Article Seizures in Children: Laboratory Diagnosis and Management · 2020. 1. 7. · The EEG can help conﬁrm the clinical diagnosis of epilepsy, classify the type of epilepsy, localize

Seizures in Children: LaboratoryDiagnosis and ManagementPhilippe Major, MD,*

Elizabeth A. Thiele, MD,

PhD*

Author Disclosure

Dr Major did not

disclose any financial

relationships relevant

to this article. Dr.

Thiele disclosed that

she is a consultant to

Abbott Laboratories.

Objectives After completing this article, readers should be able to:1. Formulate an appropriate diagnostic plan for a child who has seizures.2. Discuss the management of epilepsy.

IntroductionThe initial article on seizures in childhood (October 2007) focused on the diagnosis andclassification of seizures in children. This second article reviews investigational tools andmanagement. The evaluation of a child who has a seizure disorder must be tailored to thefindings on history and physical examination. The electroencephalogram (EEG) is theprimary electrophysiologic tool; brain neuroimaging is the primary modality for evaluatingneuroanatomic and functional features.

ElectrophysiologyThe EEG can help confirm the clinical diagnosis of epilepsy, classify the type of epilepsy,localize the epileptic focus, and help determine if treatment can be discontinued safely. Ingeneral, 21 electrodes placed on specific locations on the patient’s scalp measure voltagefluctuations of superficial neurons in relation to time. Figure 1 shows the position andlabeling of the scalp electrodes; Figures 2 through 6 show examples of typical EEGtracings. Generalized epileptic syndromes are characterized by discharges recorded simul-taneously at each electrode; partial epilepsy syndromes show localized spikes or slowing inthe epileptogenic region. Epilepsy is a clinical diagnosis that cannot be made on the basisof abnormal EEG findings. In fact, EEG abnormalities can be found in 5% of children whohave no history of seizures.

On the other hand, a normal EEG is noted in 10% to 20% of children who have epilepsy.EEG sensitivity can be enhanced by the use of activation methods such as hyperventilation,photic light stimulation, and sleep deprivation. Hyperventilation can trigger epilepticdischarges in 80% of patients who have generalized absence epilepsy, and photic stimula-tion induces EEG abnormalities in up to 40% of patients who have generalized epilepsy.When the routine EEG appears normal but the clinical suspicion of epilepsy remains high,a sleep-deprived EEG sometimes demonstrates occult abnormalities.

Long-term video-EEG monitoring is indicated primarily if the diagnosis of epilepsy is inquestion or when the seizures are intractable to medical treatment. The goal of thistechnology is to record seizures to characterize the electrical pattern on EEG during theepisodes, which often helps to pinpoint their origin. Video-EEG monitoring is essential forpresurgical evaluation if surgical ablation of an epileptic focus is being considered.Video-EEG analysis also is helpful to identify the nature of paroxysmal episodes, particu-larly in cases of pseudoseizures or nonepileptic events, frontal seizures, or paroxysmalmovement disorders.

When more precise seizure focus localization is needed prior to resective epilepsysurgery, subdural grids or depth electrodes can be placed by a neurosurgeon. Subduralgrids consist of strips of electrodes embedded in a flexible sheet of polyurethane com-pound. The grids are inserted surgically over suspected epileptogenic areas of the brain.Compared with standard EEG, subdural grids provide an electroencephalographic record-ing unaffected by artifacts and diffusion caused by the structures between the brain and thescalp. Each electrode in the grid also can be stimulated individually to delineate the

*Department of Neurology, Massachusetts General Hospital, Boston, Mass.

Article neurology

Pediatrics in Review Vol.28 No.11 November 2007 405

“eloquent” brain regions (eg, hand area) that should bespared during epilepsy surgery. Depth electrodes allowrecording of electrical activity coming from deep brainstructures (eg, hippocampus).

Brain ImagingComputed tomography (CT) scan and magnetic reso-nance imaging (MRI) provide precise anatomic brainimages and can identify potential epileptogenic lesions.Single-photon emission computed tomography (SPECT)scan, positron emission tomography (PET), and func-tional magnetic resonance imaging (fMRI) are func-tional brain imaging techniques that measure local vas-cular or metabolic changes associated with neuronalactivity. Magnetic resonance spectroscopy is used in se-lected cases to measure local biochemical abnormalities.

The decision to order brain imaging and the choicebetween CT and MRI depend on the child’s clinicalpresentation and the availability of scans. Due to higherresolution, MRI is now the gold standard for the neuro-imaging evaluation of epilepsy. Subtle lesions such asmesial temporal sclerosis, developmental brain malfor-

Figure 1. Scalp electrode positions for EEG. By convention,electrodes labeled with an even number are placed over theright hemisphere, and odd-numbered electrodes are placedover the left hemisphere. Fp�frontopolar, F�frontal,T�temporal, C�central, P�parietal, O�occipital, z�midline

Figure 2. Normal EEG tracing showing a reactive posterior alpha (9-Hz) rhythm in an 8-year-old boy who has no history of seizures.The slow waves observed in the frontal areas are associated with eye movements.

neurology seizures in children

406 Pediatrics in Review Vol.28 No.11 November 2007

mations, and arteriovenous malformations sometimescan be detected only on MRI. CT is reserved for caseswhen the MRI is not available. Although brain imaging isrecommended for children who have focal-onset sei-zures, it is not necessary for normally developing childrenwho have generalized seizures or typical febrile seizuresbecause the probability of finding a significant brainabnormality is very low (�2%) compared with a proba-bility of 26% in children who have partial epilepsy.

Functional neuroimaging (SPECT, PET, and fMRI)generally is not part of the routine epilepsy investigationbut can be useful for presurgical evaluation. SPECT andPET aim to localize the epileptic focus better. SPECTmeasures cerebral blood flow by using radiotracers (eg,99mtechnetium-HMPAO) and takes advantage of theobservation that cerebral blood flow is increased in theepileptogenic focus during a seizure. The interictalSPECT image is “subtracted” from the ictal SPECT tohighlight areas of increased cerebral blood flow. PETestimates cerebral metabolism by using molecules such as18F-2-deoxyglucose (FDG). The FDG-PET specifically

measures cerebral glucose utilization, which is correlatedwith neuronal activity. Focal hypometabolism generallyis associated with an epileptogenic zone. The fMRIrecords blood oxygen variation in different brain regionsduring the execution of specific tasks by the patient. Thistechnique allows localization of cerebral functions suchas language.

Neuropsychological EvaluationA large proportion of children afflicted with epilepsysuffer from variable learning difficulties. The neuropsy-chological evaluation is especially helpful for characteriz-ing these specific learning deficits and for developingstrategies for improving school performance. The neuro-psychological evaluation also is performed in most casesas part of the epilepsy presurgical evaluation to determinethe patient’s cognitive deficits and, if surgery is notperformed, the potential long-term consequences of ep-ilepsy. The Wada test (also called Amytal® test) often isrequired prior to surgery to localize the brain hemisphereresponsible for language and memory. This test consists

Figure 3. EEG tracing showing frequent independent left and right centrotemporal spikes in an 8-year-old child who has benignpartial epilepsy with centrotemporal spikes (also called benign rolandic epilepsy).



of language and memory testing after one brain hemi-sphere is “anesthetized” following left or right internalcarotid injection of sodium amobarbital.

TreatmentGeneral Principles

Appropriate care of a child who has epilepsy is crucialbecause this condition carries significant emotional andsocial burdens. The first step is to educate the child andthe parents about epilepsy. Demystification of this con-dition relieves a significant amount of anxiety. The pa-tient should be informed about potential precipitatingfactors: sleep deprivation, hyperventilation, alcoholabuse, recreational drugs, and photic light stimulation.The child and the family should be instructed regardingseizure first aid. (For an example of a seizure first aid plan,see: http://www.massgeneral.org/childhoodepilepsy/pdf/seizure_first_aid.pdf.) Children who have epilepsyusually can participate in sports, but basic safety precau-tions must be taken to prevent serious injuries(eg, no swimming or bathing alone). Physicians shouldfamiliarize themselves with state regulations concerning

driving restrictions for patients who have a seizurehistory.

The second step involves discussing all strategies avail-able to treat the seizures, which include antiepilepticdrugs (AEDs), special diets, surgery, and vagus nervestimulation. The decision to start an AED requires care-ful evaluation of the probability of seizure recurrenceagainst the potential risks attributed to the medication.Most neurologists do not recommend AED treatmentafter a first seizure because only about 30% of patientshave a second seizure. After two seizures, the risk ofhaving a third one increases to about 75% without treat-ment. Thus, AED treatment generally is initiated aftertwo seizures. Seizure control is achieved in most patients,but seizures become refractory to medication in aboutone third of patients.

ANTIEPILEPTIC DRUGS. Treatment is started with oneAED, with the dose gradually increased until seizures arecontrolled with minimal toxicity. If the first drug fails tocontrol seizures, the AED should be replaced by another.We usually recommend introducing the second drug

Figure 4. EEG tracing showing a right centroparietal spike (spikes observed in P4-O2, C4-P4, and F4-C4 leads) in a 12-year-old girlwho has partial epilepsy.



and, if the child tolerates this new medication, weaningthe patient from the first drug after a few weeks. If thesecond drug also is ineffective, a third medication can betried alone or added in combination. The choice ofAED depends primarily on the drug’s efficacy against aspecific seizure type, but the adverse effect profile, pres-ence of other diseases, ease of use, and cost also must beconsidered.

Classically, valproic acid was considered the firstchoice for treating generalized epilepsy; carbamazepinewas used for partial epilepsy. This scheme gradually isbeing modified as more experience is acquired with thenewer AEDs, which appear to be as effective, safer,and better tolerated than the traditional medications(Table 1). Table 2 shows a list of available AEDs andtheir associated primary adverse effects. Classification ofthe patient’s seizure type is crucial in choosing the ap-propriate AED. Some AEDs can worsen epilepsy if usedto treat certain seizure types. For example, carbamaz-epine is known to aggravate generalized epilepsy in somepatients.

Prior to AED treatment, blood should be drawn for a

complete blood count and for liver enzyme and kidneyfunction tests. Baseline complete blood count, liver en-zyme and kidney function tests, and regular blood AEDconcentrations usually are measured for the “traditional”AEDs (phenobarbital, phenytoin, valproic acid, car-bamazepine). Blood AED concentrations are useful inestimating the potential for increasing AED dosage inpatients whose seizures are uncontrolled, to check com-pliance, to determine dose-related toxicity, and to de-tect AED interactions in patients taking multiple AEDs(polytherapy).

When AEDs are used in combination, pharmacologicinteractions can be problematic. Carbamazepine, phe-nytoin, and phenobarbital are well-known cytochromeP450 inducers and can increase the metabolism of otherAEDs and of other medications (eg, oral contraceptives,steroids, warfarin). Valproic acid increases the plasmaconcentrations of phenobarbital, lamotrigine, and car-bamazepine 10, 11-epoxide (toxic metabolite), but doesnot affect the efficacy of oral contraceptives.

Because chronic AED treatment generates potentialmorbidity, the benefits of discontinuing treatment must

Figure 5. EEG tracing showing a generalized 3-Hz spike and wave discharge lasting 6 seconds in a 7-year-old girl who hasgeneralized absence epilepsy.



be balanced against the risks of seizures recurring.Known risk factors for seizure recurrence after AEDdiscontinuation are abnormal findings on neurologicexamination, seizure onset before age 2 years, EEGabnormalities, and specific epilepsy types (eg, juvenilemyoclonic epilepsy). Neurologists generally wait for aperiod of 1 to 2 seizure-free years before weaning a childoff an AED.

DIETS. The ketogenic diet has been used for morethan 80 years to treat children who have intractableepilepsy. For unknown reasons, this high-fat and low-carbohydrate diet sometimes provides dramatic improve-ment in seizure control and level of awareness. This dietrequires extensive parent training and child supervision.The potential adverse effects are renal stones, growthinhibition, hyperlipidemia, vitamin deficiencies, and con-stipation. A new diet (low-glycemic index diet) is beingdeveloped and has the advantage of being less restrictiveand more palatable than the ketogenic diet.

SURGERY. Epilepsy surgery is considered for patientswho have seizures that seriously impair their quality of

life and who have a localized seizure focus that possiblycould be resected without producing unacceptable se-quelae. Most surgical techniques aim to remove the brainarea responsible for the initiation of the seizure dis-charges. Such surgeries should be performed in special-ized epilepsy centers. Extratemporal resections are un-dertaken more commonly in children than in adultsbecause seizure foci in children are more likely to be dueto focal dysgenesis. Hemispherectomy is indicated forconditions in which the entire hemisphere generates theepileptic activity (eg, hemimegalencephaly, Sturge-Weber syndrome, Rasmussen encephalitis). Corpus cal-losotomy is a palliative procedure used to prevent thepropagation of epileptic activity from one hemisphere tothe other. Corpus callosotomy is performed primarily inpatients who have atonic seizures without any resectablelesion.

VAGUS NERVE STIMULATOR. The vagus nerve stimu-lator (VNS) is a pacemakerlike device that transmitselectrical impulses to the left vagus nerve. A lead isattached to the vagus nerve and is connected to a stimu-lator inserted subcutaneously on the chest wall. The

Figure 6. EEG showing hypsarrhythmia in a 9-month-old girl who has infantile spasms.



current indication for VNS is as adjunctive treatment ofintractable partial seizures. The mechanism of action isunknown, but presumably the stimulation modifies thebrain’s electrical activity. The device usually is well toler-ated, but possible adverse effects include hoarseness,coughing, throat paresthesias, and dyspnea as well as thepotential complications of the surgery itself.

PSEUDOSEIZURES. Management of nonepileptic events,or pseudoseizures, often poses a special challenge forclinicians, especially when a patient who has epilepsy alsohas pseudoseizures. Patient cooperation is crucial. Afterthe diagnosis is made, an appropriate strategy is to ex-plain that stress or emotions can cause seizurelike eventsunconsciously. It is important for the clinician to ac-knowledge the patient’s distress. The patient also shouldbe reassured that these events are not harmful to the

brain. The help of a mental health professional often isneeded to work on potential stressors and emotionalissues.

Specific DisordersBENIGN PARTIAL EPILEPSY WITH CENTROTEMPORAL

SPIKES. Until recently, most neurologists believed thatthe seizures associated with this condition (also known asbenign rolandic epilepsy) did not require treatment withAEDs, but this trend has changed, given the increasingliterature on cognitive deficits associated with rolandicepilepsy. It now is recommended to start AEDs after twoseizures. Almost all children enter long-term remissionby mid-adolescence.

TEMPORAL LOBE EPILEPSY. Temporal lobe seizuresoften are refractory to AEDs. Temporal lobectomy is

Table 1. Specific Use of Antiepileptic Drugs in Relation to the EpilepsyTypes

Primary Generalized Partial Onset

AbsenceMyoclonic,

Atonic, Tonic Tonic-Clonic Simple Partial Complex PartialSecondary Generalized

Tonic-Clonic

Ethosuximide Benzodiazepines Carbamazepine, Phenytoin, Phenobarbital, Primidone, Gabapentin, Tiagabine,Oxcarbazepine, Pregabalin

Valproate, Felbamate, Lamotrigine, Topiramate, Levetiracetam, Zonisamide

Table 2. Primary Adverse Effects Associated with Antiepileptic Drugs(AEDs)

AED (abbreviations) Primary Adverse Effects

Carbamazepine (CBZ) Hepatic or blood dyscrasia, ataxia, diplopia, rashClobazam* (CLB) Somnolence, ataxia, hyperactivityClonazepam (CLN) Somnolence, hyperactivityEthosuximide (ESM) Somnolence, blood dyscrasiaFelbamate (FBM) Severe aplastic anemia, severe hepatic toxicity, weight lossGabapentin (GBP) Ataxia, fatigueLamotrigine (LTG) Rash, ataxia, insomniaLevetiracetam (LEV) Somnolence, ataxia, behavioral changesOxcarbazepine (OXC) Hepatic or blood dyscrasia, ataxia, diplopiaPhenobarbital (PB) Somnolence, cognitive impairmentPhenytoin (PHT) Ataxia, nystagmus, somnolence, gingival hyperplasia, hirsutism, rashPregabalin (PGB) Ataxia, fatigueTiagabine (TGB) FatigueTopiramate (TPM) Cognitive impairment, weight loss, kidney stonesValproic acid (VPA) Severe hepatic toxicity, weight gain, osteopeniaVigabatrin* (VGB) Dizziness, retinal degenerationZonisamide (ZNS) Cognitive impairment, somnolence, weight loss, dizziness, kidney stones

*Not available in United States.



effective in approximately 80% of cases if mesial temporalsclerosis is observed on MRI.

FRONTAL LOBE EPILEPSY. Surgery is less beneficial forthis condition than for temporal lobe epilepsy becausethe seizure focus is harder to localize and lateralize andbecause larger brain areas often need to be resected. Withimproving MRI resolution, better outcomes are ex-pected after epilepsy surgery for frontal lobe epilepsy.

CHILDHOOD ABSENCE EPILEPSY. A good treatmentresponse is expected with valproic acid, ethosuximide, orlamotrigine. Seizures usually remit by adolescence orearly adulthood.

JUVENILE MYOCLONIC EPILEPSY (JANZ SYNDROME).More than 80% of patients who have this condition arewell controlled on broad-spectrum AEDs, but the sei-zures frequently relapse when the medication is discon-tinued, and treatment often is required into adulthood.

INFANTILE SPASMS. Medication controls spasmscompletely in approximately 75% of cases. Early controlof spasms is associated with a better cognitive outcome.Commonly used first-line drugs are vigabatrin (not avail-able in the United States) and adrenocorticotropic hor-mone; benzodiazepines, valproic acid, and topiramateare considered second-line therapy. The ketogenic dietand other broad-spectrum AEDs also may be effective.Carbamazepine sometimes precipitates the occurrence ofspasms.

LENNOX-GASTAUT SYNDROME. Seizure control inLennox-Gastaut syndrome is very difficult, and poly-therapy is common. Valproic acid, lamotrigine, topira-mate, and clonazepam are used commonly, with variableeffects on the different seizure types. Felbamate can beeffective but may be associated with significant morbid-ity. The ketogenic diet and VNS also may improve sei-zure control. Corpus callosotomy can reduce or abolishdrop attacks if there is no underlying major diffuse brainmalformation, but that procedure rarely influences theother seizure types seen in Lennox-Gastaut syndrome.

FEBRILE SEIZURES. Administration of an antipyretic(acetaminophen or ibuprofen) during febrile episodes isrecommended for children who experience recurrentfebrile seizures. Preventive anticonvulsant medicationshould be reserved for children who have frequent febrileseizures. Intermittent prevention strategy involves ad-ministering rectal diazepam (0.5 mg/kg) when the sei-

zure occurs or oral diazepam during the febrile episode(1 mg/kg per day divided in three doses). If the inter-mittent strategy is insufficient, continuous treatmentwith anticonvulsant medications can be started.

Status EpilepticusThe initial management of a child in status epilepticus isto secure the airway. The child should be placed on his orher side to prevent aspiration, making sure that the upperrespiratory airway is free and oxygen is provided by mask.Blood pressure and electrocardiographic monitoringshould be instituted. While gathering information fromthe parents and examining the patient, blood should bedrawn for a complete blood count, electrolytes, bloodglucose, calcium, and magnesium and toxicologic screen.An intravenous (IV) line should be placed. If the patientis known to have epilepsy and taking medication, con-centrations of AEDs should be determined. Any poten-tially epileptogenic metabolic imbalance should be cor-rected quickly.

If the seizure is not caused by metabolic derange-ment, the general consensus is to start treatment with abenzodiazepine. IV lorazepam at a dose of 0.1 mg/kg(0.15 mg/kg for patients already receiving a benzodiaz-epine) up to a maximum of 4 mg is generally the firstchoice. Diazepam at a dose of 0.3 mg/kg (0.5 mg/kgfor patients already receiving a benzodiazepine) also is agood option and can be administered intravenously,intrarectally, or endotracheally. Lorazepam or diazepamcan be repeated at the same dose if the seizure does notstop after 5 minutes.

The second step is to use IV phenytoin or phenobar-bital. Phenytoin (or fosphenytoin) is given at a dose of20 mg/kg intravenously (or 20 phenytoin equivalents/kg) up to a maximum of 1,250 mg. Phenytoin (or fosphe-nytoin) usually is ineffective for febrile status epilepticus.Phenobarbital is administered at a dose of 10 to 20 mg/kg,up to a maximum of 300 mg. If the seizure remains uncon-trolled, the third step is to induce a “barbiturate coma.” Atthis stage, intubation is mandatory, and an anesthesiologistshould be involved. Status epilepticus treatment protocolsvary at different institutions. Some physicians may use mi-dazolam, valproic acid, or other AEDs.

ConclusionMany investigational tools are available to refine theclinical evaluation of seizures in children. The additionalinformation gained from these studies helps to determineappropriate prognosis and treatment. Educating thechild and family about seizure disorders is another keyelement in effective management.



ACKNOWLEDGMENTS. We are very thankful to DrRon Thibert for his help in the preparation of this article.

Suggested ReadingCommission on Classification and Terminology of the Interna-

tional League Against Epilepsy. Proposal for a revised clinicaland electroencephalographic classification of epileptic seizures.Epilepsia. 1981;22:489–501

Commission on Classification and Terminology of the Interna-tional League Against Epilepsy. Proposal for a revised classifica-tion of epilepsies and epileptic syndromes. Epilepsia. 1989;30:389–399

Committee on Quality Improvement. Subcommittee on FebrileSeizures. Practice parameter: long-term treatment of thechild with simple febrile seizures. Pediatrics. 1999;103:1307–1309

Growing up With Epilepsy. An educational resource on childhoodepilepsy created by the MGH pediatric epilepsy program in

collaboration with the WBGH Educational Foundation. Avail-able at: www.massgeneral.org/childhoodepilepsy.

Hirtz D, Ashwal S, Berg A, et al. Report of the Quality StandardsSubcommittee of the American Academy of Neurology, theChild Neurology Society, and the American Epilepsy Society.Practice parameter: evaluating a first nonfebrile seizure in chil-dren. Neurology. 2000;55:616–623

Hirtz D, Berg A, Bettis D, et al. Report of the Quality StandardsSubcommittee of the American Academy of Neurology and thePractice Committee of the Child Neurology Society. Practiceparameter: treatment of the child with a first unprovoked sei-zure. Neurology. 2003;60:166–175

Provisional Committee on Quality Improvement. Subcommitteeon Febrile Seizures. Practice parameter: the neurodiagnosticevaluation of the child with a first simple febrile seizure. Pediat-rics. 1996;97:769–775

Sharma S, Riviello JJ, Harper MB, et al. The role of emergentneuroimaging in children with new-onset afebrile seizures.Pediatrics. 2003;111:1–5



PIR QuizQuiz also available online at www.pedsinreview.org.

1. A worried mother brings in her 16-year-old daughter for concerns over seizures at school. Her teacherreported that within 1 hour, the girl had three episodes of groaning and shaking all over with her eyes shuttight and her head moving from side to side. Each episode lasted approximately 3 minutes. There was norespiratory difficulty or urinary or fecal incontinence, and between episodes, the girl was awake and quietbut appropriately responsive. Additional history reveals no prior seizures and a recent move to the newschool. Her physical examination findings are normal. Of the following, the test that is most likely to revealthe diagnosis is:

A. Antinuclear antibody measurement.B. Computed tomography scan of the brain.C. Lumbar puncture.D. Urine toxicology screen.E. Video electroencephalography.

2. A 17-year-old girl who has had seizures for the past 5 years presents to your office. Her seizures have beenwell controlled (none in 2 years) on her current antiepileptic medication, and she asks you if it can bediscontinued. Physical examination findings are normal. Of the following, the factor that is most likely toincrease her risk of seizure recurrence after discontinuing her medication is:

A. Diagnosis of benign rolandic epilepsy.B. Diagnosis of juvenile myoclonic epilepsy.C. Family history of epilepsy.D. History of developmental delay as a young child.E. History of status epilepticus with initial seizure.

3. Of the following antiepileptic medications, which one is most likely to cause nephrolithiasis?

A. Ethosuximide.B. Lamotrigine.C. Phenobarbital.D. Topiramate.E. Valproic acid.

4. Of the following, which seizure type is matched correctly with the appropriate antiepileptic medication?

A. Absence epilepsy � Gabapentin.B. Atonic epilepsy � Phenytoin.C. Complex partial epilepsy � Carbamazepine.D. Simple partial epilepsy � Midazolam.E. Tonic-clonic epilepsy � Ethosuximide.



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Article Seizures in Children: Laboratory Diagnosis and Management · 2020. 1. 7. · The EEG can help conﬁrm the clinical diagnosis of epilepsy, classify the type of epilepsy, localize