Seizures and epilepsy in children: Clinical and laboratory diagnosis

INTRODUCTION — This review highlights the aspects of the physical and neurologic examination, imaging studies, and laboratory investigation that are relevant to the assessment of the infant and child with suspected seizure or epilepsy. Other aspects of seizures and epilepsy in infants and children are reviewed separately. (See "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Epilepsy syndromes in children" and "Seizures and epilepsy in children: Initial treatment and monitoring" and "Seizures and epilepsy in children: Refractory seizures" and "Epilepsy in children: Comorbidities, complications, and outcomes".)

Neonatal seizures are discussed in detail elsewhere. (See "Clinical features, evaluation, and diagnosis of neonatal seizures" and "Treatment of neonatal seizures" and "Etiology and prognosis of neonatal seizures" and "Overview of neonatal epilepsy syndromes".)

The detailed pediatric neurologic examination, acute illnesses accompanied by seizures, and febrile seizures are discussed separately. (See "Detailed neurologic assessment of infants and children" and "Seizures and epilepsy in children: Classification, etiology, and clinical features" and "Clinical features and evaluation of febrile seizures" and "Clinical features, evaluation, and diagnosis of neonatal seizures".)

GOALS OF THE EVALUATION — There are several goals in the evaluation of a child with suspected seizures or epilepsy.

For evaluation of possible first or new-onset seizures:

●Is the episode a seizure, or is the episode a nonepileptic event? Seizure is primarily a clinical diagnosis, and accurate diagnosis requires differentiating seizure from other common clinical events that can mimic seizure.

If seizure is diagnosed:

●Is the episode an acute symptomatic seizure (ie, a provoked seizure caused by a fever, an acute brain insult, or a metabolic derangement), which generally implies a lower risk for future epilepsy compared with unprovoked seizures?

●Alternatively, is the episode an unprovoked seizure (due to a preexisting brain lesion or progressive nervous system disorder or an unknown etiology), which generally implies a higher risk of future epilepsy compared with acute symptomatic seizures?

If seizure or epilepsy is diagnosed:

●What is the type of seizure/epilepsy (eg, focal, generalized, combined generalized and focal, or unknown)?

●Do the clinical features, signs and symptoms, and electrographic pattern suggest an epilepsy syndrome?

●What is the most likely etiology (eg, genetic, structural, metabolic, immune, infectious, or unknown)?

The accurate diagnosis and classification of seizures and epilepsy provides important information to guide therapy and inform prognosis.

INITIAL ASSESSMENT

History — The goals of the history are to characterize the event as a seizure and rule out alternative diagnoses, determine whether similar events have happened in the past, and evaluate for underlying risk factors for seizures in the past medical history, family history, and medications.

Importance of detailed history — Most children with epilepsy have an idiopathic disorder with a normal neurologic examination and neuroimaging studies. Thus, a careful history is the cornerstones of an accurate diagnosis. A detailed account of the child's behavior preceding, during, and following a "spell" is critical. This account may require a follow-up visit with witnesses or a phone call to individuals, such as a teacher, who actually saw the "seizure." The clinician should remember to include the child in the conversation; quite often the child provides valuable information.

The clinician should not accept a previous diagnosis of "epilepsy" without taking the child's history. Witnesses should be asked to describe the event in degree of severity (ie, the mildest to the most severe). Often the large seizures (ie, generalized tonic-clonic) are preceded by the identical symptoms that occur in the minor ones, confirming the suspicion of a focal seizure with secondary generalization. However, some children have two or more seizure types. The brief focal signs or aura prior to the more dramatic event, or the important localizing symptoms following the seizure, may be missed in a cursory history. A generalized tonic-clonic seizure may be preceded by brief twitching of one side of the face and followed by a transient language disorder consistent with a dysphasia, supporting the diagnosis of a focal seizure arising in the dominant hemisphere, with secondary generalization.

Setting in which episodes occur — Most seizures occur at random and without warning. By contrast, many nonepileptic spells have characteristic precipitating circumstances or occur in specific locations. Determining the time of day and the activity in which the child was engaged prior to the seizure is important.

Important questions to consider include:

●Were the seizures primarily nocturnal and, if so, what time of the night did they occur?

●Was the child taking medication (prescription and over-the-counter) or herbal substances prior to the seizure? Several herbal supplements, including St. John's wort, Ma huang, and kava, have caused seizures [1].

●Did the seizures occur only with illness and fever? Seizures occurring in the setting of fever alone may represent febrile seizures, rather than epilepsy. (See "Clinical features and evaluation of febrile seizures".) Febrile seizures occur in children between the ages of six months and five years, with the majority occurring in children between 12 and 18 months of age.

●Did the seizure occur in the setting of other acute medical events (eg, acute head injury, other acute medical illness)? Such seizures may be provoked and at lower risk of recurrence than unprovoked seizures. As an example, in one observational study of 117 children with a first seizure, seizure in the setting of acute gastroenteritis had a particularly low risk of seizure recurrence compared with other children with a first seizure (11 versus 40 percent, hazard ratio [HR] = 0.28) [2].

●Did the seizures occur only when the child was relaxed and never occur when actively involved in some type of activity? (More likely nonseizure events.)

Behavior immediately prior to the event — On rare occasions, seizures may be precipitated by environmental stimuli such as sound or an unexpected touch (reflex epilepsy). More commonly, no obvious precipitating circumstances are present. Thus, obtaining a history of the events leading up to the seizure is important because they may be more suggestive of a nonseizure diagnosis. (See 'Differential diagnosis' below.)

Important questions to consider include:

●Do the episodes always occur when the child is upset and crying (cyanotic breath-holding spells); only after a minor blow to the head or upper torso (pallid infantile syncope); only in the classroom and never seen by the parents or caregivers (staring episodes are commonly seen in children with attention deficit hyperactivity disorder); or always when standing and preceded by nausea and dizziness (simple vasovagal syncope)? (See "Nonepileptic paroxysmal disorders in children".)

●What activity was the patient engaged in immediately prior to the event? Does the patient mention any sensory or autonomic symptoms (numbness, visual distortions, auditory or visual hallucinations or illusions, nausea or unusual feelings in the abdomen or chest, an unusual smell or taste, etc) or manifest an alteration in behavior or mood? Preceding symptoms suggestive of seizure include auditory or visual hallucinations, experiential feelings like déjà vu or jamais vu, and strange smells or tastes. Symptoms suggestive of orthostatic intolerance leading to syncope include nausea, lightheadedness, dizziness, and loss of vision ("blackout").

●Did a loss of appetite, nausea, vomiting, or headache occur before or after the event? Headaches are common after a generalized convulsive seizure but are infrequent before a seizure [3]. Nausea and vomiting more often are seen in association with a migraine syndrome, which can mimic a seizure. (See "Nonepileptic paroxysmal disorders in children".)

●Are the events precipitated by a particular stimulus? Seizures are rarely precipitated by mild trauma. Pallid infantile syncope is a common benign pediatric syndrome characterized by sudden transient bradycardia followed by an anoxic seizure (with pallor) and spontaneous recovery that are precipitated by a mild unexpected blow to the head and upper torso. It is caused by excessive vagal tone and is of unknown etiology. Pointed questioning may be necessary to uncover the history of mild trauma. (See "Nonepileptic paroxysmal disorders in children".)

●Were focal signs or symptoms present? Examples include face or extremity twitching, an illusion of a bad smell or taste, and a déjà vu experience. Some of these symptoms are considered an "aura," or a focal seizure involving subjective sensory or psychic phenomena, which may be the first clinical manifestation of the seizure. This information can be valuable for localizing the epileptic focus [4,5]. Patients may not remember these symptoms because retrograde amnesia often accompanies seizures, particularly those with generalized motor activity.

●Does the child predictably cry before an event? In studies of adults, weeping during an event was typical of a nonepileptic seizure [6]. Consistent crying before a "seizure" is suggestive of a cyanotic breath-holding spell.

Physical appearance during the event — The clinician should obtain a description of the patient's color during the event and determine whether anyone checked the child's heart rate or pulse. Anoxic nonepileptic seizures may be secondary to a cardiac arrhythmia. If a child has a color change during a seizure, particularly a generalized motor seizure, they usually will become cyanotic. A cardiac cause for the event should be considered if the child is described as pale. A description of forceful eye or head deviation to one side can be a useful localizing feature.

Behavior during the event — An accurate description of behavior during the event is critical to making the diagnosis. The clinician can ask the parent or caregiver or witness to mime the event, or the clinician can mimic different kinds of seizures to find a match for the child's episodes. Often the family, caregivers, or the initial clinician involved with the child will describe the episode as simply a "grand mal" or "petit mal" seizure. Frequently, the clinician is told that the child had "staring episodes" or "fell down and shook all over." These descriptions are not adequate for arriving at a definite diagnosis.

Important questions to consider include:

●Are limb movements unilateral, bilateral, synchronous, and clonic (rhythmic flexion movements or rhythmically interrupted tonus), or irregular and thrashing? Repeatedly and consistently stereotyped behaviors suggest seizures as compared with nonepileptic events.

Bilateral motor seizures, particularly those involving all the extremities and the trunk with generalized, relatively symmetric, tonic or clonic movements, are usually associated with altered consciousness. A nonepileptic seizure should be suspected if the patient has generalized motor activity with normal responsiveness, particularly if it lasts longer than five minutes. Prolonged waxing and waning of clonic or tonic activity or stimulus-provoked clonic/tonic activity during a generalized motor seizure is more consistent with a nonepileptic seizure.

●Are the eyes and mouth closed? A nonepileptic seizure should be considered if the patient keeps the eyes tightly closed during the seizure and, particularly, if passive eye-opening is actively resisted [7-9]. Sustained eye deviation or nystagmoid eye movements are relatively subtle clinical manifestations of seizure activity. Patients with true generalized motor seizures tend to keep their mouths open during the tonic phase of the seizure; in generalized motor nonepileptic seizures, the mouth is partially or tightly closed (clenched).

●What was the patient's response to verbal commands, pinching, or more painful stimulation? Generalized motor seizures cannot be interrupted by vocal or tactile/painful stimulation. By contrast, a patient with a nonepileptic seizure may suddenly return to normal after a painful stimulus or shouting of his or her name. However, an abrupt return to consciousness is often seen in frontal lobe seizures and should not be considered a reliable sign of nonepileptic seizures.

●What was the duration of the event? Most seizures are short lived; an episode of confusion or loss of contact with the environment that lasts more than five minutes should raise the suspicion of a nonepileptic event.

Behavior after the event — Important questions to consider include:

●What was the patient's behavior after the event (postictal state)? Did they recover immediately, or was there confusion or somnolence? Was the child able to communicate verbally immediately after the event (eg, could the patient form appropriate and full sentences; was the child oriented; could the child follow complex or simple verbal commands)?

●Were there focal findings during the postictal state, such as a hemiparesis (Todd paralysis)? These features are helpful for localization. As an example, if a child had a generalized motor seizure, but in the postictal period could not talk despite being able to follow simple commands (postictal aphasia), a focal onset in the speech area of the dominant hemisphere would be suspected.

Other elements of the history

●A developmental history should be obtained, with particular attention given to any plateau or loss of developmental milestones. In older children, a history of academic performance and social interactions are also essential parts of the history.

●The examiner should search for a history of previous illnesses that are associated with seizures (eg, meningitis, hypoxic-ischemic encephalopathy, head trauma).

●A detailed family history is mandatory. Consanguinity should raise a suspicion of an inherited disorder, particularly a recessively inherited inborn error of metabolism. A family history of seizures may suggest a dominantly inherited epileptic disorder.

●The teenager with seizures should be questioned about drug use.

Examination — The general history and physical examination of children with seizures includes several elements.

●In addition to searching for medical causes of the patient's seizures, close attention should be paid to the eye examination. The clinician should look for congenital ocular defects, the retinal changes associated with certain neurocutaneous and neurodegenerative disorders, or signs of an earlier infection. Ophthalmology consultation should be obtained if the funduscopic examination is difficult, as in the active infant.

●The neurologic examination should look for evidence of findings associated with seizures, such as sustained head and eye deviation, hemispatial neglect, focal myoclonus of the face or limbs, and automatisms (repetitive stereotypic, purposeless movements including lip smacking, orofacial twitching, arm and hand movements such as picking or fidgeting)

●A cardiac examination, including an electrocardiogram (ECG), is necessary if concern exists about a cardiogenic cause for the patient's episodes. Episodes of disturbed neurologic function caused by decreased cardiac output (eg, prolonged QT syndrome or pulmonary hypertension) may closely mimic focal seizures, including the presence of an aura [10]. (See "Congenital long QT syndrome: Epidemiology and clinical manifestations" and "Pulmonary hypertension in children: Classification, evaluation, and diagnosis".)

●The abdominal examination may reveal hepatosplenomegaly, suggesting a storage disease.

●The skin examination is of particular importance in the evaluation of children with seizures, as many neurocutaneous disorders are associated with epilepsy. The cutaneous features of tuberous sclerosis, the facial angioma of Sturge-Weber syndrome, the café-au-lait spots of neurofibromatosis, the nevi of the linear nevus syndrome [11], and the swirling hypopigmentation of Ito syndrome [12] all are characteristic physical findings. Wood lamp examination to identify the hypopigmented macules (ash leaf spots) of tuberous sclerosis is an essential feature of the examination of a child with seizures. Dermatologic consultation should be considered in a child with seizures who has a skin lesion that cannot be identified easily. Most neurocutaneous disorders are hereditary and, if identified, should lead to family or caregiver counseling and possibly genetic consultation. (See "The genodermatoses: An overview", section on 'Neurocutaneous syndromes'.)

●An assessment for genetic disorders is important. Dysmorphic features and other congenital anomalies, body asymmetries, and unusual skull shapes should be noted. As an example, some children with a referral diagnosis of cerebral palsy and epilepsy have the obvious and often striking clinical and dysmorphic features of Angelman syndrome, a chromosomal disorder caused by a deletion of chromosome 15q12. (See "Microdeletion syndromes (chromosomes 1 to 11)" and "Microdeletion syndromes (chromosomes 12 to 22)".)

Initial studies

●Laboratory tests – Rapid point-of-care glucose should be checked in all patients with a possible first seizure. Other laboratory evaluations that may be appropriate for the evaluation include electrolytes, glucose, calcium, magnesium, complete blood count, renal function tests, liver function tests, urinalysis, and toxicology screens, although the likelihood of finding a relevant abnormality in unselected patients is low [13].

A pregnancy test in girls and women of childbearing age is commonly performed, as pregnancy may affect testing and treatment decisions.

A urine toxicology test is warranted across the entire pediatric age range if drug exposure or withdrawal is suspected as a cause of seizures [14]. However, many recreational substances are not detected by urine toxicology; expanded drug screening can be pursued if there is high suspicion for substance exposure as the cause of seizures. (See "Testing for drugs of abuse (DOAs)".)

Serum prolactin assessment has limited utility as a diagnostic test for epileptic seizures and is not recommended as part of the routine evaluation [15]. In selected cases, an elevated serum prolactin may be useful in differentiating generalized tonic-clonic and focal seizures from psychogenic nonepileptic seizures in adults and older children [16]. A low serum prolactin does not exclude epileptic seizure, although it lowers the likelihood of an epileptic seizure if the event appeared to be a generalized tonic-clonic seizure. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis", section on 'Serum testing'.)

Other laboratory abnormalities that may be present after a generalized convulsive seizure, such as elevated creatine kinase (CK), cortisol, white blood cell count, lactate dehydrogenase, and neuron-specific enolase [17-21], are nonspecific and not generally useful in the diagnostic evaluation of suspected seizure.

●Neuroimaging – Immediate or urgent neuroimaging is indicated for infants and children with new-onset seizures if there is focal seizure onset, new focal neurologic findings on examination, or a prolonged altered mental status following the event. (See 'Neuroimaging' below.)

●Electrocardiogram – An ECG is necessary if concern exists about a cardiogenic cause for the patient's episodes.

●Lumbar puncture – Lumbar puncture should be performed if the clinical presentation is suggestive of an acute infectious process that involves the central nervous system. In other circumstances the test is not likely to be helpful and may be misleading, since a prolonged convulsive seizure itself can cause transient, mild cerebrospinal fluid pleocytosis [14].

Lumbar puncture should be performed after a space-occupying brain lesion has been reasonably excluded on clinical grounds or by appropriate neuroimaging studies.

Making the diagnosis — The diagnosis of seizure is primarily based on clinical history as described above and is supported when the clinical features are most consistent with seizure rather than alternative diagnoses. Seizures are typically episodic, brief, stereotyped, paroxysmal, events that cause sudden transient motor, sensory, experiential, or behavioral symptoms or signs.

Findings from neuroimaging, electroencephalography (EEG), laboratory studies and genetic testing may provide supportive evidence for the diagnosis and are particularly important when the diagnosis or etiology remains uncertain after the initial evaluation. (See 'Diagnostic and etiologic investigations' below.)

Referral to a specialist — Children with a first nonfebrile seizure or suspected seizure should be evaluated by a pediatrician or neurologist with experience in pediatric epilepsy to ensure an accurate diagnosis and appropriate management [22].

DIAGNOSTIC AND ETIOLOGIC INVESTIGATIONS

Who should be tested? — When a child presents with a first seizure, the initial evaluation is directed toward uncovering a potential medical etiology. If an acute cause cannot be found, the child may be experiencing the initial seizure of an epileptic disorder. Most children diagnosed with an unprovoked seizure or epilepsy of unknown etiology will need testing with neuroimaging, preferably with magnetic resonance imaging (MRI), and electroencephalography (EEG) at a minimum.

If the history, physical examination, MRI, and EEG do not reveal an etiology for recurrent seizures, the child should be evaluated for potential underlying metabolic, genetic, immune-mediated, or neurodegenerative disorders [23].

Extensive diagnostic testing may not be necessary if the history and physical examination provide an obvious etiology for the seizure. As an example, the infant with a history of pneumococcal meningitis and persistent seizures does not need extensive metabolic or genetic testing, although baseline laboratory examinations are indicated prior to initiating antiseizure medications.

Similarly, the normal child with nocturnal generalized seizures and/or diurnal focal seizures involving the face and upper extremity without impairment of consciousness whose EEG shows bilateral, independent centrotemporal spike and wave discharges, particularly if a family history of seizures exists, may not have to undergo imaging studies. The diagnosis of benign childhood epilepsy with centrotemporal spikes (benign rolandic epilepsy of childhood) can be made without these studies.

Neuroimaging

Indications for imaging — The necessity, timing, and choice of neuroimaging study for patients with suspected seizure or epilepsy depends upon the circumstances and clinical findings.

●Urgent imaging – Immediate or urgent neuroimaging is indicated for infants and children with new-onset seizures if there is focal seizure onset, new focal neurologic findings on examination, or a prolonged altered mental status following the event [24]. In this setting, head computed tomography (CT) is usually preferred, as it can be performed without sedation and is widely available (see 'Utility of CT' below). However, rapid MRI scans are increasingly available.

●Deferred imaging – In the absence of focal neurologic findings or prolonged altered mentation, CT has a low yield, and outpatient evaluation with electroencephalography (EEG) followed by selective use of MRI is preferred. (See 'Electroencephalography' below and 'Utility of MRI' below.)

MRI scan is indicated for those children with known or suspected localization-related epilepsy or with associated developmental delays or focal findings on EEG. Imaging, preferably with MRI, is also indicated for children suspected or known to have a remote cause of an epilepsy syndrome or a past medical history suggestive of high risk (eg, history of a brain tumor or other neoplasm, stroke, coagulopathy, sickle cell disease, cardiac defect, or ventricular shunt) [25,26], or for children with epilepsy whose classification is in doubt [24].

●Imaging not necessary – Neuroimaging may not be necessary in children who have an obvious cause for their seizures identified on the history and physical examination, such as febrile seizures. In addition, children with clearly benign epilepsy (such as epilepsy with centrotemporal spikes) based upon the history, family history, and EEG may not need imaging studies.

Goals of imaging — The initial imaging investigation should be directed toward finding a structural abnormality as the basis of the seizures, thereby avoiding expensive laboratory tests for the less common inherited neurometabolic, degenerative, or developmental disorders. Common categories of structural abnormality that are associated with chronic epilepsy include:

●Neoplastic (eg, dysembryoplastic neuroepithelial tumor)

●Malformative/genetic (eg, schizencephaly, focal cortical dysplasia)

●Metabolic (ie, inborn errors of metabolism)

●Familial/neurocutaneous

●Vascular/hypoxic-ischemic

●Traumatic

●Infectious/inflammatory

●Hippocampal sclerosis/deformation

Utility of CT — A CT scan is most often used for emergency department assessment of children with suspected new-onset seizure who have focal findings on neurologic examination and/or prolonged alteration in mental status following the event. In the setting of a first seizure, a noncontrast CT scan reveals urgent findings that change acute management in 3 to 9 percent of children and infants [25,27]. Among children with a first seizure that is apparently unprovoked, the risk of an urgent finding may be even lower; in a prospective multicenter study of 475 children (age 1 month to 18 years) with an unprovoked first seizure, CT or MRI identified an urgent finding in approximately 1 percent of patients and nonurgent findings in an additional 10 percent [26].

Infants less than six months of age will have a clinical relevant abnormality on CT scan 50 percent of the time [25,27].

Utility of MRI — In non-urgent settings, brain MRI is the preferred neuroimaging study for the evaluation of a child with seizures [23]. MRI is more sensitive than CT for detecting brain malformations and dysplastic lesions, as well as subtle temporal lobe pathology, particularly in the hippocampus, a common site of seizure onset [27]. Gadolinium contrast is not routinely requested, but is used when tumor, vascular malformation, inflammation, or infection is suspected based on clinical information or review of noncontrast study [24]. Special thin cuts and imaging angles are necessary to adequately assess hippocampal anatomy and are part of the standard MRI "seizure protocol" (see "Neuroimaging in the evaluation of seizures and epilepsy", section on 'Epilepsy protocol for MRI').

Special MRI sequences are required in children younger than two years, as immature myelination patterns may obscure some pathologies [24]. MRI in these younger patients should include:

●Sagittal, axial, and coronal T1-weighted sequences in children one to two years of age

●Sagittal, axial, and coronal high-resolution T2-weighted sequences in children less than one year of age

The most common structural abnormalities found on MRI in children with epilepsy are congenital malformations, neurocutaneous syndromes, neoplasms, and patterns of brain injury suggestive of prior trauma, infection, or hypoxic-ischemic insult that cause a static encephalopathy. In one case series of 150 children with a first afebrile, unprovoked seizure, significant MRI abnormalities were present in 16 percent and were associated with a significant increased risk of seizure recurrence [28]. A community-based study of 518 children with epilepsy also revealed a 16 percent incidence of relevant MRI abnormalities [29].

If the MRI is normal in children less than two years of age and seizures persist, a follow-up study after 30 months of age may allow for visualization of an underlying cortical dysplasia when more mature myelination patterns have developed [24]. This should be considered when seizures are intractable. Where available and when performed and interpreted with an appropriate level of expertise, magnetic resonance spectroscopy can add diagnostic value in selected patients (eg, distinguishing neoplasm from dysplasia) or prompt more intensified evaluation for inborn errors of metabolism or other genetic causes of epilepsy (eg, unexplained lactate peak on an otherwise normal MRI) [30].

In children with temporal lobe epilepsy, MRI abnormalities (eg, hippocampal sclerosis, tumor, cortical dysplasia) are associated with a higher likelihood of medical intractability [31]. While CT scan is better than MRI in identifying calcifications associated with congenital infections (eg, cytomegalovirus and toxoplasmosis) and some of the neurocutaneous syndromes (eg, tuberous sclerosis), MRI is usually also abnormal in these settings.

Electroencephalography — The EEG is a valuable adjunct to the assessment of children with suspected epilepsy.

Indications for EEG — Virtually every child with an unexplained seizure or recurrent seizures should have an EEG awake and while sleeping.

Utility of EEG — EEG is useful to support the diagnosis of epilepsy and may assist in determining the type of seizure and epilepsy [22]. (See 'Use of the EEG to determine the type of epilepsy' below.)

EEG is not useful when the most likely diagnosis is syncope, due to the possibility of a false-positive EEG finding [22]. Each EEG recording should be performed with specific questions in mind, an understanding and anticipation of the possible results, and a planned response to these results.

EEG has important limitations:

●A normal EEG never rules out epilepsy. Even with repeated EEGs, use of specialized techniques, or prolonged monitoring, a significant number of patients with epilepsy will have not have interictal epileptiform discharges.

●An "abnormal" EEG does not define epilepsy; most abnormal findings are nonspecific. Interictal epileptiform discharges are the most specific finding for epilepsy, but these can occur in normal children. (See 'Abnormal EEGs in healthy children' below.)

The use of EEG in the diagnosis of seizures and epilepsy is reviewed in greater detail separately. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy".)

Interpretation — The value of the EEG interpretation is related directly to the interpretive skills of the electroencephalographer. Only individuals with significant pediatric experience are able to recognize the characteristic features of a benign epileptic disorder and differentiate it from more serious syndromes. A phone consultation with the electroencephalographer prior to the EEG often is helpful in planning the study. Obtaining an EEG recording during sleep and wakefulness and optimizing the timing of the EEG will help maximize the chances of finding epileptiform activity.

Sleep EEG — An awake and asleep EEG should always be obtained. Epileptiform activity may appear in only one state (usually sleep). Even if epileptiform activity is evident on the initial awake tracing, a sleep recording is indicated. As an example, in the benign focal epilepsies, focal or multifocal spike and slow wave discharges, which are diagnostic of these syndromes, typically appear only during drowsiness and light sleep. In these children, fragments of generalized spike and wave activity can be seen during wakefulness and may erroneously suggest a generalized epilepsy. The benign focal epilepsy syndromes may also manifest a photoparoxysmal response (epileptiform activity provoked by repetitive light flashes); however, these are more typically seen in the idiopathic generalized epilepsies.

The child should be allowed to sleep naturally in the EEG laboratory. Many laboratories use sleep deprivation by requesting that the child is kept up a significant portion of the night prior to the EEG. However, while sleep deprivation increases the likelihood of detecting epileptiform discharges, even in the absence of recording sleep, the increased yield is modest. One study found that 11 sleep-deprived EEGs would be required to identify one additional child with epileptiform discharges compared with a routine EEG [32]. Sleep deprivation can be a difficult task for parents and caregivers, and sleep-deprived children, particularly those with cognitive impairment or behavioral disorders, can be difficult to manage in the EEG laboratory [33]. In one case series, the diagnostic yield of a sleep-deprived EEG was similar to that of an EEG obtained within 24 hours of a seizure [34]. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy", section on 'Sleep and sleep deprivation'.)

Timing of the EEG — The EEG should be obtained as soon as possible after a seizure [35]. In most patients, the incidence of epileptiform discharges is highest in the first 24 hours after a seizure [34]. In some children, however, the EEG immediately after a seizure will be normal or will show nonspecific background abnormalities (postictal slowing) but no epileptiform activity.

Utility of repeat EEGs — If the diagnosis is still in question after the initial EEG, a repeat tracing should be done. One group found the initial EEG to be normal in 44 percent of 552 children ages one month to 16 years with one or more newly diagnosed idiopathic or remote symptomatic seizures [36]. When the EEG was repeated with sleep deprivation in 177 children with an initially normal EEG, epileptiform abnormalities were found in 61 (35 percent), increasing the yield of an abnormal test by 11 percent.

Attempts should be made to obtain the repeat EEG at a time when the child is most likely to have a seizure. As an example, the EEG should be done in the morning if seizures are occurring primarily in the morning upon awakening (as often occurs in juvenile myoclonic epilepsy). If the seizures are nocturnal (as often occurs in frontal lobe and benign rolandic epilepsy), an all-night sleep recording in the laboratory or an ambulatory EEG should be considered.

More than three repeat EEGs adds little further information [37]. Up to 30 to 50 percent of children with epilepsy will be "EEG negative." In patients with serial negative EEGs and an undiagnosed paroxysmal disorder, inpatient video-EEG or ambulatory EEG recording can be helpful. Before considering one of these more expensive procedures, the case should be discussed with an epileptologist to maximize the chances of obtaining useful information on the EEG and to explore other possibilities in the differential diagnosis.

Use of the EEG to determine the type of epilepsy — The interictal epileptiform pattern on the EEG is often used to help determine the epilepsy syndrome and consequently the class of antiseizure medication (ie, narrow or broad spectrum) used for treatment. As examples, medications such as carbamazepine and oxcarbazepine often are used for focal epilepsies, whereas valproic acid, lamotrigine, or ethosuximide are preferred for the generalized epilepsies. However, the EEG pattern should not be used exclusively to make treatment decisions [38,39]. The detailed clinical description of the child's behavior during a seizure is equally, if not more, important than the EEG in selecting an antiseizure medication.

The most informative aspects of the interictal EEG pattern are the background organization and the morphology and topography of epileptiform discharges [40]. Stereotyped, generalized interictal discharges in the setting of a normal background suggest a genetic generalized epilepsy, whereas pleomorphic, multifocal discharges on a diffusely slowed background suggest an epileptogenic encephalopathy. Focal structural epilepsies often manifest pleomorphic focal discharges and focal background slowing. By contrast, the focal discharges seen in self-limited focal epilepsies such as benign epilepsy with centrotemporal spikes are associated with a normal background. (See "Electroencephalography (EEG) in the diagnosis of seizures and epilepsy", section on 'EEG findings in patients with epilepsy'.)

Abnormal EEGs in healthy children — EEGs of many healthy children without seizures contain epileptiform activity. In one study, epileptiform discharges were noted in 53 of 1057 (5 percent) normal school children ages 6 to 12 years [41]. In a second report, epileptiform abnormalities were found in 131 of 3726 normal children (3.5 percent) [42]. Follow-up studies over an eight- to nine-year period showed that only seven individuals subsequently developed epilepsy. The most common abnormalities were centrotemporal spikes (37 cases) and generalized spike and wave discharges (10 cases). There was a history of febrile seizures in 19 percent of the children with epileptiform discharges, and in 9 percent of those without EEG abnormalities. A higher incidence of epileptiform activity was also noted in the families, particularly the siblings, of children with idiopathic epilepsy, as well as in children with transient metabolic or other acute illnesses. With digital EEG recordings, the prevalence may be higher; in one prospective case series, 6.5 percent of 382 healthy children (except for recent mild head trauma) had epileptiform discharges on routine EEG [43].

Laboratory and genetic testing in undiagnosed epilepsy — Numerous tests may be indicated in the search for an underlying etiology of acute seizures. This section will emphasize the more common studies performed in the child with recurrent seizures of unknown etiology. Studies to consider in infants and children with unexplained seizures, particularly those with developmental delay and abnormal neurologic examination, include:

●Serum and cerebrospinal fluid (CSF) amino acid analysis

●Urine for quantitative organic acids

●Serum calcium, glucose, liver function tests (if not already evaluated)

●Serum acylcarnitine profile, ammonia, lactate, and pyruvate; serum lactate can be helpful in the evaluation of a suspected mitochondrial or other metabolic disorder (see "Mitochondrial myopathies: Clinical features and diagnosis", section on 'Laboratory studies')

●Arterial blood gas and pH

●CSF lactate and glucose (paired with blood glucose)

●Chromosomal karyotype

●Serum and CSF autoantibodies (eg, anti-N-methyl-D-aspartate receptor [NMDAR] antibodies)

In a retrospective review of patients with refractory epilepsy and developmental delay, metabolic abnormalities were identified in more than 70 percent of those without a previously identified diagnosis [44]. Multifocal interictal epileptiform discharges were associated with a finding of metabolic abnormality.

●Chromosomal syndromes – Virtually all chromosomal syndromes can manifest seizures. Another consideration in this regard is DNA analysis for fragile X syndrome in both males and females with maternal family histories of intellectual disability. Approximately 20 percent of males with fragile X syndrome have seizures, and female carriers of fragile X syndrome, even some with normal intelligence, can have seizures with focal EEG abnormalities [45,46]. More sophisticated genetic analyses such as chromosomal microarrays may be needed to diagnose those syndromes missed on routine karyotype analysis, such as Angelman and Rett syndromes [47]. (See "Fragile X syndrome: Clinical features and diagnosis in children and adolescents".)

●Neurodegenerative disorders – If a neurodegenerative disorder is suggested by the clinical or family history or parental consanguinity, further studies, including lysosomal enzymes, long-chain fatty acids (for peroxisomal disorders), and other biochemical analyses, are indicated, usually in consultation with a child neurologist and/or pediatric geneticist. The CSF should be examined for routine chemistries (protein, glucose) as well as lactate and amino acids. A tube should be frozen if needed for future measurement of metabolites and neurotransmitters associated with rare neurometabolic disorders.

●Autoimmune encephalitis – Several forms of immune-mediated encephalitis can present in childhood and adolescence, including anti-NMDAR encephalitis and encephalitis associated with antibodies to other synaptic proteins such as contactin-associated protein-like 2 (Caspr2) [48,49]. Such disorders can present with a broad range of symptoms in an otherwise healthy child, including psychosis, catatonia, behavioral and memory alterations, seizures, abnormal movements, and autonomic dysregulation. Unlike adults, children often do not have an underlying tumor or malignancy identified. While rare, these disorders are important to recognize because they may be highly responsive to immunotherapy. (See "Autoimmune (including paraneoplastic) encephalitis: Clinical features and diagnosis".)

●GLUT1 deficiency syndrome – A low CSF glucose in a child with no symptoms of infection and an otherwise normal CSF profile often is ignored, but may be the critical laboratory finding in the diagnosis of a rare disorder called glucose transporter protein syndrome (GLUT1 deficiency syndrome), which has a deficiency of the enzyme necessary for the transport of glucose into the CSF [50,51]. Diagnosis can be confirmed by an erythrocyte glucose uptake assay that shows low uptake [52]. Molecular genetic testing for pathogenic variants in SLC2A1 can also be used to identify some of these patients. Infants with this disorder have slowly progressive neurologic deterioration, seizures (often absence-type), and occasionally microcephaly [53,54]. Although few cases have been reported, it is probably underdetected. Glucose load may bring about transient improvement [51]. Children with this disorder are treated with the ketogenic diet. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

●Genetic testing – Genetic testing is increasingly available for a number of inherited syndromes but has variable clinical utility depending on clinical and genetic heterogeneity of a particular syndrome [55,56]. Targeted testing may be used to confirm a suspected clinical diagnosis, and broader genetic screening (eg, epilepsy gene panel, whole exome sequencing) may be performed in the hopes of identifying the underlying diagnosis in a child with epilepsy of unknown cause [47]. The diagnostic yield of genetic testing is likely to be highest in children diagnosed with neonatal and early-life epilepsy syndromes [57-60].

The type of genetic testing that may be useful varies according to the clinical context:

•Targeted gene testing – Targeted gene testing is appropriate if there is a high clinical suspicion for one specific disorder. As an example, TSC1 and TSC2 gene testing might be performed in an infant who presents with infantile spasms, hypsarhythmia on electroencephalogram (EEG), hypopigmented macules, but an inconclusive MRI in order to confirm the diagnosis of tuberous sclerosis complex. (See "Tuberous sclerosis complex: Clinical features".)

•Epilepsy gene panels – Epilepsy gene panels are most appropriate for infants who present with a specific epilepsy syndrome for which a number of different genetic etiologies exist (eg, neonatal seizures or infantile spasms without obvious cause by history, physical examination, or MRI scan). (See "Infantile epileptic spasms syndrome: Clinical features and diagnosis", section on 'Metabolic and genetic testing'.)

There are several commercially available epilepsy gene panels that are often grouped according to the patient's age. These panels perform specific gene sequencing for relevant disorders that could cause seizures in that age range. For example, an epilepsy gene panel for infants would including testing on known genes causing conditions such as Alpers disease, Angelman syndrome, benign neonatal familial seizures, Ohtahara syndrome, glucose transporter deficiency, West syndrome, and neuronal ceroid lipofuscinosis, among others. (See "Overview of neonatal epilepsy syndromes" and "Epilepsy syndromes in children".)

•Whole exome sequencing – Whole exome sequencing may be considered in infants who present with epilepsy without any clinical clues as to an underlying etiology [61]. This is a more comprehensive analysis that sequences an individual's entire exome, irrespective of the condition being investigated. (See "Next-generation DNA sequencing (NGS): Principles and clinical applications".)

Online resources that compile phenotypic information on genetic disorders and information on which commercial laboratories perform specific genetic tests include Genetic Testing Registry. Counseling for genetic testing is discussed separately. (See "Genetic testing".)

DIFFERENTIAL DIAGNOSIS

Nonepileptic events that may mimic seizures — The diagnosis of seizures is primarily based on clinical history, and accurate diagnosis requires differentiating seizures and epilepsy from other clinical events that can mimic seizures. The common nonepileptic disorders that can mimic seizures are listed in the table (table 1) and grouped by age.

Nonepileptic paroxysmal events more common in infancy, children, and adolescents are presented separately. (See "Emergency evaluation of syncope in children and adolescents" and "Nonepileptic paroxysmal disorders in infancy" and "Nonepileptic paroxysmal disorders in children" and "Nonepileptic paroxysmal disorders in adolescents and adults".)

Clinical behavior during seizures and nonepileptic events — Some general rules apply to the majority of seizures and provide the information necessary to distinguish true epileptic events from psychogenic nonepileptic events, other paroxysmal behavior or physiological events that may mimic seizures such as those based on cardiovascular dysfunction, and nonepileptic events with a central nervous system origin (eg, paroxysmal dystonia, infantile shuddering attacks, tics).

As examples:

●Episodes of sudden loss of tone with or without loss of consciousness in otherwise healthy children often are cardiogenic in origin. Occasionally, a child with atonic seizures will make a protective move during the fall. However, these seizures usually occur in a neurologically abnormal child (eg, Lennox-Gastaut syndrome, other developmental encephalopathies) and are rarely the sole seizure type. (See "Epilepsy syndromes in children".)

●If there is color change during a seizure, usually a generalized motor seizure, it will be cyanosis. Consider syncope as a cause for the event if the child is described as pale. (See "Emergency evaluation of syncope in children and adolescents".)

●Consistent crying before a "seizure" is suggestive of a cyanotic breath-holding spell. (See "Nonepileptic paroxysmal disorders in infancy", section on 'Cyanotic breath-holding spells'.)

●Pallid infantile syncope is a common benign pediatric syndrome characterized by sudden transient bradycardia with collapse and pallor, sometimes followed by an anoxic seizure. Recovery is spontaneous. These are often precipitated by a mild unexpected blow to the head and upper torso and are caused by excessive vagal tone of unknown etiology. (See "Nonepileptic paroxysmal disorders in infancy", section on 'Breath-holding spells'.)

●True absence seizures cannot be predictably interrupted by calling the child's name or by tactile stimulation, as can the staring spells or behavioral inattentiveness ("spacing out") commonly seen in children with attention deficit hyperactivity disorder (ADHD). Absence seizures often interrupt conversation or ongoing physical activity such as eating and play, whereas a pseudoabsence of inattention or "daydreaming" tend to occur during more sedentary activity (eg, sitting at a school desk). Absence seizures usually occur multiple times during the day and last only a few (rarely more than 10 to 30) seconds. (See "Nonepileptic paroxysmal disorders in children", section on 'Nonepileptic staring spells'.)

Although psychogenic nonepileptic seizures are more common in adults, they can occur in children in the second half of the first decade and are more common in adolescents [62]. Certain behaviors may help distinguish epileptic from psychogenic nonepileptic features, as listed in the table (table 2). These are described in detail separately. (See "Psychogenic nonepileptic seizures: Etiology, clinical features, and diagnosis", section on 'Clinical manifestations'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Seizures and epilepsy in children".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: EEG (The Basics)")

●Beyond the Basics topic (see "Patient education: Seizures in children (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The assessment of an infant or child with possible seizures or epilepsy includes a detailed history of events that include (see 'History' above):

•The setting in which episodes occur

•Behavior immediately prior to, during, and after the episode

•A physical description of the child before, during, and after the episode

•Frequency and duration of the episode

Other important aspects of the history include:

•A neurodevelopmental history

•A past and current psychosocial history, including potential stressors

•A family history

•A medical history, emphasizing conditions known to be associated with epilepsy (central nervous system infection, trauma, etc)

•Prescription and illicit drugs

●In addition to a detailed neurologic examination, the general medical examination is also important in the evaluation of a child with possible seizure or epilepsy, and should include a careful eye and skin examination. (See 'Examination' above.)

●Immediate or urgent neuroimaging is indicated for infants and children with new-onset seizures if there is focal seizure onset, new focal neurologic findings on examination, or a prolonged altered mental status following the event. Computed tomography (CT) may be used in the emergency department evaluation. Magnetic resonance imaging (MRI) scan is indicated for those children with known or suspected localization-related epilepsy or with associated developmental delays or focal findings on electroencephalography (EEG). (See 'Neuroimaging' above.)

●EEG is recommended in the evaluation of a child with suspected seizures or epilepsy. In addition to providing support for the diagnosis of epilepsy, the EEG also helps define the epilepsy syndrome and directs optimal therapy. Obtaining a tracing in the awake and sleep states, close in time to an event, and repeating the tracing can increase the diagnostic yield of the study. Nonetheless, the sensitivity and specificity of EEG is imperfect. EEG is not useful when the most likely diagnosis is syncope. (See 'Electroencephalography' above.)

●If the history, physical examination, MRI, and EEG do not reveal an etiology for seizures, the child should be evaluated for potential underlying metabolic, genetic, immune-mediated, and neurodegenerative disorders. (See 'Laboratory and genetic testing in undiagnosed epilepsy' above.)