Clinical manifestations

Presentation and course

The approach to a child presenting with a seizure should be systematic and begin with a thorough history. The International League Against Epilepsy (ILAE) classification system for seizures divides seizures into generalized and focal seizures (09). These may be distinguished from one another by discussion with eyewitnesses of the event. Often, families focus on the later, sometimes secondarily generalized tonic-clonic portion of the seizure and may not realize, until they are directly and explicitly questioned, that they can recall certain specifics about the earlier portions of the event. When obtaining the history, mentally dividing seizures into preictal, ictal, and postictal phases can guide questioning of the family.

Identifying preictal phenomena, such as auras, in preverbal children can be particularly challenging. Families may recall that the child attempted to seek out a parent or had an unusual behavior prior to the event, such as acting as if they had visual hallucinations. Young children may realize they are going to have a seizure, but be unable to fully describe this phenomenon. They may be helped to elaborate the description of their auras by specific questioning in age-appropriate vocabulary.

Questioning about the ictal phase of the seizure should focus on the progression of the seizure, with particular attention to any lateralizing signs that might suggest focal onset (74). These signs are often initially overlooked by the family because of the anxiety associated with the event, but they may be recalled on direct questioning. Young children are less likely to have lateralizing features, probably as a function of the immaturity of the central nervous system and relative paucity of myelinated tracks (36).

After the seizure, a postictal condition often exists including symptoms such as headache, weakness, difficulty concentrating, confusion, fatigue and, in rare cases, even psychosis. The more frequently a child has seizures and the longer a particular seizure, the more likely the child is to experience postictal symptoms. Rest in a quiet place can be an alleviating factor. These symptoms should not be ignored as they can interfere with a child’s normal functioning and ability to return to normal childhood activities. This could impact school performance and social interactions (76).

Data have been reported for classification by EEG of seizure semiology in newborns (86). The postictal phase can also provide clues to the type of seizure with which the patient presented, as patients with focal seizures are more likely to have persistent focal or lateralized deficits.

Discussing the circumstances under which the event occurred can help to identify provoking factors. Fever, sleep deprivation, history of stroke, and head injury may all be associated with an increased risk of a seizure in childhood (13). Adverse effects of medications such as GABA antagonists can be a provoking factor. It is important to note not only the child’s medications but also the mother’s medications if she is breastfeeding the child (52). In contrast, certain other factors favor onset of nonepileptic events, such as breath-holding, syncope, or stereotypy. Events associated with a positional change or physical exercise are less likely to be epileptic in nature.

Identification of risk factors for seizures is important. A history of recent head trauma or febrile illness will likely alter the approach used to assess the patient. A strong family history of epilepsy can sometimes be useful in diagnosing seizures, particularly in the neonatal period. Parents may be unaware of their family history, and obtaining it from a grandparent can lead to unexpected, useful findings.

The birth history is critical in caring for patients with seizures, as it may clarify the etiology of seizures in neonates and may suggest risk factors for epilepsy in older children. Children with a neurologic abnormality at baseline are more likely to have recurrent seizures, and developmental regression should always be met with significant concern by the physician (08; 15).

Prognosis and complications

The prognosis of a child who presents with a single seizure is generally favorable, with a 40% to 50% chance of a seizure recurring within 2 years. An abnormal EEG or neurologic examination, or a symptomatic cause, appear to be important risk factors for an increased risk for recurrence, whereas other factors, such as seizure type or sleep state, are inconsistently associated with an increased recurrence risk. The recurrence rate for the low-risk group without the above-mentioned factors is moderately low (less than 30%) and increases to about 70% with both risk factors (08). A study looking only at children with nonsyndromic seizures identified seizure outcome at 2 years (remission, pharmacoresistent) and underlying etiology to help distinguish which patients would achieve remission (10). Also, higher age at onset was associated with lower rates of remission.

Clinical vignette

A 5-year-old male presented with multiple episodes of staring, lasting several seconds and interrupting activities. He was otherwise a healthy child with no medical problems or seizure risk factors, including negative family history. Hyperventilation in the office induced a 6-second staring spell associated with repeated eye blinking, during which the patient was not responsive, and afterwards the patient did not remember the event. EEG demonstrated multiple bursts of 3 Hz generalized spike-wave discharges, especially during hyperventilation. Because his neurologic exam was normal, no brain imaging was done. The child was diagnosed with childhood absence epilepsy and treated with ethosuximide. After 2 years of treatment without any seizures, a repeat EEG was done and was normal, and the child was weaned off ethosuximide without recurrence of seizures.

Biological basis

Localization

The thalamocortical system is critical in generating the generalized spike-and-wave discharges seen in primary generalized seizures, such as in absence epilepsy (12; 72). Focal onset seizures often have typical features representing the functions of the lobe involved. Frontal lobe seizures typically present with motor phenomena, such as tonic, clonic, hypermotor, or bilateral asymmetric tonic movements, whereas occipital lobe seizures may present with visual phenomena. Interestingly, some thalamic nuclei appear involved in partial epilepsy and have become the targets for experimental therapy using electrical stimulation (12).

Etiology and pathogenesis

The diverse morphologies of seizures and types of epilepsy reflect the numerous etiologies associated with these phenomena. There is no unifying pathophysiology except for the proximate increase in cortical excitability and hypersynchrony associated with seizures. Numerous changes are occurring at various levels in the developing brain, which likely accounts for the higher incidence of epilepsy in childhood. Higher levels of excitatory receptor expression in the neonatal brain are felt to be a factor for hyperexcitability and the ease of seizure generation (106; 120). In addition, maturational changes in various neuronal membrane-bound receptors are thought to impact the response of neonatal seizures to therapy and are exemplified by the developmental shift in cation chloride cotransporters from NKCC1 to KCC2 and the associated paroxysmal GABA-mediated excitation in response to therapy that is typically seizure suppressive (30; 21).

Genetic mutations have been identified in a number of idiopathic epilepsy syndromes. The initial reports of a mutation in the neuronal nicotinic acetylcholine receptor in autosomal dominant nocturnal frontal lobe epilepsy opened the door for the identification of other mutations leading to epilepsy (34). Many mutations lead to a hyperexcitable state through either decreased inhibition in networks or increased excitation. Sodium, potassium, and calcium channel mutations, along with mutations in GABA and acetylcholine receptors, have all been implicated as a cause for various idiopathic epilepsy syndromes (54; 21; 48). A wide spectrum of disease may be seen with mutations in the same channel, including mutations in SCN1A sodium channel associated with both the devastating Dravet syndrome (ie, severe myoclonic epilepsy of infancy) and the relatively benign generalized epilepsy with febrile seizures plus (GEFS+) (42; 32; 28; 17). Microarray analyses and epilepsy panels are currently contributing to the database of genetic changes seen in epilepsy patients, although the interpretation of the alterations is not always clear and demonstrates that epilepsy is multifactorial (84). It is important, however, to realize that patients with identifiable monogenetic mutations causing epilepsy constitute a small minority and that many other genes other than channels can be involved in the predisposition to seizures (102; 46; 105). Also, the ever-expanding list of genes included in the available epilepsy panels has demonstrated that many patients harbor mutations that may in part be causative for their seizure disorder (100; 107).

Pathophysiology

Testing may demonstrate abnormal discharges on EEG (epileptiform discharges, slowing, etc.), abnormality in brain imaging such as congenital malformations (heterotopias, polymicrogyria, schizencephaly, etc.), acquired abnormality (stroke, vascular malformation, etc.), genomic and/or metabolic abnormalities, or abnormal findings on neurologic exam, or all of these tests may be normal. Abnormalities on any of these tests increases the risk of seizures and may reduce the likelihood that the child will outgrow their epilepsy because they may imply symptomatic etiology (Bert et al 2001; 112).

The diverse morphologies of seizures and types of epilepsy reflect the numerous etiologies associated with these phenomena. There is no unifying pathophysiology except for the proximate increase in cortical excitability and hypersynchrony associated with seizures. Numerous changes are occurring at various levels in the developing brain, which likely accounts for the higher incidence of epilepsy in childhood. Higher levels of excitatory receptor expression in the neonatal brain are felt to be a factor for hyperexcitability and the ease of seizure generation (106; 120). In addition, maturational changes in various neuronal membrane-bound receptors are thought to impact the response of neonatal seizures to therapy and are exemplified by the developmental shift in cation chloride cotransporters from NKCC1 to KCC2 and the associated paroxysmal GABA-mediated excitation in response to therapy that is typically seizure suppressive (30; 21).

Genetic mutations have been identified in a number of idiopathic epilepsy syndromes. The initial reports of a mutation in the neuronal nicotinic acetylcholine receptor in autosomal dominant nocturnal frontal lobe epilepsy opened the door for the identification of other mutations leading to epilepsy (34). Many mutations lead to a hyperexcitable state through either decreased inhibition in networks or increased excitation. Sodium, potassium, and calcium channel mutations, along with mutations in GABA and acetylcholine receptors, have all been implicated as a cause for various idiopathic epilepsy syndromes (54; 21; 48). A wide spectrum of disease may be seen with mutations in the same channel, including mutations in SCN1A sodium channel associated with both the devastating Dravet syndrome (ie, severe myoclonic epilepsy of infancy) and the relatively benign generalized epilepsy with febrile seizures plus (GEFS+) (42; 32; 28). Microarray analyses are currently contributing to the database of genetic changes seen in epilepsy patients, although the interpretation of the alterations is not always clear and demonstrates that epilepsy is multifactorial (84). It is important, however, to realize that patients with identifiable monogenetic mutations causing epilepsy constitute a small minority, and that many other genes other than channels can be involved in the predisposition to seizures (102; 46; 105).

Chronic inflammation has been shown to have an impact on numerous chronic diseases. In childhood epilepsy, increased interleukin-6, interleukin-8, and high sensitivity C-reactive protein levels along with lower IL-1RA/IL-6 ratio could affect prognosis and explain some of the variability in severity of symptoms (57; 41). The gut-brain axis has also been implicated in chronic inflammation and could have an effect on cases of drug resistant seizures (33).

Epidemiology

Epilepsy is one of the most frequent neurologic diseases in children and adolescents, with a prevalence of 4 to 6 cases per 1000 children (Ünver et al 2015). Febrile seizures are defined as occurring between 6 months and 5 years of age and occur more commonly in children with a family history of febrile seizures or epilepsy. Symptomatic epilepsies are more common in children with abnormal developmental delay or cognitive impairment, abnormal brain imaging, or abnormal neurologic exams. Idiopathic epilepsies are most likely multi-factorial to include genetic and environmental factors. The age associated with the highest risk for seizures is the neonatal period (106), and the risk gradually declines towards that of adults by the end of the first decade of life. Epilepsy incidence and prevalence are higher in underdeveloped countries compared to developed countries, with rural areas having higher numbers than urban areas (16; 118).

Differential diagnosis

Confusing conditions

A variety of nonepileptic events can be confused with seizures and epilepsy. Table 1 lists some of the more commonly seen mimickers of seizure activity (60; 27; 93; 122; 05).

Table 1. Differential Diagnoses for Seizures

Diagnosis	Age of presentation	Characteristics
Jitteriness	Neonates	Fine tremor movements that are suppressible.
Sleep myoclonus	Neonates	Sudden muscle contractions occurring during drowsiness and light sleep.
Hyperekplexia	Neonates to early childhood	Exaggerated startle due to glycine receptor mutations.
Benign infantile shuddering	Infancy and early childhood	Bilateral movement of the arms and shoulders lasting a few seconds without loss of awareness.
Breath-holding spell	Infancy and early childhood	Precipitated by fear or frustration with vigorous crying followed by breath-holding on exhalation (cyanotic), or occurs after minor injury without crying (pallid).
Gastroesophageal reflux (Sandifer syndrome)	Infancy and early childhood	May present with dystonic head posturing or opisthotonus, apnea, laryngospasm, bradycardia, or abnormal eye movements. Often occurs in relation to feeds.
Night terrors	Early childhood	Typically occur during slow-wave sleep with sudden onset of screaming with bizarre movements and altered awareness (first part of the night).
Self-gratification phenomenon	Early childhood	More commonly occurs in girls. May present with autonomic signs and is usually distractible.
Rage attacks	Early childhood	Goal-directed violent outbursts that are provoked.
Syncope	Any age	May be provoked with change in position or specific situations (hair grooming). Typically with autonomic symptoms.
Motor tics	School-aged children	Stereotyped nonrhythmic movements that are often suppressible and disappear during sleep.
Complex migraine	Childhood to teenage years	May have hemiplegia, vision loss, vertigo, paresthesias, ataxia, confusion, or other symptoms.
Paroxysmal dyskinesia	Childhood to teenage years	Episodic dystonic or choreic movements that may be precipitated by sudden movement or stress. There is no loss of awareness.
Narcolepsy	Typically teenage years	Associated with sleep paralysis, sleep attacks, hallucinations, and cataplexy.
Non-epileptic seizures	Teenage years	More frequent in girls. Occur during wakefulness. Often prolonged with gradual onset and bizarre movements.

In patients presenting for evaluation of seizure activity, 2 studies found discordant numbers of patients with nonepileptic spells. The study by Hindley and colleagues found that 77% of patients had events other than epileptic seizures whereas only 24% of patients evaluated by Hamiwka and colleagues were classified as having nonepileptic events (53; 49). One of the difficulties with interpreting these data is that even specialists in pediatric epilepsy can have significant misdiagnosis rates after a patient has had only a single seizure (15). Syncope was the most common nonepileptic event in both studies. In another retrospective review of 10 years of video-EEG data for evaluation of paroxysmal events, 43% of the subjects had nonepileptic events (14). Nonepileptic staring was the most common diagnosis whereas benign sleep phenomena were the next most common.

Events thought to be epileptic that fail to respond to appropriate treatment should be evaluated with video-EEG monitoring to ensure that the events are properly classified. If video-EEG monitoring is readily available, patients with a normal routine EEG and paroxysmal events suspicious for seizures should be considered for video-EEG monitoring before the institution of therapy, in an effort to capture an event. Although psychogenic, nonepileptic spells are commonly encountered in adults; they do not represent a large proportion of events in children. They are more likely to be encountered in teenagers than in younger children (67). Early identification and treatment of non-epileptic seizures is important, leading to both decreased medical costs and improved patient outcome (45; 82).

Associated and underlying disorders

Detailed discussion of all of the epilepsy syndromes is beyond the scope of this clinical summary; however, some epilepsy syndromes present frequently enough to warrant further discussion.

The risk of developing a seizure is highest during the neonatal period (106). Unlike seizures in adults and older children, the semiology may include subtle automatisms such as bicycling or chewing, which are easily missed and may be difficult to distinguish from normal neonatal behaviors (86). Electroclinical dissociation, in which patients exhibit no clinical signs despite clear electrographic seizures, or in which patients exhibit behaviors suspicious for seizures without electrographic correlate, is commonly seen in neonates and stresses the importance of EEG (93). Suppression of events by restraint suggests that the events in question may not be epileptic in nature (108). Although phenobarbital is the medication most commonly used for treatment of neonatal seizures, it may adversely affect the developing brain, and levetiracetam is now used by many neonatal intensive care units (62; 117; 123; 83).

Benign familial neonatal seizures typically present during the neonatal period, with about 50% presenting in the first week of life. Clonic or focal seizures are most commonly seen and typically last less than 2 minutes. The EEG does not have a characteristic pattern of abnormality, but may show focal epileptiform activity or slowing (79). Mutations in the voltage-gated potassium channel subunit KCNQ2, or much less commonly KCNQ3, have been associated with benign familial neonatal seizures (35; 02). Mild delayed psychomotor development may be seen in up to 40% of cases (110), and there is a higher long-term rate of epilepsy (79). In contrast, benign idiopathic neonatal seizures often present with focal status epilepticus (often alternating sides), classically on the fifth day of life, and are not associated with genetic mutations, and long-term risk for epilepsy and developmental delays are negligible (93). Benign familial infantile seizures are an autosomal dominant disorder characterized by clusters of afebrile seizures presenting in the first year of life and usually resolving by 2 years of age, occurring in otherwise well infants with normal interictal MRIs and EEGs, and has been demonstrated to be due to mutation in the PPRT2 gene (47). In reality, the semiology of these syndromes can overlap, and it is probably more accurate to define the infant by the genetic mutation rather than the epilepsy syndrome.

West syndrome commonly begins in infancy between 4 and 7 months of age (with more than 90% of onset by 12 months) and consists of the triad of infantile spasms, hypsarrhythmia on EEG, and developmental delay. The seizures are stereotyped and consist of brief tonic extension or flexion of the extremities and trunk that often recur in clusters, usually on arousal. They are often misdiagnosed initially as gastroesophageal reflux, but their lack of relation to feedings and their stereotyped nature suggest the diagnosis. Infantile spasms are often accompanied by a decline or plateau in development. The EEG typically demonstrates a hypsarrhythmic pattern of high-voltage, disorganized background with multifocal and generalized spike-wave discharges. An etiology is found in approximately 80% of patients (39). Treatment classically has been with high dose adrenocorticotropic hormone (ACTH), although data have demonstrated that high-dose oral steroids or low-dose ACTH protocols may be equally effective (95; 44; 56; 66).

Febrile seizures constitute a special syndrome in the ILAE classification. They occur in children between 6 months and 5 years of age and are considered simple (duration less than 15 minutes, generalized semiology, and do not recur within 24 hours) or complex (about 30% to 40% of febrile seizures; duration longer than 15 minutes, focal or lateralizing semiology, or recur within 24 hours) febrile seizures. There is increased risk of recurrence in children who have a family history of febrile seizures, or who have febrile seizures with a low magnitude of fever or beginning before 12 months of age (104). Febrile seizures are considered benign and self-limited, and at least for simple febrile seizures, evaluation with EEG or neuroimaging is not recommended, and pharmacologic treatment is generally not indicated (113). Unlike simple febrile seizures, complex febrile seizures are associated with an increased risk of epilepsy, although studies suggest the risk is very small (104). Although no guidelines for the evaluation and treatment of complex febrile seizures have been established, the yield of EEG and neuroimaging has been shown to be very low overall, suggesting that these studies should not be routinely performed (50; 64). The exceptions would be children presenting with focal seizures, abnormal neurologic exams or development, or a family history of epilepsy; in these children, EEG and neuroimaging studies should be considered. Furthermore, the yield of lumbar puncture in these children is equally low in the absence of other signs or symptoms of bacterial meningitis (64). Khair and Elmagrabi review old and current knowledge of febrile seizures (61).

Lennox-Gastaut syndrome is a challenging epilepsy encephalopathy syndrome that often follows a history of infantile spasms and is typically encountered in children from 3 to 5 years of age. The syndrome consists of a mixture of seizure types, including myoclonic, atonic, nocturnal tonic, and atypical absence seizures. The EEG characteristically demonstrates generalized slow spike-wave complexes (less than 2.5 Hz) and bursts of generalized fast rhythms of 10 to 12 Hz during sleep. A symptomatic etiology is encountered in approximately 75% of patients. The seizures are typically frequent and refractory to treatment, and at least moderate mental impairment is observed in more than 85% of patients (18; 81). Ketogenic diet and vagal nerve stimulator are treatment options that may be effective when combined with multi-drug antiepileptic medication combinations (01).

Childhood absence epilepsy (CAE) typically begins in school-aged children, with a peak incidence at about 6 years of age. Patients typically present with recurrent absence seizures consisting of brief episodes of behavioral and motor arrest associated with unresponsiveness. Oral and motor automatisms are seen in almost 40% of patients with absence seizures (101). Differentiation from nonepileptic staring can sometimes be difficult, but seizure induction with bedside hyperventilation strongly suggests the diagnosis. An EEG demonstrating 3 Hz generalized spike-wave activity is important in differentiating absence seizures from nonepileptic staring. One study demonstrated the superiority of ethosuximide as the optimal initial empiric treatment (43), whereas another study demonstrated that the low dose valproic acid and lamotrigine combination was superior to any monotherapy (63). In the absence of generalized tonic-clonic seizures or myoclonus, prognosis is good, and most children achieve seizure remission (103).

Benign epilepsy with centrotemporal spikes (ie, benign rolandic epilepsy, BECTS) is the most common idiopathic partial epilepsy presenting in childhood and constitutes nearly 20% of all childhood epilepsy (85). The usual age of onset is usually around 7 to 10 years old, and remission is usually within 2 to 4 years of onset or before the age of 16. Nocturnal seizures with unilateral facial or extremity clonic activity and hypersalivation are the characteristic semiological features. Patients may be aphasic or dysarthric and may seek out family members, as consciousness is maintained in about 50% of patients. Nocturnal seizures alone occur in about 75% of patients with BECTS and are generally infrequent, favoring observation over treatment in the majority of cases. The EEG has a typical pattern of high-amplitude spike and slow-wave complexes in the centrotemporal region (C3-C4 or C5-C6), usually bilateral and more abundant during non-REM sleep (93). Studies have demonstrated a high prevalence of attention deficit hyperactivity disorder (ADHD), cognitive deficits, and behavioral abnormalities in these children (116), especially reading and phonological processing deficits (109). Children have shown altered behavioral responses and lowered fMRI activity in response to exposure to fearful faces, suggesting delayed social cognition network development in affected children (20). Focal epilepsies are common in family members of children with benign childhood occipital epilepsy syndrome, suggesting complex genetic inheritance (119). Prognosis is excellent irrespective of treatment (03).

Early-onset benign childhood occipital epilepsy (also referred to as Panayiotopoulos syndrome) is a less common idiopathic epilepsy occurring in about 2% of patients (93). This syndrome typically begins between 3 and 6 years of age and is characterized by significant autonomic symptoms, including emesis, pallor, mydriasis, and syncopal symptoms. Although consciousness is initially retained, eye deviation, speech arrest, and progressive confusion are frequently associated with the seizure. The seizures tend to be prolonged, usually lasting more than 6 minutes, with about half lasting more than 30 minutes. The majority of children have only a single or small number of seizures, and remission is within 1 to 2 years. The EEG will show multifocal high-amplitude sharp-slow-wave complexes in about 90% of patients occurring anywhere on the EEG (93; 48; 126). In contrast, late-onset idiopathic occipital epilepsy (of Gastaut) is a purely occipital lobe epilepsy occurring in children, with a mean onset around 8 years old. The seizures consist of elementary visual hallucinations and/or blindness, and the EEG typically shows occipital paroxysms. Postictal headache is common, and misdiagnosis of patients as migraine with aura is common (19; 93).

Juvenile myoclonic epilepsy (JME) typically presents in the late teenage years, and myoclonus may often be overlooked prior to the patient presenting with a generalized tonic-clonic seizure. The EEG typically demonstrates generalized fast 4 to 6 Hz spike-wave and polyspike-wave activity, and photosensitivity is seen in about 30% of patients. Treatment is indicated for all patients, and studies indicate the risk of recurrence is high, suggesting that later tapering of the medications is unfavorable (128). Genetic studies have shown that juvenile myoclonic epilepsy is inherited in autosomal dominant fashion, and heterozygous mutations in myoclonin 1/EFHC1 (a microtubule-associated protein) have been shown to cause classic juvenile myoclonic epilepsy (26), as well as mutations in GABA receptors and chloride channels, both important for inhibition (22). There is genetic overlap with generalized epilepsy with febrile seizures plus (GEFS+), juvenile absence epilepsy (JAE), and childhood absence epilepsy (CAE), with various members of the same family manifesting these disorders (124).

In their study, Park and colleagues provide a comprehensive review of pediatric epilepsy syndromes and seizures (94).

Diagnostic workup

Evaluation of the patient presenting with new-onset seizures should be considered in relation to the history and presenting clinical picture. Patients presenting with signs and symptoms of infection will need a different evaluation than patients who are afebrile. After 2 confirmed seizures, the child’s condition can be classified as childhood epilepsy according to the International League Against Epilepsy guidelines. Further classifications may be made with follow up (118).

Children with simple febrile seizures present a unique situation with clear guidelines. A febrile seizure is defined as occurring in otherwise healthy children aged 6 to 60 months old with a documented fever greater than or equal to 100.4°F. Simple febrile seizures are further defined as generalized, occurring only once in 24 hours, and lasting less than 15 minutes in length. Lumbar puncture should be performed in any child with a seizure and fever that has physical exam findings suggestive of meningitis (such as neck stiffness or persistent encephalopathy). In children aged 6 to 12 months of age, lumbar puncture should be considered if immunizations are not up-to-date (or status is unknown). Furthermore, lumbar puncture should be considered in all children pretreated with antibiotics who present with a seizure in the setting of fever due to the risk of partially treated meningitis. Neuroimaging, EEG, and routine blood tests are typically unrevealing and should be performed only in the presence of strong clinical indicators. Any testing beyond the decision to perform a lumbar puncture should be to identify a source for the fever, rather than because the child had a febrile seizure (113).

Similarly, well-appearing patients presenting with unprovoked seizures rarely need extensive testing in the emergency department, where they frequently present. Lumbar puncture and metabolic testing are of limited value except in cases in which the history suggests a metabolic, infectious, or neurodegenerative problem (55). A lumbar puncture is recommended in children under 6 months of age, with persistent alteration of consciousness, or with any meningeal signs. A study showed that 0 of 76 afebrile well-appearing infants younger than 6 months of age had confirmed meningitis or encephalitis, and thus, the authors felt that the CSF analysis was not warranted in well-appearing afebrile infants with new-onset seizures (73). Toxicology screening is recommended for all ages if there is any concern for drug or chemical exposure (55).

An EEG has been recommended for all children with a first afebrile seizure (55). Studies primarily in adult patients suggest that an earlier EEG increases the yield of capturing interictal findings, but feasibility can be an issue (65; 92). Common EEG findings for self-limited idiopathic focal epilepsy are characterized by stereotyped sleep-activated centrotemporal sharp waves, occipital sharp waves, or less commonly, bilateral occipito-frontal sharp waves (125). Emergent EEGs are primarily used when there is concern for ongoing seizure activity and often lack useful provoking procedures, such as hyperventilation and photic stimulation. In addition, the patient may have received medications or have postictal EEG changes that can make determination of the typical background activity difficult. Sleep-EEG recordings can be valuable in diagnosing and classifying epilepsy, and it can be challenging to obtain a sleep tracing in the emergency room (11; 59).

Neuroimaging is not recommended for children with a simple febrile seizure (113). In addition, in idiopathic epilepsies such as absence epilepsy or benign epilepsy with centrotemporal spikes, neuroimaging studies are typically of limited value. Neuroimaging should be considered, however, in all patients with localization-related epilepsy (by history or EEG), abnormal neurologic examination including developmental delay, or age less than 2 years old (40; 99). MRI is the preferred imaging modality and is favored over CT except when there is concern regarding an acute etiology for the seizure, as suggested by prolonged altered mental status or focal neurologic deficit (55; 40). In fact, a study of over 600 children with first unprovoked seizure demonstrated that 11% had an intracranial abnormality detected by neuroimaging, but less than 1% required urgent imaging (24). ). In patients with intractable epileptic infantile spasms, PET scans may reveal focal abnormalities that are not detected by conventional neuroimaging and may contribute to the presurgical planning and postsurgical prognostication for such patients (98).

The utility of routine electrocardiographic (ECG) screening of pediatric patients presenting with a seizure has not been studied systematically. Patients with cardiac symptoms or a seizure with exertion, however, should undergo a screening ECG to evaluate for cardiac arrhythmia because syncope associated with long QT syndrome can often be mistaken for convulsive syncope or followed by a seizure (23; 75).

Management

Management of seizures presenting in childhood is based on the risk of recurrence versus the potential side effects of antiepileptic medications. For example, febrile seizures may be reduced with prophylactic therapy, but the minimal risks associated with febrile seizures do not outweigh the potential side effects from treatment (29). Furthermore, treatment with antipyretics has not been shown to be effective for preventing febrile seizures, and therefore, is not recommended (111). A Cochrane review failed to demonstrate the benefit of any medications for the prevention of febrile seizures, and thus, parents should be discouraged from using over-the-counter medications to prevent these due to the higher risk associated with medication overuse (90).

For those patients deemed at a high risk of recurrence, treatment is based on the seizure type or epilepsy syndrome (if classifiable). There are limited randomized controlled data comparing various antiepileptic drugs in children with epilepsy, making treatment decisions challenging. Certain medications, such as ethosuximide, offer a narrow spectrum of prevention of seizures, whereas other medications often offer a wider spectrum of protection. When choosing a medication, certain factors can play an important role in determining which may be the best choice for an individual patient. Factors such as effectiveness, dosing (once a day compared to multiple times per day), formulation, cost, and side effects can all influence which medication should be prescribed.

Neonatal seizures are typically treated with phenobarbital due to the favorable pharmacokinetic profile compared to phenytoin, but both have been shown to be equally effective (91). Levetiracetam has also been shown to be safe and effective in neonates and is becoming widely used (62). ACTH or high dose oral steroids are the treatment of choice for infantile spasms, except in patients with tuberous sclerosis where vigabatrin has proven effective (95). Absence seizures are particularly responsive to ethosuximide, whereas valproic acid and lamotrigine may be used alternatively, especially if both absence and tonic-clonic seizures are present (43). In adults, generalized seizures are often treated with valproic acid, and it appears to be more effective than other medications (78). The side-effect profile of valproic acid in children and adolescents, however, makes levetiracetam, lamotrigine, topiramate, and zonisamide attractive alternatives in these age groups. Partial seizures are treated nowadays with newer generation medications, ie, oxcarbazepine, lamotrigine, and topiramate, because they have been shown to be equally efficacious to, and perhaps more benign than, the traditionally used drugs carbamazepine, phenobarbital, phenytoin, and valproic acid (37).

For patients with no insurance coverage and limited resources, consideration of cost helps ensure compliance with medications. Although phenobarbital, valproate, and carbamazepine have the potential for more side effects, they are very inexpensive compared to newer antiepileptic agents. In areas of limited treatment choice and medication accessibility, dietary therapy such as the ketogenic diet may have potential as a sustainable alternative for children with drug-resistant epilepsy (87).

Providing families with abortive therapy, such as rectal diazepam gel, can be very reassuring, and both reduce anxiety and prevent prolonged status epilepticus. Abortive therapy may provide parents with a feeling of empowerment over a frightening condition and give them the confidence to allow children to travel or participate in activities that would otherwise be avoided (89). Concern for injury to the child may lead to overprotection by the family, with parents looking to the physician for guidance on limitations of activities to help prevent injury during a seizure. Avoidance of unsupervised activities around water and the preference of showers over baths are prudent. The use of a helmet when riding a bicycle is recommended for all children and should be reinforced (15). Because the risk of recurrence is most commonly within the first 6 months to 1 year, special restrictions should be discouraged beyond this time frame. A study demonstrated that adequate education and support to families to help them deal with the possibility and then occurrence of future seizures can have a dramatic positive impact on improved quality of life for the family and patient (04).

In the emergency department, intravenous diazepam and, when intravenous access cannot be obtained, intramuscular midazolam are among the drugs used to treat prolonged or multiply recurrent seizures. When comparing the 2 drugs, intramuscular midazolam achieves more rapid cessation of the seizures (97).

Adolescents of driving age should be instructed not to drive until cleared by their local department of motor vehicles. The decision to start medications in adults and driving adolescents and the decision on when to wean medications may be tempered by the desire of the patient to drive and the burden of loss of driving privileges due to a recurrence of seizure activity (68).

For patients with medically intractable epileptic infantile spasms, surgical resection of an epileptic focus may be considered, particularly if neuroimaging reveals a focal onset. The goal of surgical resection may be curative or palliative depending on the epileptogenic focus (98). Neurostimulation modalities including vagal nerve stimulation, responsive neurostimulation system (RNS system), and open-loop deep brain stimulation have been considered as potential therapeutic alternatives to surgical approaches in children (07).

Outcomes

Although treatment with antiepileptic medications is associated with a reduction of seizure recurrence, no study has demonstrated that antiepileptic drug treatment alters long-term outcome (77; 121; 25). In addition, a randomized trial demonstrated that the quality of life of patients who were started on early treatment versus deferred treatment was no different, presumably due to side effects of the medications (77). For those who wish to wean off of their treatments, individual risk should be calculated based on factors such as epilepsy duration before remission, seizure-free interval before withdrawal, number of seizures before remission, family history, sex, whether the seizures are focal or not, and number of antiepileptic drugs taken before withdrawal (71). Families often worry about their child dying during a seizure, but studies addressing the risk of sudden unexpected death in epilepsy (SUDEP) suggest that it occurs in about 1 out of 4500 children and 1 out of 1000 adults (51). The risk factors and pathophysiology for SUDEP are still being elucidated but include drug resistant epilepsy, longer time with epilepsy, and older age (114; 127; 88), and families should generally be reassured by the rarity of this outcome (15). Although brain MRI and EEG can assist with determining risk of recurrence after a first seizure, there is still controversy about what abnormalities predispose to seizures and the role of these studies in patients with a single seizure (96; 80). For patients with multiple seizures, important factors to determine length of treatment include response to therapy, total number of seizures, presence of intellectual disability, ability to tolerate medical therapy, family history, and others (06; 112). In a long-term follow-up (5 to 10 years) of children in Sweden who previously underwent surgical resection for drug-resistant focal epilepsy, 50% of children became seizure-free, with 86% no longer requiring antiepileptic medication (31). Seizure-free outcomes may vary depending on the surgery type; however, there is reasonable evidence to consider curative and palliative surgery on a case-by-case basis (115; 98). A single center retrospective study of responsive neurostimulation system implantation in 6 pediatric patients provides promising results in the use of neurostimulation modalities to reduce seizure burden and improve quality of life in children with drug-resistant focal epilepsy (07). One study of 2 pediatric patients with drug-resistant epilepsy secondary to Lennox-Gastaut Syndrome and autism spectrum disorder resulted in 75% to 99% clinical seizure reductions in less than 1 year of follow-up with responsive neurostimulation system implantation (69).

Special considerations

Pregnancy

The treatment of pregnant patients with epilepsy is complicated by the fact that many of the antiepileptic medications can cause birth defects. Any pregnant patient should be treated with caution, and the risks and benefits of each medication should be discussed between the patient and the patient’s obstetrician (70).

Anesthesia

Anesthesia is generally safe in epilepsy patients; the main complication is the need to take nothing by mouth prior to receiving anesthesia and, thus, the potential of missed medication doses leading to breakthrough seizures (58).