Clinical manifestations

Presentation and course

	• When gathering history, emphasis should be on the initial symptoms reported by the child or initial signs observed by a witness.
	• Evaluate for risk factors that may increase a child’s propensity towards having epilepsy, including family history of epilepsy, history of central nervous system infections, prior stroke or traumatic brain injury, or autism spectrum disorder.
	• Screen for features in the history that may decrease seizure threshold for a particular seizure event, such as fever or sleep deprivation.

The approach to a child presenting with abnormal involuntary movements or other stereotyped, involuntary symptoms should be systematic and begin with a thorough history. The first symptoms of an event that are noticed or reported are crucial for determining seizure type (based on the 2017 ILAE classification system for seizures) or whether a paroxysmal event is a seizure. Often, families focus on the later evolution of the seizure, especially the bilateral tonic-clonic portion. Direct and explicit questions about what is first noticed when a seizure starts, whether any asymmetry in the side of the body is involved, or whether the child reports any warning symptoms (such as a rising sensation from the abdomen or epigastric reason, or auditory or vision changes) leading into the seizure are important. When obtaining the history, dividing the description of observations into the prodrome, auras, seizure (ictal phase), and postictal phase can guide questioning of the family and child.

Identifying prodromal symptoms, sensations that can precede the seizure by several minutes or hours, and “warning” symptoms called auras (which are actually the very beginning of a seizure) immediately leading into the more obvious seizure symptoms can be challenging, particularly in nonverbal children. A child may seek out a parent, have a look of fear, or act in a different way (eg, a child with vision changes as part of their seizure semiology may look up as if they are seeing things). A child may have an aura that is vague or difficult to describe. Giving examples of auras or identifying the part of the body in which they have a sensation can be helpful, though caution is needed to not inadvertently ask leading questions.

Questioning about the remainder of the ictal phase should focus on the progression of the seizure, with particular attention to any lateralizing or localizing signs that might suggest focal onset (67). Examples of lateralizing signs include versive head turn with gaze deviation, motor movements or sensory changes involving only one side of the body, side of last clonic jerk, dystonic posturing of one hand with manual automatisms in the other hand, or aphasia (or preserved speech).

The postictal phase refers to the period after the seizure. There are some lateralizing postictal signs as well, such as postictal nose wipe (referring to the ipsilateral temporal lobe), postictal aphasia (referring to the dominant temporal lobe), and Todd paralysis (contralateral hemisphere involving the motor cortex). Other postictal symptoms include headache, generalized weakness/malaise, difficulty concentrating, emesis, confusion, fatigue, and, in rare cases, even psychosis. These symptoms and their duration are important to note as they can also impair or disrupt the child’s ability to return to normal activity, negatively impact school performance and social interactions, and result in an overall worsening of the child’s quality of life (71; 43; 72).

Identification of risk factors for developing epilepsy is an important aspect of history taking. These include, but are not limited to, a personal prior history of stroke (commonly occurring in the perinatal period) or traumatic brain injury, known diagnosis of autism spectrum disorder, history of prior central nervous system infections (like encephalitis), and family history of epilepsy (13; 96; 73). Known structural cortical brain abnormalities, whether congenital or acquired, may increase the risk of developing focal or multifocal epilepsy. People with autism spectrum disorder are more likely to develop epilepsy than those without autism spectrum disorder (median overall period prevalence of 11.2%), and people with epilepsy have a higher likelihood of having autism spectrum disorder (median overall period prevalence of 8.1%) compared to the general population (for which the prevalence of autism spectrum disorder is approximately 0.8%) (68). Family history of epilepsy is also a relevant risk factor and can sometimes guide etiologic work-up. For example, in neurotypically developing infants with new-onset seizures and a family history of other relatives with self-limited epilepsy in infancy, genetic testing would be performed to evaluate for pathogenic variants in PRRT2 (associated with self-limited familial infantile epilepsy), likely in addition to neuroimaging but, in some cases, foregoing an extensive metabolic work-up. Birth history is critical in caring for patients with epilepsy as it may clarify the etiology of seizures in neonates and may suggest risk factors for epilepsy in older children. Examples of pertinent neonatal history include intraventricular hemorrhage in prematurity, traumatic delivery, and episodes of significant hypoglycemia. Developmental history is also important to consider. Early life hand preference should also be screened for, as it may suggest an early life stroke. Developmental delays and developmental regression are also important to screen for as they will also guide the etiologic work-up (ie, genetic or metabolic causes may be more likely in a person with epilepsy who also has developmental delays or regression).

Moreover, to distinguish whether a child has had a seizure as the initial presentation of their epilepsy versus a simple or complex febrile seizure versus another type of symptomatic seizure, evaluation for factors that could have decreased seizure threshold in that particular instance is also needed. For example, fever or other signs and symptoms of illness and sleep deprivation can increase the risk of seizure in any person, especially in someone with epilepsy. When a child with a known diagnosis of epilepsy on medication has a breakthrough seizure, knowing whether there was a trigger for that seizure plays a role in determining whether a medication change is indicated. Adverse effects of medications, such as GABA antagonists (ie, flumazenil), rapid withdrawal of GABA agonists (ie, alcohol withdrawal), or medications such as certain antibiotics (ie, cefepime) (58) or antidepressants (ie, bupropion) (20; 94), can cause seizures or lower seizure threshold. It is important to note the child’s medications; in cases in which the child is being breastfed, the mother’s medications are also relevant (48).

In contrast, nonepileptic events may be associated with factors such as positional changes (as in vasovagal syncope) or periods of high emotion (as in stereotypes).

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. A child with two or more lifetime seizures (occurring more than 24 hours apart) has at least a 60% probability of having another seizure, constituting a diagnosis of epilepsy (70). An abnormal EEG or neurologic examination, or a symptomatic cause, increase the 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 abovementioned factors is moderately low (less than 30%) but increases to 70% with both risk factors (10) and is, therefore, consistent with a diagnosis of epilepsy. Complete remission of epilepsy, as defined in one study as being seizure-free and off medication for 5 or more years, is more likely when epilepsy presentation is uncomplicated, the type of epilepsy is uncharacterized, or the type is consistent with a focal self-limited epilepsy syndrome. In contrast, later age at seizure onset (over 10 years old) and early developmental or academic difficulties are predictive against complete remission (11).

Clinical vignette

A 6-year-old male child presented with multiple episodes of staring that interrupted his activities and lasted several seconds. He was otherwise healthy, with no medical problems or seizure risk factors. Hyperventilation in the office induced a 6-second staring spell associated with repeated eye blinking and repetitive mouth chewing movements, during which the patient was not responsive to questions being asked. Afterwards, the patient did not remember the event but immediately returned to his baseline. EEG demonstrated occasional bursts of 3 Hz generalized spike-wave discharges, occurring more frequently 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, with resolution of absence seizures. A repeat EEG was performed a few years later and was normal in the awake and asleep states and during hyperventilation. He was then weaned off ethosuximide without recurrence of seizures.

Biological basis

	• Seizures are thalamocortically generated.
	• Semiology of seizures help localize or lateralize the seizure onset zone or involved networks.
	• The etiology of childhood-onset epilepsies is varied, especially when compared to those of adult-onset epilepsies. For example, they include genetic malformations of cortical development and acquired structural and metabolic causes.

Localization

The thalamocortical system is critical in generating seizures, whether they be generalized or focal in onset. Focal-onset seizures often have clinical features representing the functions of the cortical region involved. For example, temporal lobe seizures can present with an epigastric rising sensation or smell of burning rubber or aphasia, whereas occipital lobe seizures may present with visual phenomena or autonomic changes. Importantly, the clinical features seen during a seizure represent the symptomatogenic zone, the region of cortex involved in the seizure causing symptoms. However, the symptomatogenic zone may not always be the same as the ictal onset zone, the region of cortex from which the seizure starts, or the epileptogenic zone, “the area of cortex that is necessary and sufficient for initiation seizures and whose removal (or disconnection) is necessary for complete abolition of seizures” (53).

Etiology and pathogenesis

The diversity of seizure semiologies 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 (103; 114). 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 (28; 18).

One of the most significant developments in understanding epilepsy has been by discovery of many putative genetic variants aided by the rise in and availability of genetic testing. Epilepsies previously classified as “cryptogenic” or “idiopathic” are now suspected to be genetic in etiology. The overall yield of genetic testing is 17%, with the highest yield seen with whole-genome sequencing (48%) followed by whole-exome sequencing (24%), multi-gene panels (19%), and, lastly, chromosomal microarray (9%) (101). Patients with developmental and epileptic encephalopathies or other neurodevelopmental symptoms should undergo testing, as genetic testing yield is highest in this group. From such testing, additional insight into different causes of epilepsy have been elucidated.

For example, ion channelopathies resulting from gain- or loss-of-function mutations have been associated with epilepsy. One of the most common monogenic genetic epilepsies described to date is a loss-of-function mutation in the SCN1A gene affecting the NaV1.1 subtype. Voltage-gated sodium channels are important in generating and propagating action potentials, particularly in inhibitory neurons (75). Therefore, loss-of-function mutations affecting this gene result in decreased cortical inhibition and in a broad spectrum of disease phenotypes, from generalized epilepsy and febrile seizures plus (GEFS+) syndrome to Dravet syndrome. Antiseizure medications that work via blockage of sodium channels can exacerbate or precipitate seizures in patients with SCN1A-related epilepsy. In contrast, gain-of-function mutations in SCN8A, a gene that encodes a particular alpha subunit of voltage-gated sodium channels, results in epilepsy that responds best to sodium channel blockers (ie, phenytoin, carbamazepine) and consists of a wide range of clinical phenotypes (75). There are also epilepsies caused by channelopathies that affect potassium channels (involving genes such as KCNQ2), which are important for the hyperpolarization phase following a neuron’s action potential (40), and by channelopathies that affect calcium channels (involving genes such as CACNA1B, for example), which are generally important for synaptic neurotransmission (39).

The mTOR signaling pathway is critical for cell growth, differentiation, proliferation, and metabolism. Many genes are part of this pathway, and loss-of-function mutations have been associated with epilepsy as well as malformations of cortical development (like dysplasia) and neurodevelopmental disorders (35). For example, pathogenic variants in TSC1 or TSC2, two genes in this pathway, can result in tuberous sclerosis complex. The GATOR1 protein complex, which inhibits part of the mTOR pathway, consists of DEPDC5, NPRL2, and NPRL3. Pathogenic variants in all three of those genes are associated with epilepsy, focal and nonfocal, and can be associated with focal cortical dysplasia (99; 06).

Therefore, although structural abnormalities, such as focal cortical dysplasia, polymicrogyria, and neural migration disorders like periventricular nodular heterotopia, may occur sporadically and the mechanism of pathogenesis may not be well understood in those cases, genetic causes of malformations of cortical development are also possible.

Pathophysiology

EEG is a noninvasive test measuring difference in voltage potentials in the cortex. Several features of cortical neurophysiology can be assessed from an EEG: the background organization in each state; the presence of focal or regionalized slowing, which is indicative of neuronal dysfunction in that region often prompting neuroimaging; ictal seizure patterns; and interictal epileptiform discharges, which signify decreased seizure threshold in the distribution where the discharges are seen. There are times that concomitant surface EMG electrodes are used to identify the movement artifact associated with certain seizures, which can help elucidate seizure semiology (ie, tonic versus atonic seizures or epileptic spasms). Although EEG demonstrates good time resolution, spatial resolution is limited. In other words, identifying seizure onset on EEG helps regionalize the epileptogenic zone.

In contrast, brain MRI has excellent spatial resolution but limited time-scale resolution. Brain MRIs evaluate for structural abnormalities that may be associated with epilepsy (such as polymicrogyria, heterotopias, encephalomalacia, and gliosis from a prior stroke or focal cortical dysplasia) or a genetic or metabolic condition (such as absent or dysmorphic corpus callosum or certain patterns of white matter changes). In particular, when a child has refractory focal epilepsy, an updated 3 Tesla MRI of the brain with epilepsy protocol (which typically includes thinner slices and smaller skips between slices, as well as particular sequences for adequate visualization of the hippocampus, for example) should be performed. Higher-resolution MRIs are now being developed, including high-resolution scans in a 3T scanner when focusing on a particular region of the brain or even acquiring MRIs on a 7T scanner. However, brain MRI does not reflect function of the brain. Instead, there is position emission tomography (PET) to image brain glucose metabolism using 18F-fluorodeoxyglucose (FDG) tracer (FDG-PET), such that hypometabolism of the radiotracer can be seen involving the seizure onset zone (and sometimes beyond that area) during the interictal state. Reasons for this regionalized glucose hypometabolism remain poorly understood.

Single photon emission computed tomography (SPECT) is an imaging study reflecting regional cerebral blood flow using 99mTc-hexamethyl-propylene-amine-oxime or 99mTc-ethylene-cysteine-diethylester radioisotope. Distinct regionalized cerebral blood flow changes can be seen in the interictal state and in the ictal state, such that hypoperfusion can be seen from an epileptogenic focus interictally and hyperperfusion in that region ictally. Optimal sensitivity and specificity for identifying the epileptogenic focus is highest when subtracting interictal from ictal SPECT, with the ictal SPECT injection occurring as close to the seizure onset as possible and ideally when a seizure remains focal for a long time (or doesn’t generalize quickly). These nuclear medicine tests can be quite helpful to direct or focus reanalysis of a brain MRI that, on initial review, shows no obvious structural lesion.

Epidemiology

• The risk of epilepsy is bimodal: greatest in the first year of life and then in the later decades of life.

Epilepsy is one of the most frequent neurologic diseases in children and adolescents, with a prevalence of three to seven cases per 1000 children (04). 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 incidence of seizures is highest in the first year of life, and the risk gradually declines towards that of adults by the end of the first decade of life (120; 08). Epilepsy incidence and prevalence are higher in underdeveloped countries compared to developed countries, with rural areas having higher numbers than urban areas (16; 113).

Prevention

• No interventions currently exist to prevent or mitigate the risk of developing epilepsy.

Insofar as preventing epileptogenesis, there are unfortunately no existing interventions. Antiseizure medications treat seizures but do not change the underlying cause of epilepsy (thus, they are not called antiepileptogenic medications). Although there are treatments for epilepsy involving certain dietary regimens, such as low glycemic index, modified Atkins diet, and ketogenic diet, there is no evidence to date that implementation of such diets or anything in between decreased the risk of developing epilepsy. With the rapidly evolving area of epilepsy genetics, it is conceivable that there will be gene therapy to address monogenic causes of epilepsy in the next several decades.

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 (55; 25; 87; 88; 118; 07).

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 high-amplitude tremulousness 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). Rarely occur more than once in an evening.
Self-gratification phenomenon	Early childhood	May present with autonomic signs like facial flushing and leg crossing. 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.
Tics	School-aged children	Stereotyped nonrhythmic movements or vocalizations that are often suppressible, accompanied by a premonitory urge, and disappear during sleep.
Complex migraine	Childhood to adulthood	May have hemiplegia, vision loss, vertigo, paresthesias, ataxia, confusion, or other symptoms.
Paroxysmal dyskinesia	Childhood to teenage years	Episodic abnormal movements (dystonic, ballistic, athetotic, choreiform) that may be precipitated by sudden movement (kinesigenic) or no movement and possibly stress (non-kinesigenic) or exercise (exercise-induced). There is no loss of awareness.
Narcolepsy	Typically teenage years	Associated with sleep paralysis, sleep attacks, hypnogogic hallucinations, and cataplexy.
Psychogenic nonepileptic spells (PNES)	Childhood through adulthood	Higher prevalence in girls. Occurs during wakefulness. Often, there is co-occurring anxiety, depression, or post-traumatic stress disorder. The movements seen can be similar in appearance to epileptic seizures but may be able to be interrupted, are less likely to be stereotyped, and are not diagnostically associated with an ictal pattern on EEG.

In patients presenting for evaluation of seizure activity, two 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 (49; 44). 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. Psychogenic nonepileptic spells (PNES), a type of functional neurologic disorder, consist of involuntary abrupt changes in consciousness or behavior that can even resemble epileptic seizures but are not associated with an ictal pattern on EEG. Their pathophysiology is complex and poorly understood. Common comorbidities are a history of anxiety, depression, posttraumatic stress disorder, or negative life events and exposure to someone with epilepsy. Importantly, PNES is different from malingering as these episodes are not volitional or for intentional secondary gain. Treatment is with cognitive behavioral therapy, not antiseizure medications. Early identification and appropriate treatment of PNES, as well as consensus among all providers and family regarding the diagnosis, are associated with better prognosis (38; 79; 97). There has been a rise in the incidence of PNES, underscoring the importance of all pediatric healthcare providers being aware of this entity (which can also coexist in people with epilepsy) (45).

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, as defined by the 2017 ILAE classification system.

The risk of developing seizures in childhood is highest during the first year of life (103). 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 (81). 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 underscores the importance of EEG (87). Suppression of events by restraint suggests that the events in question may not be epileptic in nature (104). 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 (57; 112; 119; 80; 56; 115).

Self-limited familial neonatal epilepsy typically presents 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 (76). Mutations in the voltage-gated potassium channel subunit KCNQ2, or much less commonly KCNQ3, have been associated with benign familial neonatal seizures (31; 03). Mild delayed psychomotor development may be seen in up to 40% of cases (107), and there is a higher long-term rate of epilepsy (76). 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 (87). 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 (42). 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 initially misdiagnosed 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 (33). Treatment has classically been with adrenocorticotropic hormone (ACTH), or high-dose oral steroids as first line according to the UKISS protocol; however, when the etiology is tuberous sclerosis, vigabatrin is first line (90; 37; 52; 61; 41). Combination therapy with steroids and vigabatrin has not been shown to improve long-term developmental or epilepsy outcomes (at 18 months). Lag time to diagnosis and treatment plays a bigger role in determining outcomes (83).

Self-limited focal epilepsies of childhood are typically of unknown cause, though they are presumed to be genetic. Each syndrome is characterized by age of occurrence, absence of structural brain lesion, an often unremarkable perinatal course and neurologic exam with a classic semiology, and with remission typically around puberty. There are often specific EEG features characterizing each syndrome. The first is self-limited epilepsy with centrotemporal spikes (SeLECTS), formerly known as “benign” epilepsy with centrotemporal spikes (BECTS) or “benign” Rolandic epilepsy. Onset is often between 4 and 10 years of age, with remission usually by puberty but sometimes at 18 years of age. Seizures most often occur out of sleep and consist of maintained awareness with unilateral sensory or motor symptoms of the face and sometimes the hand, with sialorrhea and speech arrest or dysarthria speech. Sometimes, these can evolve into bilateral tonic-clonic seizures. EEG, as evident from the name, shows sleep-potentiated triphasic sharp waves in the centrotemporal regions, often bilaterally and independently, without focal slowing. Childhood occipital visual epilepsy, formerly known as late-onset benign occipital epilepsy or Gastaut syndrome, typically has onset at 8 to 9 years of age, with remission by puberty in a majority of patients with or without antiseizure medications, more likely in those with only focal seizures. Seizure semiology typically consists of elementary visual phenomena occurring in the awake state. EEG shows occipital spikes or spike-and-wave abnormalities. Finally, seizures seen in self-limited epilepsy with autonomic features (SeLEAS), formerly known as Panayiotopoulos syndrome or early-onset benign occipital epilepsy, most often have onset between 3 and 6 years of age. Seizure semiology consists of autonomic symptoms like retching; pallor; flushing; nausea and vomiting; or heart rate, temperature, or pupillary changes. They often evolve into hemiclonic or bilateral tonic-clonic seizure activity. Seizures are infrequent but long. In fact, this is the most common cause of afebrile nonconvulsive status epilepticus in childhood. EEG findings are variable, but commonly consist of high-amplitude sleep-potentiated focal spikes in any distribution.

There is a broad spectrum of developmental and epileptic encephalopathies in which (a) the epileptic activity contributes to significant cognitive and behavioral impairments beyond what could be expected from the underlying etiology alone; and (b) abnormal development secondary to the underlying etiology is present in addition to the epileptic encephalopathy. One of the most common developmental and epileptic encephalopathies is Lennox-Gastaut syndrome, which is more of a clinical and EEG phenotype with heterogeneous etiologies. Lennox-Gastaut syndrome consists of a mixture of seizure types, the most prominent of which is tonic seizures, but may also include myoclonic, atonic, and atypical absence seizures. There is a history of developmental delay/disability and regression. The EEG characteristically demonstrates generalized 1 to 2.5 Hz slow spike-wave complexes and bursts of paroxysmal fast rhythms of 10 to 12 Hz during sleep that can be asymptomatic. It often evolves from a history of infantile spasms, with a peak age of 3 to 5 years. Seizures are typically frequent and refractory to antiseizure medications, and at least moderate intellectual disability is observed in more than 85% of patients (17; 78). In addition to antiseizure medications such as clobazam, valproate, cannabidiol, and fenfluramine that are commonly used in children with Lennox-Gastaut syndrome, ketogenic diet, vagal nerve stimulator, deep brain stimulator, and corpus callosotomy (to target tonic or atonic drop seizures) are also considered for optimal palliation of seizures (65; 02; 62; 116; 102; 105).

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 (95). 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 (36), whereas another study demonstrated that the low dose valproic acid and lamotrigine combination was superior to any monotherapy (59). In the absence of generalized tonic-clonic seizures or myoclonus, prognosis is good, and most children achieve seizure remission (100).

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 (124). 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 (24), as well as mutations in GABA receptors and chloride channels, both important for inhibition (19). 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 (121).

Diagnostic workup

Evaluation of the child 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. Any child having two confirmed unprovoked seizures more than 24 hours apart or one unprovoked seizure and a greater than 60% likelihood of having another seizure based on history or work-up, or any child with presentation consistent with an epilepsy syndrome, meets criteria for a diagnosis of epilepsy based on the ILAE’s 2014 revised definition of epilepsy (29).

The overall seizure recurrence rate after the first one is approximately 40%, with most occurring within the first 1.5 years, more often within the first 6 months. Early age at seizure onset, presence of focal or focal to bilateral seizure semiology, abnormalities on EEG (including abnormal background and epileptiform discharges, regardless of whether they are focal, generalized, multifocal), and family history of epilepsy have all been associated with an increased risk of seizure recurrence (OR 1.5–2.4) (01; 89). Additionally, etiology of seizure that is structural, posttraumatic, postmeningitic/encephalitis, or post-stroke are also more likely to have seizure recurrence. Comorbidities like cerebral palsy and motor or cognitive delays are also associated with risk of seizures (01; 89).

Children with simple febrile seizures present a unique situation with clear guidelines. Febrile seizures are the most common seizure of childhood, with an incidence of 2% to 5% in Europe and the United States (98). A febrile seizure is defined as occurring in otherwise healthy children aged 6 months through 5 years with a documented fever greater than 38°C (100.4°F). Simple febrile seizures are further defined as generalized in semiology, occurring only once in 24 hours, and lasting less than 15 minutes in length. It excludes seizures related to an underlying CNS infection. 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). 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 (110).

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 (51). 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 (66). Toxicology screening is recommended for all ages if there is any concern for drug or chemical exposure (51).

An EEG has been recommended for all children with a first afebrile seizure (51). Studies primarily in adult patients suggest that an earlier EEG increases the yield of capturing interictal findings, but feasibility can be an issue (60; 86). 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 (122). 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 (12; 54).

Neuroimaging is not recommended for children with a simple febrile seizure (110). 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 (34; 93). 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 (51; 34). 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 (22). 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 (92).

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 (21; 69).

Management

• Selection of an appropriate antiseizure medication should be guided by seizure type and patient comorbidities (such that the side effect profile of the selected medication is less likely to compound preexisting problems).

• Optimize one medication by increasing the dose in a stepwise fashion as needed until seizure control is achieved, the maximum safe dosage is reached, or the maximum tolerated dosage is achieved (above which intolerable or unacceptable side effects are experienced). When possible, avoid starting multiple medications that are at low doses as this increases the risk of more side effects without necessarily increasing the antiseizure benefit.

Management of seizures presenting in childhood is based on the risk of recurrence versus the potential side effects of antiseizure 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 (27). Furthermore, treatment with antipyretics has not been shown to be effective for preventing febrile seizures, and therefore, is not recommended (108). 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 (84).

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 (85). Levetiracetam has also been shown to be safe and effective in neonates and is becoming widely used (57). 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 (90). 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 (36). It is important to be familiar with classes of medications that are indicated for generalized seizures more than focal seizures and for which the majority can be used for both types.

For patients with no insurance coverage and limited resources, consideration of cost helps ensure compliance with medications.

Providing families with abortive therapy, such as rectal diazepam gel, especially for children younger than 6 years of age, or intranasal midazolam for those older than 11 years of age, or intranasal diazepam for those older than 6 years of age, is recommended, particularly for convulsive seizures or seizures associated with autonomic changes and for patients at risk of status epilepticus or with a tendency to have cluster seizures. Adequate education on the indication for when to use the rescue medication and demonstrations on how to use it are also important. A seizure action plan should also be provided to the school nurse if an abortive medication is going to be made available at school when a nurse is available.

Counseling on seizure precautions is also important. 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). When possible, avoiding being in rooms alone with doors locked is advised. Avoiding heights greater than 5 to 6 feet unless harnessed and helmeted is also important. Striking a balance between abiding by these seizure precautions while not unduly limiting a child’s activities is important, though admittedly difficult. 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 (05).

Adolescents of driving age should be instructed to abide by their state’s regulations as set by the Department of Motor Vehicles as they determine when a person can resume (start) driving and not the neurologist. When making medication changes, such as weaning an antiseizure medication, it is advised to also halt driving during that timeframe and for some period afterwards because this may be a more vulnerable period for breakthrough seizures.

Outcomes

Although treatment with antiseizure medications is associated with a reduction of seizure recurrence, no study has demonstrated that treatment with antiseizure medications alters long-term outcome (74; 117; 23). 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 (74). 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 (64). 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 of 4500 children and 1 of 1000 adults (46). The risk factors and pathophysiology for SUDEP are still being elucidated but include drug resistant epilepsy, frequent seizures, nocturnal seizures, and, specifically, bilateral tonic-clonic seizure semiology (111; 123; 82). The advent of seizure detection devices emerged from this rising awareness of and concern for SUDEP. Currently, the Embrace2 seizure detection watch is the only FDA-cleared, commercially available device for seizure detection and specifically detects bilateral tonic-clonic seizures in people 6 years of age and older. 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 (91; 77). 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 (09; 109).

For children with focal epilepsy that is not part of a self-limited focal epilepsy of childhood syndrome, early consideration for referral to an epilepsy center is recommended. Although over two thirds of people with epilepsy will achieve seizure freedom with the first or second antiseizure medication, one third will continue to have seizures despite adequate trials of two medications and are classified as having refractory or medically intractable epilepsy. The likelihood that subsequent medications will render a person with refractory epilepsy seizure free becomes less than 5%. It is in this setting that other treatment options, in parallel to medications, should be considered, including ketogenic diet and surgery. Ketogenic diet or other medical diet therapies in this arena, like modified Atkins diet or low glycemic index diet, should be done under the direct supervision of a ketogenic diet team, which is typically comprised of a dietician who specializes in the ketogenic diet and a neurology/epilepsy provider. Presurgical work-up should be done at an appropriate comprehensive epilepsy center that has the resources to perform the necessary testing, as previously reviewed, and a multidisciplinary case conference to present patients and come to a consensus agreement regarding epilepsy surgery is recommended. It is important to note that in addition to focal resective surgeries, corpus callosotomies, and hemispherectomies, laser interstitial thermal therapy and focused ultrasound are new technical advances for focal surgery, and implantation of neuromodulatory devices, such as responsive neurostimulation, deep brain stimulation, and vagal nerve stimulation, are palliative options for patients who may not have previously been considered surgical candidates.

Special considerations

Pregnancy

The treatment of pregnant patients with epilepsy is complicated by the fact that many of the antiseizure medications can be teratogenic. This risk should be mentioned when considering its use in any person of childbearing age with childbearing potential, even if there are no plans for getting pregnant. Additionally, 2009 guidelines from the American Academy of Neurology recommend supplementation with folic acid in people of childbearing age with childbearing potential to possibly reduce the risk of major congenital malformations of the fetus (47). Although there is only class C evidence for the recommendation, the potential for benefit outweighs the negligible (if any) risk of taking folic acid. Although there is a risk of antiseizure medications affecting a developing fetus, including neural tube defects, small size, or lower IQ, these risks (while on an antiseizure medication regimen that may be adequately controlling seizures) have to be weighed against the risk of having uncontrolled seizures during pregnancy. Generalized tonic-clonic seizures in a pregnant person pose a significant risk to the developing fetus. 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 (63).

Anesthesia

Anesthesia is generally safe in people with epilepsy. In fact, many anesthetics can be used to treat seizures. The primary consideration is the need to take nothing by mouth several hours before undergoing anesthesia. However, there is a notable risk of breakthrough seizures with missed doses of antiseizure medications. Therefore, it is generally advised to allow people with epilepsy to take their antiseizure medications with the smallest volume of water possible the morning of the procedure for which they will be under anesthesia. If needed, medications can be taken a few hours earlier. If medications absolutely cannot be given the morning of the sedated procedure, or if the patient is unable to take medications enterally (by mouth, G-tube if applicable, or via NG) following the procedure, then antiseizure medications for which there is an intravenous formulation should be given (comparable dose) at the time(s) they would typically be due. This also applies for any medication that may be taken at baseline three times daily, with the midday dose being due perioperatively. Intravenous benzodiazepines, such as midazolam, diazepam, or lorazepam, can also be given at appropriate dosages as a “bridge” to provide additional antiseizure coverage to make up for the medications for which there are no appropriate intravenous formulations.