aminobutyric acid aminotransferase (GABA-AT) and another treatment option for infantile spasms and has been favored for many years in the treatment of infants with TSC.

  • Vigabatrin’s effect on infantile spasms in infants with TSC is excellent, although it does not reduce the risk for other seizures or intellectual impairments in children with TSC.

  • Adverse effects include sedation, irritability, insomnia, and importantly, the development of concentric visual-field defects (reported in 10%-40% of adult patients treated with vigabatrin). Data in children on visual field defects with vigabatrin is limited. Recommendations for monitoring with ophthalmologic evaluations continue to evolve.

  • Vigabatrin can only be prescribed by providers enrolled in the Risk Evaluation and Mitigation Strategy (REMS) program required by the U.S. Food and Drug Administration.

Prognosis: Long-term prognosis for developmental outcomes in children with infantile spasms seems to depend on the underlying disease. Whether treatment improves developmental outcome is uncertain, but observational studies suggest better outcomes with early treatment.

(Source: Summary of Recommendations for the Management of Infantile Seizures: Task Force Report for the ILAE Commission of Pediatrics. Epilepsia 2015.)

Status Epilepticus

Status epilepticus is the most common neurologic emergency during childhood. Status epilepticus is typically defined as a single seizure lasting longer than 30 minutes or a series of seizures without return to baseline between seizures lasting longer than 30 minutes. Most other seizures resolve spontaneously within 5 minutes. Status epilepticus results from failure of the normal mechanisms that limit the spread and recurrence of seizure.

Treatment: Status epilepticus is potentially life-threatening. Mortality is due to respiratory, cardiovascular, or metabolic complications. In addition, seizure duration longer than 30 minutes may cause lasting neurologic impairment. A seizure that lasts longer than 5 minutes is at high risk of lasting 30 minutes or longer. Therefore, seizures lasting longer than 5 minutes should be treated acutely with medication to stop the seizure.

Basic emergency measures include supporting respiration, maintaining blood pressure, gaining intravenous (IV) access, and identifying and treating the underlying cause of the seizure. (See Altered Mental Status in the Pediatric Emergency Medicine rotation guide for assessment and management of status epilepticus in the emergency department [ED].)

Many studies in adults and children have evaluated the efficacy of initial therapy for status epilepticus. From this research, the following conclusions have been drawn:

• First-line treatment: A benzodiazepine is the first-line treatment for status epilepticus. In children, IV lorazepam and IV diazepam are established as effective for cessation of seizure activity lasting at least 5 minutes. If a seizure continues after the first dose of benzodiazepine, standard practice is to repeat the dose. Benzodiazepines are effective in terminating status epilepticus in 40% to 60% of patients.

  • Rectal diazepam, intramuscular (IM) midazolam, intranasal midazolam, and buccal midazolam are probably effective at stopping seizures lasting at least 5 minutes (IV lorazepam or IM midazolam are preferred in the ED and hospital setting at Cincinnati Children’s Hospital Medical Center). In an outpatient setting, children with established seizures are often given a prescription for rectal diazepam or intranasal midazolam for home treatment of prolonged seizures.

• Second-line treatment: If a seizure continues after two doses of benzodiazepines, providers should provide second-line treatment. Preferred second-line therapy may vary from institution to institution, or from patient to patient with established epilepsy diagnoses, depending on the patient’s current medication regimen. Phenytoin (or fosphenytoin, where available), levetiracetam, and valproic acid are common second-line agents.

  • Until recently, the evidence for second-line agents was primarily based on observational studies and expert opinion. However, recent randomized controlled trials of levetiracetam versus phenytoin for second-line treatment of convulsive status epilepticus in children have demonstrated comparable efficacy of 50% to 60% in stopping status epilepticus. In the randomized Established Status Epilepticus Treatment Trial (ESETT), IV fosphenytoin, valproic acid, and levetiracetam yielded similar efficacy in the ED treatment of patients with benzodiazepine-refractory status epilepticus.

• If the seizure does not cease with second-line therapy, management choices include an alternative second-line agent or proceeding with anesthesia. The treatment of refractory status epilepticus with anesthetics is beyond the scope of this review.

The American Epilepsy Society treatment algorithm for status epilepticus is widely used In the United States for the treatment of prolonged seizures.