Case-based Learning – Pediatric Seizures - macpeds.com

Case-based Learning – Pediatric Seizures Objectives:

1. What are the components of a focused seizure history? 2. What is a simple vs. complex febrile seizure? 3. What are red flags on physical examination following a seizure? 4. When do you need to investigate a febrile seizure? 5. How and what do you counsel regarding simple febrile seizures? 6. How do you manage status epilepticus? 7. How do you counsel about seizure safety?

You’re the Pediatrician on-call for a community hospital. The ER doctor has called you in to see David, a 20 month old boy who was brought in by his parents for a seizure. From what the ER doctor told you over the phone, you know that the boy is previously healthy, but had been having URTI symptoms for the past few days. As you walk towards the ER, you think of what you will ask the parents on history, especially your focused seizure history. <Pause for discussion> You walk into the room and introduce yourself. David’s parents are polite but are visibly anxious and worried. David is standing happily in the hospital crib. He points at you and smiles at his parents when you walk in. Pleased that he seems to be stable, you proceed with asking your history. David’s parents tell you that he started getting a runny nose and cough 3 days ago. Starting yesterday, he developed a fever that they controlled with Tylenol. His appetite decreased, but his drinking and urine output remained normal. There was no vomiting, diarrhea, or rash. There have been no sick contacts or recent travel. David awoke this morning with a fever of T 38.7°C axillary and was again treated with Tylenol. However, as his parents were getting him dressed, David started having “full body shaking with jerking of both his arms and legs”. The movements were rhythmic and he seemed “out of it”. His eyes were stared straight ahead, and parents did not notice any facial or mouth movements. He was still wearing his overnight diaper, so they are unsure of any bowel/bladder incontinence. They did hear some grunting, but there was no change in his colour. The entire episode lasted about 1 minute and David was sleepy afterwards for about 30 minutes, during which his parents had brought him to the hospital. He is now back to his normal behaviour. This has never happened before. His pregnancy and birth history are unremarkable. He is previously healthy with no history of seizures, head trauma, or meningitis. He is not on any regular medications, has no known drug allergies, and his immunizations are up to date. He and his family did not get the flu shot this year. He is developmentally normal for his age.

The family is not consanguineous. There is no family history of developmental delay or metabolic disorders. David’s maternal uncle had febrile seizures as a child but “grew out of it”. David currently attends full-time daycare while both parents are at work. There is no prior CAS involvement, no financial concerns, and good social supports. After obtaining your history, you proceed with the physical examination. Since David is an active 20 month old, you know you must be both systematic and organized. <Pause for discussion> David is alert and looks well. Not dysmorphic. HR 110, RR 25, BP 85/55, O2 sat 99% in RA, T 38.5°C ax at triage, now T 36.3°C after Tylenol. He has some nasal congestion with an erythematous throat and tympanic membranes bilaterally. Chest is clear. Pupils are equal 4mm and reactive to light. He has normal tone and reflexes 2+ throughout. He is active and playful with normal gait and no neurological deficits. You determine based on your history and physical examination that David most likely had a simple febrile seizure. You debate in your mind whether any investigations, such as bloodwork, lumbar puncture, EEG, and/or head imaging is warranted. <Pause for discussion> Because you are a newly graduated Pediatrician, and therefore tend to be overly cautious, you decide to order some basic blood work (CBC, electrolytes, extended lytes) knowing that they will likely be of low yield. However, you will not investigate further with a LP, EEG, or head imaging. As anticipated, the blood work is entirely benign and David is practically climbing out of his crib. He definitely looks well enough for you to send him home. His parents, however, are still quite anxious about the whole event and have many questions. “What’s the likelihood that this will happen again? What are the risk factors for recurrence?” “What should we do if it happens again? Should we call 911 or bring him back here?” “Is this epilepsy? Does he need anti-seizure medications?” <Pause for discussion> After reassurance and counselling, David and his parents head home. You have arranged follow-up with his family doctor in 2 days. You’re about to leave the ER when your pager goes off again. You turn around to see EMS wheeling in a young girl on a stretcher. She has an oxygen mask over her face and she is actively seizing. EMS tells you that Emily is a 7 year old girl with a known seizure disorder. Her neurologist has been trying to wean her off her anti-epileptics, with her most recent dose reduction occurring yesterday. She has already been seizing for at least 15 minutes. As your

medical team connects her to monitors, gets a set of vital signs, and obtains IV access, you quickly run through the status epilepticus algorithm in your mind. <Pause for discussion> Thankfully, Emily’s generalized-tonic-clonic seizure stopped after 2 doses of IV lorazepam and she did not require a loading dose of phenobarbital or phenytoin. You decide to admit her overnight for further monitoring and will contact her neurologist in the morning. You remind yourself that you should discuss seizure safety with Emily’s family prior to discharge. You head to your call room hoping to catch some sleep, since you have a full day in the office tomorrow.

DOI: 10.1542/pir.34-8-3332013;34;333Pediatrics in Review

Reet Sidhu, Kohilavani Velayudam and Gregory BarnesPediatric Seizures

http://pedsinreview.aappublications.org/content/34/8/333located on the World Wide Web at:

The online version of this article, along with updated information and services, is

Pediatrics. All rights reserved. Print ISSN: 0191-9601. Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of published, and trademarked by the American Academy of Pediatrics, 141 Northwest Pointpublication, it has been published continuously since 1979. Pediatrics in Review is owned, Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly

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Pediatric SeizuresReet Sidhu, MD,*

Kohilavani Velayudam, MD,†

Gregory Barnes, MD, PhD†

Author Disclosure

Drs Sidhu, Velayudam,

and Barnes have

disclosed no financial

relationships relevant

to this article. This

commentary does

contain discussion of

unapproved/

investigative use of

a commercial product/

device.

Educational Gap

The causes of seizures are many, and a number of other conditions can mimic seizures,

making careful evaluation of seizurelike episodes critical. Febrile seizures are the most

common type of seizure in children, and their management is usually the task of the gen-

eral pediatrician. Status epilepticus constitutes an emergency situation that can have

severe consequences and requires skilled therapy.

Objectives After completing this article, readers should be able to:

1. Identify the key elements in the evaluation of an individual who has seizures.

2. Know the main features of febrile seizures.

3. Understand the core principles in the treatment of status epilepticus.

4. Identify the salient clinical features of the main childhood epilepsy syndromes.

5. Be aware of common comorbidities in epilepsy syndromes.

6. Recognize the key differences between epileptic and nonepileptic seizures.

Definition and Pathophysiology of EpilepsySeizures (sometimes called epileptic seizures) are the stereotypical clinical manifestations(signs and symptoms) of excessive synchronous, usually self-limited, abnormal electrical ac-tivity of neurons situated in the cerebral cortex. Epilepsy is defined as 2 or more unpro-voked afebrile seizures (International League Against Epilepsy). Although both childrenwho have normal development and children who have developmental delay can display un-usual movements, the clinical signs (semiology) of epileptic seizures have specific stereo-typical features.

At the cellular level, ordinarily the neurons of the cerebral cortex fire asynchronously,albeit in patterns that facilitate learning, memory, sensory input, and behavioral output ofdefined neural circuits. A zone of ictogenesis (an area of brain capable of generating sei-zures) contains millions of neurons, all of which can fire synchronously. During electroen-cephalography (EEG), the recording electrodes on the scalp detect the synchronous firingof at least a 1-cm2 brain region as a spike and slow wave, the so-called epileptiform activity.

Causes of Acute Seizures and MimicsThe causes of epilepsy are varied. The most common causes of acute seizures are fevers,

infections, and head injury, which are detected through his-tory and laboratory testing. These types of seizures are re-ferred to as symptomatic seizures. In general, patients whohave focal seizures or focal neurologic signs should have neu-roimaging on initial presentation.

The evaluation process begins with a careful history anddescription of the spells. Parents may not always recognizethe symptoms of a seizure. Many epileptic seizures presentas a substantial but stereotypical episode in which childrendemonstrate jerking of the limbs, drooling, and eye rolling,during which consciousness is clearly impaired. After this

Abbreviations

ADHD: attention-deficit/hyperactivity disorderAED: antiepileptic drugCAE: childhood absence epilepsyCNS: central nervous systemEEG: electroencephalographyGTC: generalized tonic-clonic

*Department of Neurology, Columbia University School of Medicine, New York, NY.†Departments of Neurology and Pediatrics, Vanderbilt University Medical Center, Nashville, TN.

Article neurologic disorders

Pediatrics in Review Vol.34 No.8 August 2013 333

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type of seizure, most children are confused and tired andmay sleep for a prolonged period (postictal phase). How-ever, not all seizures are easily recognized.

Signs can be subtle, with staring that resembles day-dreaming or a vacant stare. During these types of sei-zures, children will not respond to tactile stimulation.Pertinent points in the history include the presence ofclonic movements or jerks, facial movements, eye andhead version, loss of bladder or bowel function, colorchanges, unusual noises, breathing abnormalities, heartrate changes, and other stereotypical movements. Thelength of each spell, the presence of a postictal phase,and how often the spell occurs should be determined.

Children often stare and do not respond to voice attimes. This behavior is commonly referred to as day-dreaming or mind-wandering. These benign, nonepilep-tic episodes may be characterized by the child quicklyreorienting to the parents or caregiver, and no other signsor symptoms of a seizure are present. When a child ap-pears to be daydreaming but has accompanying facialmovements (eye rolling, blinking, or fluttering) or a pausein activity commonly referred to as behavioral arrest, oneshould consider the possibility of a seizure.

Episodic movements with altered consciousness sug-gest seizure activity when any of the following featuresare present: (1) no response to tactile stimulation (touchof the face or body), (2) unusual eye movements (rapideye fluttering or fixed eye deviation), (3) unusual headmovements (forced head version), (4) unusual mouthmovements (chewing or lip smacking), (5) unusual facialmovements (twitching of the face), (6) stereotyped handmovements (repetitive reaching), (7) unusual posturingof a limb (freezing of an arm or leg), or (8) unexpectedincontinence.

The environmental setting and time of the day are alsoimportant to diagnose because nonepileptic spells mayhave inciting events. Nonepileptic spells during the nightmay be associated with sleep disorders, such as sleep ap-nea or sleepwalking. Nocturnal seizures may present asunexpected arousals with odd or repetitive hypermotorbehavior or complex behavioral automatisms, such aslip smacking or other facial movements, stereotyped handmovements, unusual posturing, unexpected inconti-nence, or gelastic (laughing) spells. Nocturnal seizuresare not associated with difficulty falling asleep, earlymorning or multiple awakenings, or prolonged periodsof wakefulness without altered consciousness or otherautomatisms.

It is crucial to assess for other conditions that maymimic seizures, including sleep disorders, gastroesopha-geal reflux and other gastrointestinal disorders, and

psychiatric disorders, including attention-deficit/hyperac-tivity disorder (ADHD). Review of the child’s medica-tions occasionally can reveal a medication that maylower the seizure threshold, although buspirone is theonly psychotropic medication associated consistentlywith unprovoked seizures in children. Other medica-tions used in the pediatric population, including stimu-lants and neuroleptics, rarely, if ever, lower the seizurethreshold in an individual patient.

A family history of epilepsy is a risk factor for epilepsyin children and should be assessed. Parents should keepa seizure diary describing the spells in detail and includingthe time of day the spells occur, the length of the spells,and whether there was a postictal phase. Videotape re-cording of the spells is encouraged, especially when theevent is not clearly epileptic. One should note a previoushistory of epilepsy; whether the child is taking antiepilepticdrugs (AEDs); presence of conditions associated with elec-trolyte (magnesium, phosphate, or calcium) disturbances,such as diarrhea or rickets; presence of acidosis associatedwith hypoxia; and history of ingestion. Provoking factors,such as sleep deprivation, fevers, and illness or infections,should be noted.

A child who presents with a change in sensorium andrepetitive seizures, with or without fever, should be inves-tigated for encephalitis. Focal neurologic signs may ormay not be present with encephalitis. Persistent focalneurologic signs after seizures not associated with fevershould alert one to the possibility of an arterial strokeor cerebral venous sinus thrombosis. Persistent focal neu-rologic deficits usually warrant acute neurodiagnostictesting with computed tomography of the head withcontrast.

Febrile SeizuresThe most common type of seizures in the pediatric pop-ulation is the febrile seizure. Febrile seizures are definedas seizures occurring in childhood after age 1 month, as-sociated with febrile illness but not caused by infection ofthe central nervous system (CNS), unassociated with pre-vious neonatal seizures or unprovoked seizures, and notmeeting criteria for other acute symptomatic seizures. Fe-brile seizures usually occur in children ages 6 months to 5years, with a peak age at onset of approximately 18months. The incidence is 3% to 8% in children youngerthan 5 years.

There are 2 types of febrile seizures: simple and com-plex. Simple febrile seizures are the most common typeand are characterized by (1) generalized clinical features,(2) duration less than 15 minutes, and (3) a single seizurein a 24-hour period. In contrast, complex febrile seizures

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are characterized by (1) focal clinical manifestation, (2)duration longer than 15 minutes, and (3) more thanone in a 24-hour period. Approximately 25% to 40% ofchildren who have febrile seizures have a family historyof febrile seizures; 9% to 22% of children have a siblingwho has a history of febrile seizures.

A high incidence of sodium channel mutations is re-ported in patients who have febrile seizures in childhood.The most important risk factors that predispose childrento having febrile seizures include peak temperature dur-ing the illness, history of febrile seizure in first-degree rel-atives, neurodevelopmental delays, increased exposure tohuman herpesvirus 6, and vaccinations with measles-mumps-rubella, diphtheria-tetanus-pertussis, and influ-enza vaccines. Almost 50% of the children who presentwith febrile seizures will not have any identified riskfactors.

The main purpose of the evaluation of children whohave febrile seizures is to exclude underlying CNS infec-tions. Lumbar puncture should be considered strongly ininfants younger than 12months, those who have prolongedcomplex febrile seizures or febrile status epilepticus, andchildren who are partially treated with antibiotics. Rou-tine EEG and neuroimaging are not indicated for simplefebrile seizures. Neuroimaging is recommended in pa-tients who have complex febrile seizures, neurologic def-icit on examination, prolonged postictal state, and signsof raised intracranial pressure. Patients who have febrilestatus epilepticus require EEG testing.

Reassurance and counseling are essential in the man-agement of febrile seizures. Rectal diazepam can be usedin the short term in a child who has risk factors for re-current febrile seizures, prolonged febrile seizures, or avery low threshold for febrile seizures. Daily prophylacticantiepileptic medication may reduce the recurrence of thefebrile seizures but will not reduce the risk of developingepilepsy and is not recommended routinely. Recurrenceof a febrile seizure usually occurs within the initial 1 to 2years after the initial seizure. (1) This association is im-portant to note when counseling families, given the highdegree of anxiety surrounding seizures.

The risk of recurrence of a febrile seizure is approxi-mately 60% after the initial febrile seizure. Risk factorsfor recurrence include younger age of onset, having aninitial febrile seizure associated with a relatively low tem-perature, family history of febrile seizures in a first-degreerelative, and brief duration between the onset of the feverand seizure. Approximately 2% to 7% of children whohave a history of febrile seizures have a risk of developingepilepsy. Risk factors for developing subsequent epilepsyafter febrile seizures include having a family history of

epilepsy, complex febrile seizure, and neurodevelopmen-tal abnormalities.

Approximately 40% of adults who have a history ofcomplex febrile seizures and febrile status epilepticus inchildhood develop mesial temporal lobe epilepsy. Simplefebrile seizures have a benign prognosis. There is no sig-nificant association between febrile seizures and later sig-nificant cognitive developmental delay or with suddeninfant death syndrome.

Treatment of SeizuresIn the pediatric population, treatment with AEDs is rec-ommended after 2 or more recurrent afebrile seizures.The characteristics of different types of seizures and drugsof choice for treating them are presented in the Table.Most children (approximately 60%) who experience a sin-gle unprovoked seizure will not have another. As indi-cated below, the choice of AEDs is dictated mainly bythe seizure type and interictal findings on EEG. How-ever, the other factors should be considered, includingthe need to control mood stability, the presence of co-morbid conditions (obesity), and the simultaneous useof other medications (long-term antibiotic therapy, suchas with macrolides).

The Food and Drug Administration has approveda number of drugs, including levetiracetam and oxcarba-mazepine, for use as therapy in pediatric seizures. Leve-tiracetam can be used to treat partial or generalizedseizures, whereas oxcarbamazepine is indicated for partialseizures. Initial doses of levetiracetam (20 mg/kg daily;range, 20-60 mg/kg daily) and oxcarbamazepine (10mg/kg daily; range, 10-40 mg/kg daily) can be increasedevery week to a higher dose. Other AEDs are discussedbelow and include valproic acid, used to treat juvenilemyoclonic epilepsy; ethosuximide-lamotrigine, used totreat childhood absence epilepsy (CAE); and carbamaze-pine-gabapentin, used to treat benign rolandic epilepsy.

Fast-metabolizing individuals between 6 and 60months of age can be identified by measuring troughAED levels before the initial morning dose. Oxcarbama-zepine and carbamazepine levels can be elevated by mac-rolide antibiotics. Levetiracetam can exacerbate knownneurobehavioral symptoms. A total of 100 mg/d of vita-min B6 can mitigate this problem. Complete blood cellcounts and serum sodium levels are monitored in patientstaking oxcarbamazepine because this drug can depressthe white blood cell counts and sodium levels.

When doses of AEDs are missed, the medicationshould be taken at the next opportunity (after the reali-zation that the dose was missed). When patients are seen





in the emergency department with frequent seizures aftermissing doses, levetiracetam can be reloaded intrave-nously at 20 to 30 mg/kg per dose.

In general, AED therapy is continued for at least 2years of seizure freedom. AEDs should be weaned grad-ually for months when possible. The risk of seizure recur-rence (approximately 90%) is highest in the 2 years aftertherapy discontinuation, with most recurrences in thefirst year.

Children who have the highest risk of seizure recur-rence are those having (1) a history in the distant pastof a disorder, such as viral encephalitis, that is knownto cause seizures; (2) abnormal EEG findings (epilepti-form discharges or focal slowing); (3) nocturnal seizures;(4) a history of febrile seizures; and (5) a history of Toddparesis. (2)

Pediatric patients who have active epilepsy should notparticipate in contact sports that can cause head injury,such as football, and should never swim unsupervisedor alone or ride a bicycle without a helmet. In addition,every family should be educated about seizure first aid,when rescue medications should be administered, andwhen to go to the emergency department for increasedseizure frequency.

Uncontrolled seizures put patients at risk for signifi-cant morbidity and mortality. For instance, the risk ofdeath is elevated 8-fold for children who have autismwho also have epilepsy. Sudden unexplained death in ep-ilepsy can occur in patients who have uncontrolled seiz-ures. Current standard of care in these patients includesconversations about the deadly consequences of seizures,the implication on prognosis, and the impact on qualityof life.

Treatment of Status EpilepticusStatus epilepticus is defined commonly as repeated seiz-ures without a return to consciousness lasting longer than

30 minutes. Most types of epileptic seizures can be man-ifested as status epilepticus. The 2 major types of statusepilepticus, generalized convulsive status epilepticus (ma-jor motor seizures and recurrent generalized tonic-clonic[GTC] convulsions) and nonconvulsive status epilepticus(recurrent nonconvulsive seizures, which include absencestatus, partial complex status, and simple partial status),are recognized clinically.

Convulsive status epilepticus is the most commonemergency associated with neurologic disease becausebrain damage and death can result from the systemic con-sequences of repeated GTC seizures. Most persons whoexperience GTC status epilepticus have localized cerebraldisturbances as a cause and therefore have secondary gen-eralized partial seizures.

Repeated cerebral epileptic activity can disrupt brainstructures or otherwise cause permanent neurologic orintellectual deficits. Common causes of status epilepticusinclude CNS infections, toxins, ingestions (includingAED ingestion), and drug withdrawal, such as from opi-ates or benzodiazepines. The most common cause ofbenzodiazepine withdrawal seizures is abrupt discontinu-ation of clonazepam use in patients undergoing long-term therapy for seizures or anxiety.

Therapy must be directed at suppressing all ictal (elec-trical seizure) activity on EEG. Ictal EEG activity canshow the following progression: (1) discrete seizures,(2) merging of seizures with waxing and waning of am-plitude and frequency in variable locations, (3) continu-ous ictal activity, (4) continuous ictal activity intermixedwith periods of isoelectric EEG, and (5) a periodic later-alized or generalized epileptic discharge pattern.

Frequent repetitive GTC seizures create a life-threateningsystemic condition of hyperpyrexia, failure of cerebrovas-cular autoregulation, acidosis, and severe hypoxia, caus-ing hypotension, hypoperfusion of the brain, pulmonaryedema, electrolyte disturbances, and eventual circulatorycollapse. Even after cessation of status epilepticus and

Table. Characteristics of Distinct Seizure Phenotypes

Seizure Type Interictal EEG Features Treatment of Choice

Partial complex Focal epileptiform or focal slowing Oxcarbamazepine, levetiracetamGeneralizedTonic-clonic Generalized epileptiform activity Lamotrigine, valproic acid topiramateAbsence 3-Hz generalized spike wave Ethosuximide, valproic acid, lamotrigineAtypical absence £2.5-Hz generalized spike wave Valproic acidMyoclonic tonicor atonic

4- to 6-Hz spike/polyspike and 1.5- to2.5-Hz generalized spike wave

Valproic acid, levetiracetamLamotrigine, topiramate, clobazam, rufinamide,felbamate





correction of systemic abnormalities, sepsis from aspira-tion pneumonia can be a late but life-threateningcomplication.

Treatment of status epilepticus consists of correctionof glucose, electrolyte, magnesium, and calcium distur-bances; control of blood pressure and oxygenation; andthe administration of benzodiazepines and a series of rou-tine anticonvulsants. At home, caregivers and parents canadminister rectal diazepam, which is absorbed rapidlythrough blood vessels, while they call 911 to summonemergency medical personnel.

Intravenous lorazepam (0.1 mg/kg per dose) usuallyis administered first in treating status epilepticus. If theseizures do not break, a second dose of intravenous lor-azepam (0.1 mg./kg per dose) is followed by fospheny-toin (20 mg/kg per dose). Next, a loading dose ofphenobarbital (20 mg/kg per dose) is considered if seiz-ures continue. Intubation is a consideration if respiratorydepression is observed with either benzodiazepines orphenobarbital. Seizures that are refractory to the treat-ments described may necessitate the use of inhaled gasesor, more commonly, pentobarbital-induced medical co-ma. During status epilepticus, transport to a facilityskilled in dealing with pediatric status epilepticus, pediat-ric intensive care monitoring, and continuous video EEGmonitoring is essential.

Partial Complex EpilepsyThe most common type of seizure during childhood,a partial seizure, is described in 2 categories. Simple par-tial seizures are those in which the initial clinical signs andEEG signatures begin focally in one area of the brainwithout impairment of consciousness. Simple partial sei-zures show focal neurologic signs, such as focal jerking ofone hand or arm, sensory change or pain in one limb, ora unilateral contraction of the face.

Partial complex seizures (psychomotor seizures) arethe more common of the 2 types of partial seizures thatmanifest as focal neurologic signs with impairment ofconsciousness. Commonly, for instance, in temporal lobeepilepsy, patients may experience a gustatory sensation,rising epigastric feeling, or some other aura followedby behavioral arrest. The child does not respond, oftenstaring off, then becomes lethargic. Sometimes childrendevelop jerking movements of limbs contralateral tothe seizure focus.

Secondary generalization of partial complex seizuresoccurs when seizures spread to the opposite hemisphereand are manifest clinically as GTC seizures. Thus, whenobtaining a clinical history in a patient who has had GTC

seizures, it is important to consider partial epilepsy. Theinterictal epileptiform activity (between seizures) is uni-lateral, focal, or multifocal epileptiform discharges. Theictal manifestations on EEG usually include evolvingfocal sharp waves or spike and slow wave discharges.Levetiracetam or oxcarbazepine often are used as first-line monotherapy for the treatment of pediatric partialseizures.

As children become older, epileptiform discharges onEEG are more frequent in the frontal or centrofrontal re-gions. Adolescents can have multifocal epilepsy, in whichthe predominant seizure type is a partial complex seizure.However, most seizures in the adolescent are generalizedseizures. GTC seizures are the most common type ofgeneralized seizures.

The seizure may have a prodrome in which a change inbehavior is seen. However, most seizures begin withoutwarning when the patient falls to the floor and cries out,the eyes roll toward the back of the head, and the limbsexhibit a rhythmic, tonic-clonic-tonic pattern of jerking.The individual may lose bowel or bladder function at theend of the seizure (ictal phase). Cyanosis can develop butusually is transient.

GTC seizures are typical of frontal lobe epilepsy, whichoccurs in adolescents. The EEG correlate is a buildup oflow-voltage fast activity, which evolves into high-amplitudespike/polyspike or polyspike and wave discharges. Patientstypically are sleepy or confused for a period after the sei-zure (postictal phase).

Many broad-spectrum AEDs, including levetiracetam,lamotrigine, topiramate, valproic acid, and zonisamide,are used in the treatment of GTC seizures.

Idiopathic Generalized EpilepsiesThe second most common type of epilepsy, CAE, ac-counts for 8% of epilepsy cases in school-age childrenand has an estimated incidence of 7 in 100,000 childrenages 1 to 15 years. The incidence peaks at age 5 years, andgirls constitute 60% to 70% of those who have CAE. Ab-sence seizures are characterized by lapses in consciousnessin which one can see a motionless stare, usually lasting 10to 15 seconds. During this brief event, eyelids may droop,flutter, or briefly roll backwards. The children usually re-sume their full activity after the seizure or may be brieflyconfused (<30 seconds).

Absence seizures can be associated with other activity,including automatisms, brief clonic movements of armsor eyelids, or loss of postural tone. The onset of absenceseizures is associated with an EEG pattern of regular, bi-laterally frontal-predominant generalized 3-Hz spike and





wave discharges, which begin and end suddenly in thesetting of a normal EEG background.

With either absence or GTC seizures, children canhave fragments of interictal discharges, which include bi-laterally frontal-predominant generalized spike and slowwave discharges. In the clinical trial study of CAE, treat-ment with ethosuximide, valproic acid, and lamotriginehad the greatest efficacy. (3) Ethosuximide, which causesgastric upset, is taken in capsules or liquid at a dose of 20mg/kg daily divided twice a day. Lamotrigine had theleast efficacy but the best adverse effect profile in the trial.With its black box warning regarding the risk of rash andStevens-Johnson syndrome, lamotrigine should be ad-ministered cautiously, with dose changes every 10 to14 days, until reaching a dose of 5 mg/kg daily dividedtwice a daily. Valproic acid is discussed below. In general,most children who have CAE have remission of absenceseizures by ages 12 to 16 years. Comorbidities are com-mon and include subtle cognitive deficits, linguistic diffi-culties, and psychiatric disorders, particularly ADHD andanxiety.

Atypical absence seizures are lapses in consciousness inwhich the patient can manifest a motionless stare, butthese spells are associated more with motor signs, partic-ularly changes in tone, and can be more apparent thantypical absence seizures. These seizures can have focal orlateralizing signs. The onset and cessation of these seizuresare less clear, and the duration is longer, typically 15 to 60seconds, with variable postictal confusion. These childrenare more likely to have absence status epilepticus.

The clinical onset is associated with similar generalizedspike-wave discharges but usually at a frequency of lessthan 2.5 Hz. Although atypical absence seizures can beseen in the setting of Lennox-Gastaut syndrome, theseseizures are not common in this population. These sei-zures and typical childhood absence seizures often are re-sponsive to valproic acid. Valproic acid usually is given at10 to 15 mg/kg daily divided twice daily and should beavoided in children younger than 2 years. Maintenancedoses usually are 25 to 30 mg/kg daily. Because of itsability to depress platelet counts and elevate liver functiontest results and pancreatic enzyme levels, routine bloodmonitoring of valproic acid levels, blood cell counts,and liver and pancreas function tests is recommended.

Juvenile myoclonic epilepsy is an epileptic syndromeof the idiopathic generalized epilepsy type of CAE, whichbegins at approximately ages 5 to 15 years. This epilepsyis defined by (1) myoclonic jerks on awakening, (2) GTCseizures in 90% of patients, and (3) development of ab-sence seizures in one-third of all patients. Myoclonic seiz-ures (epileptic myoclonus) are relatively rare outside the

syndrome of juvenile myoclonic epilepsy and usually areseen in the most profoundly affected epilepsy patients,such as those who have Lennox-Gastaut syndrome.The broader term myoclonus refers to quick, involuntarymuscle jerks that involve any part of the neuroaxis. Myo-clonic seizures can be differentiated both by semiologyand neurophysiologically from movement disorders, hy-perreflexia, and rare cases of spasticity. Myoclonic seiz-ures usually are bilateral generalized jerks (althoughthey can be unifocal, multifocal, or unilateral), whichare either sporadic or rhythmic in nature.

Commonly, myoclonic seizures are rapid, rhythmic,bilateral synchronous jerks (2-8 Hz) of the upper extrem-ities with occasional lower-extremity or whole bodyinvolvement. The ictal EEG is characterized by general-ized 4- to 6-Hz polyspike and slow wave discharges asso-ciated with the quick jerks. Most neuroimaging does notdetect abnormalities in classic juvenile myoclonic epilepsy.Seizures usually are controlled easily with valproic acid(20-40 mg/kg daily divided twice daily) or levetiracetam(20-40 mg/kg daily divided twice daily).

Symptomatic Generalized EpilepsiesTonic and atonic seizures are more common than, butnot necessarily always associated with, Lennox-Gastautsyndrome. Those AEDs with Food and Drug Adminis-tration indications for Lennox-Gastaut syndrome, includ-ing lamotrigine, topiramate, rufinamide, clobazam, andfelbamate, are all effective for seizures that collectivelyare causes of drops attacks (tonic, atonic, and myoclonicseizures).

Tonic seizures are more common in childhood andrepresent a continuum of the atonic-tonic seizures. Theseseizures are characterized by tonic spasms of the face orchest and trunk, with tonic flexion of the upper extrem-ities and flexion or extension of the lower extremities.Along with impairment of consciousness, patients canhave papillary dilation, tachycardia, apnea or cyanosis,and urinary incontinence, followed by a period of postictalconfusion. Ictal EEG is low-amplitude, very fast activity.

Atonic seizures (usually called drop attacks) consist ofa sudden loss of postural tone. In some patients, the dropattacks are preceded by one or more clonic jerks. In mildforms, the child may have a brief head drop (forward flex-ion of head and neck). In severe forms, the patient’swhole body may drop to the floor and, if refractory tomedications, may require a seizure helmet. The atonicseizure usually lasts only a few seconds and has little tono postictal period. The ictal EEG of an atonic seizureexhibits either generalized polyspike and wave discharges





or a sudden electrodecrement (suppression) of the EEG.Because synchronization of discharges between hemi-spheres is important for these seizure types to develop,a corpus callosotomy can be an effective surgical treat-ment to abolish these seizures.

Benign Rolandic EpilepsyBenign rolandic epilepsy, also referred to as benign child-hood epilepsy with centrotemporal spikes, is the mostcommon type of partial epilepsy in childhood, with onsetusually between the ages of 5 and 10 years. On the basisof its neuroanatomical location, most of these seizures in-volve unilateral facial sensory-motor and oropharyngo-gutteral symptoms, hypersalivation, and speech arrest.This partial seizure is the hallmark of benign rolandic ep-ilepsy. The child is awake, fully aware but unable to speak,drooling, and experiencing unilateral face and armtwitching. GTC seizures also occur, and approximately75% of children have these seizures only during sleepand have 5 or fewer seizures in their lifetime. Seizurescan happen during the day and with more frequency insome patients.

Most child neurologists will prescribe medications onlyafter 3 or more seizures, and, even then, the interval be-tween seizures plus parental concern and anxiety are con-sidered when initiating treatment with AEDs. Almost all ofthese seizures usually remit by age 16 years. However, ap-proximately 20% have a medication-resistant epilepsy withseveral seizures or clusters of seizures during the day.

The hallmark of the EEG is biphasic, focal centrotem-poral spikes and slow waves. The centrotemporal spikesare a clinical biomarker, with a strong genetic influenceand linked clinical phenotype. Some patients who havecentrotemporal spikes have a chromosome 11p13 auto-somal dominant inheritance pattern with variants of theELP4 gene, a gene important in cortical maturation. Halfof the children who demonstrate centrotemporal spikesmight not show any clinical presentation of this EEGtrait. According to 2006 International League AgainstEpilepsy guidelines, no AED has level A or level B evi-dence for efficacy and effectiveness. Carbamazepine, lev-etiracetam, valproic acid, phenobarbital, phenytoin, andclonazepam have equivalent efficacy in this syndrome.If AEDs are prescribed, they may be slowly tapered in pa-tients who are seizure free for 2 years or more. Most seiz-ures remit by age 16 years.

Infantile SpasmsInfantile spasms (West syndrome) are a specific type ofseizure occurring in infancy that often is classified as an

epileptic encephalopathy. This condition is consideredamong the most severe developmental epilepsies of in-fancy and childhood. With more than 200 known causes,infantile spasms has a diverse set of causes, including hyp-oxic ischemic encephalopathy; tuberous sclerosis; brainmalformations; central nervous system infections, includ-ing TORCH (toxoplasmosis, other [syphilis, varicella-zoster, parvovirus B19], rubella, cytomegalovirus, herpes)infections and encephalitis with herpes simplex virus;metabolic disorders; and genetic causes, such as Downsyndrome.

Gene mutations that affect synapse development, iontransport, protein phosphorylation, gene transcription,and other cellular functions are novel genetic causes asso-ciated with infantile spasms.

The clinical presentation of infants ages 3 to 9 monthsincludes spasmlike seizures that involve flexion, exten-sion, or mixed flexion-extension of the arms, legs, andtrunk. The spasms occur in clusters associated with elec-trodecremental response on EEG. The background or in-terictal EEG is chaotic, with a characteristic pattern calledhypsarrhythmia.

High-dose adrenocorticotropic hormone therapy(150 IU/m2 body surface area per day) for 2 weeks, fol-lowed by a taper, is considered by the American Academyof Neurology and the Child Neurology Society to be thetreatment of choice for infantile spasms. Adrenocortico-tropic hormone therapy remains the gold standard for thetermination of spasms and resolution of hypsarrhythmiaon EEG. Both goals are considered important to maxi-mize neurodevelopmental outcome. Thus, it is consid-ered important to identify and begin therapy as soon aspossible in patients who are having infantile spasms.

Vigabatrin (100-150 mg/kg daily divided twice daily)usually is the treatment of choice for children who have tu-berous sclerosis who have infantile spasms. Treatment withvigabatrin typically is for 6 months, during which time for-mal eye examinations should be monitored for retinal toxiceffects. The overall neurologic outcome is poor in patientswho have symptomatic causes of infantile spasms, whereasthose who have cryptogenic infantile spasms can have betteroutcomes. Children who have Down syndrome, however,respond well to treatment of infantile spasms. Recurrenceof other seizure types after treatment of infantile spasms iscommon. Patients who experience cessation of infantilespasms should be considered for long-term AED therapyfor at least 1 year after treatment.

Cognitive and Behavioral Issues in EpilepsyMany epileptic syndromes, such as benign rolandic epi-lepsy and CAE, demonstrate that pediatric epilepsies





can have significant potential comorbidities that involvebehavior and cognition. (4) Recent studies in childrenwho have new-onset epilepsy suggest that the mecha-nisms responsible for seizures in childhood rather thanthe epilepsy itself may be responsible for cognitive diffi-culties. Children who have new-onset seizures havea higher occurrence of depressive disorders (22.6%), anx-iety disorder (35.8%), and ADHD (26.4%) comparedwith controls (P<.01), but no difference was found inchildren who have focal vs generalized seizures. In 45%of the children who have epilepsy, psychiatric comorbid-ity antedated epilepsy. (5)

In a similar group of patients who have new-onsetseizures, ADHD, inattentive type, was seen in 31% of pa-tients vs 6% of controls (P<.001). The onset of ADHDantedated the diagnosis of epilepsy in 82% of patients,with 65% of patients having been referred for educationalsupport services. Again, no difference was seen in gener-alized vs focal epilepsy.

Data on cognitive ability, language skills, and presenceof psychopathology in 69 children who have CAE and103 age- and sex-matched healthy children suggesteda similar theme. Patients and their parents had semistruc-tured psychiatric interviews, cognitive evaluation, andlanguage testing. Twenty-five percent and 43% of thechildren who had absence epilepsy had subtle cognitiveand linguistic deficits, respectively. Interestingly, a surpris-ing 61% of children who have absence epilepsy satisfiedDiagnostic and Statistical Manual of Mental Disorders(Fourth Edition) criteria for a psychiatric illness, particu-larly ADHD and anxiety. Parents reported significantscores on the Child Behavioral Checklist in the areas ofattention, somatic symptoms, and social and thoughtproblems. (3)

The relation of these symptoms to the overall durationand frequency of absence seizures and to AED treatmentssuggests that the electrographic signature of 3-Hz spikeand wave, even after disappearance of clinical seizureswith AED treatment, may herald continuing neuronaldysfunction in multiple cortical-thalamic circuits.

Pediatric PseudoseizuresPsychogenic nonepileptic seizures, also referred to aspseudoseizures, are relatively rare in the pediatric popu-lations. (6) The prevalence is rare in adults (2-30 per100,000 population), without similar data existing forpediatric populations. Approximately 5% of all eventsseen in the pediatric epilepsy monitoring of a children’shospital are psychogenic nonepileptic seizures. Most ofthese episodes occur in patients who have no history of

epilepsy (67%), although one-third may occur in childrenwho have epilepsy.

Psychogenic nonepileptic seizures are paroxysmalevents that often resemble epileptic seizures but are psy-chological in origin. The major causes are stressors, usu-ally associated with family, school, or friends. Less than5% are due to physical or sexual abuse, but nonethelessit is important to screen for this important potentialcause.

In younger patients, prolonged unresponsiveness withsubtle motor changes tends to be the norm without anyelectrical changes on the EEG. Overall, children whohave nonepileptic seizures typically are older, in the agerange of 11 to 14 years. The mean duration of nonepilep-tic seizures (‡3-4 minutes) is much longer than the typ-ical pediatric epileptic seizure duration of 1 to 2 minutes.Tremors, either synchronous or asynchronous, in the up-per extremity are the most common motor signs. Trem-ors confined to one limb are observed commonly in thesetting of at least some responsiveness.

Unresponsiveness with expression of mostly negativeemotion (weeping, crying, painful facial expression, orfear) or laughing was observed more in the older patients.More complex motor movements, often asynchronousand involving multiple limbs, often are associated withdisturbed consciousness. Memories of these events anda short apparent postevent period with quick return tonormal activity should increase the suspicion of a nonepi-leptic seizure.

Treatment of nonepileptic seizure begins immediatelyafter video EEG monitoring with a consultation witha child psychiatrist. Before the consultation, a conversa-tion with the child’s caregivers regarding the nature ofthe spells and video EEG findings is of paramount im-portance. Nonepileptic seizures do not have an organiccause but require a search for psychogenic factors. Theloss of consciousness that can occur during nonepilepticseizures is puzzling but should be discussed with thefamily.

Typical conversations center around the reactions ofthe body, comparing nonepileptic seizures to other stressreactions. It is important to point out that although thecause is psychological in origin, the condition is no lessimportant and also very amenable to treatment if insti-tuted promptly. It is important to emphasize to parentsthat undergoing further unnecessary medical diagnostictesting only delays treatment and should be avoided.

Treatment of psychological factors with medicationsfor anxiety or depression with or without cognitive be-havioral therapy usually results in a lessening and thencomplete disappearance of the nonepileptic seizures.





Suicidal and homicidal thoughts or delusions should betreated aggressively in conjunction with a child psychia-trist. Success with these treatment modalities is high inchildren up to age 18 years, with more than 80% of pa-tients experiencing significant reductions or cessation oftheir nonepileptic seizures.

References1. American Academy of Pediatrics Subcommittee on FebrileSeizures. Neurodiagnostic evaluation of the child with a simplefebrile seizure. Pediatrics. 2011;127(2):389–394

2. Shinnar S, Berg AT, Moshe SL, et al. The risk of seizurerecurrence after a first unprovoked afebrile seizure in childhood: anextended follow-up. Pediatrics. 1996;98(2 pt 1):216–2253. Glauser TA, Cnaan A, Shinnar S, et al, for the ChildhoodAbsence Epilepsy Study Team. Ethosuximide, valproic acid, andlamotrigine in childhood absence epilepsy: initial monotherapyoutcomes at 12 months. Epilepsia. 2013;54(1):1–154. Jones JE, Austin JK, Caplan R, Dunn D, Plioplys S, Salpekar JA.Psychiatric disorders in children and adolescents who have epilepsy.Pediatr Rev. 2008;29(2):e9–e145. Kerr MP, Mensah S, Besag F, et al; International League ofEpilepsy (ILAE) Commission on the Neuropsychiatric Aspects ofEpilepsy. International consensus clinical practice statements for thetreatment of neuropsychiatric conditions associated with epilepsy.Epilepsia. 2011;52(11):2133–21386. Szabó L, Siegler Z, Zubek L, et al. A detailed semiologic analysisof childhood psychogenic nonepileptic seizures. Epilepsia. 2012;53(3):565–570

Suggested ReadingCostello DJ, Cole AJ. Treatment of acute seizures and status

epilepticus. J Intensive Care Med. 2007;22(6):319–347Gaillard WD, Chiron C, Cross JH, et al; ILAE, Committee for

Neuroimaging, Subcommittee for Pediatric. Guidelines forimaging infants and children with recent-onset epilepsy. Epi-lepsia. 2009;50(9):2147–2153

Glauser T, Ben-Menachem E, Bourgeois B, et al. ILAE treatmentguidelines: evidence-based analysis of antiepileptic drug efficacyand effectiveness as initial monotherapy for epileptic seizuresand syndromes. Epilepsia. 2006;47(7):1094–1120

Go CY, Mackay MT, Weiss SK, et al. Evidence-based guidelineupdate: medical treatment of infantile spasms: report of theGuideline Development Subcommittee of the American Acad-emy of Neurology and the Practice Committee of the ChildNeurology Society. Neurology. 2012;78(24):1974–1980

Wheless JW, Clarke DF, Arzimanoglou A, Carpenter D. Treatmentof pediatric epilepsy: European expert opinion, 2007. EpilepticDisord. 2007;9(4):353–412

Summary

• On the basis of strong evidence, treatment is highlydependent on the seizure semiology results,electroencephalography (EEG) findings, and origin.

• On the basis of moderate evidence and consensus,vigorous use of video EEG recordings and home videocameras should be used to delineate the epilepticsyndromes.

• On the basis of strong evidence, pediatric epilepsysyndromes have common comorbidities. Asa consensus, some pediatric epilepsy centers considerreferral to a neuropsychologist to be first-line care inthese patients.

• On the basis of strong evidence and consensus,antiepileptic drug therapy has its own complicationsand should be discontinued after an appropriatetreatment course.

• On the basis of moderate evidence and consensus,uncontrolled seizures put patients at risk forsignificant morbidity and mortality.

Parent Resources From the AAP at HealthyChildren.org

The reader is likely to find material relevant to this article to share with parents by visiting these links:

• http://www.healthychildren.org/English/health-issues/injuries-emergencies/Pages/Seizures.aspx• http://www.healthychildren.org/English/health-issues/conditions/head-neck-nervous-system/Pages/Difference-Between-

Seizure-and-Convulsion.aspx• http://www.healthychildren.org/English/health-issues/conditions/head-neck-nervous-system/Pages/Seizures-Convulsions-

and-Epilepsy.aspx





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New Minimum Performance Level RequirementsPer the 2010 revision of the American Medical Association (AMA) Physician’s Recognition Award (PRA) and credit system, a minimum performancelevel must be established on enduring material and journal-based CME activities that are certified for AMA PRA Category 1 CreditTM. In order tosuccessfully complete 2013 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance levelof 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity.

In Pediatrics in Review, AMA PRA Category 1 CreditTM may be claimed only if 60% or more of the questions are answered correctly. If you score lessthan 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved.

1. A 2-year-old has febrile seizures. Which of the following factors will increase her risk of subsequentlydeveloping epilepsy?

A. An initial febrile seizure with a relatively low temperature.B. Brief duration between onset of the fever and seizure.C. Complex febrile seizure.D. Family history of febrile seizures in a first-degree relative.E. Younger age at onset of febrile seizures.

2. Treatment with antiepileptic drugs is recommended after 2 or more recurrent afebrile seizures. A commonquestion from parents in response to this treatment parameter is, “What percentage of children whoexperience a single unprovoked seizure will not have another?”

A. 10%.B. 20%.C. 40%.D. 60%.E. 80%.

3. An 8-year-old child with a long history of recurrent generalized tonic-clonic seizures develops generalizedconvulsive status epilepticus. Which of the following is the first treatment of choice on encountering trainedmedical personnel?

A. Diazepam.B. Fosphenytoin.C. Lorazepam.D. Pentobarbital.E. Phenobarbital.

4. A 7-year-old boy develops spells that consist of a unilateral contraction of the left side of his face withoutimpairment of consciousness or speech arrest. Which of the following is the most likely diagnosis?

A. Absence seizures.B. Benign rolandic epilepsy.C. Juvenile myoclonic epilepsy.D. Psychomotor seizures.E. Simple partial seizures.

5. Generalized tonic-clonic seizures in adolescents are typical of which epileptic region of the brain?

A. Centrofrontal lobe region.B. Corpus callosum region.C. Frontal lobe region.D. Parietal lobe region.E. Temporal lobe region.





DOI: 10.1542/pir.34-8-3332013;34;333Pediatrics in Review

Reet Sidhu, Kohilavani Velayudam and Gregory BarnesPediatric Seizures

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ACUTE CARE COMMITTEE, CANADIAN PAEDIATRIC SOCIETY | 1

Emergency management of the paediatric patient with generalized convulsive status epilepticusJN Friedman; Canadian Paediatric SocietyAcute Care CommitteePaediatr Child Health 2011;16(2):91-7

AbstractThe present guideline paper addresses the emergency management of generalized convulsive status epilepticus (CSE) in children and infants older than one month of age. It replaces the previous statement from 1996, and includes a new treatment algorithm and table of recommended medications, reflecting new evidence and the evolution of clinical practice over the past 15 years. The document focuses on the acute pharmacological management of CSE, but some issues regarding supportive care, diagnostic approach and treatment of refractory CSE are discussed.

Key Words: Convulsions; Emergency management; Paediatrics; Seizures; Status epilepticus

Background and epidemiology

The conventional definition of convulsive status epilepticus (CSE) is continuous generalized tonic-clonic seizure activity with loss of consciousness for longer than 30 min, or two or more discrete seizures without a return to baseline mental status [1]. More recently, the terms ‘early’ or ‘impending’ status epilepticus have been based on a definition of continuous or intermittent seizures lasting longer than 5 min without full recovery of consciousness between seizures. It has been shown that early treatment is more effective in stopping the seizure, and treatment delay results in increased morbidity and mortality [2].

The annual incidence of CSE in children is reported as 10 to 73 episodes/100,000 children and is highest (135/100,000 to 156/100,000 children) in children younger than two years of age [3]. Common etiologies are listed in Table 1 [3]. Mortality has been reported to be between 2.7% and 8%, with an over

all morbidity (mainly newly diagnosed neurological disorders) of between 10% and 20% [2].

TABLE 1Common etiologies of convulsive status epilepticus in children and incidences from population-based studies

Acute

• Acute symptomatic (17% to 52%)– Acute CNS infection (bacterial meningitis, viral meningitis or en

cephalitis)

– Metabolic derangement (hypoglycemia, hyperglycemia, hyponatremia, hypocalcemia or anoxic injury)

– Antiepileptic drug noncompliance or withdrawal

– Antiepileptic drug overdose

– Non-antiepileptic drug overdose

• Prolonged febrile convulsion (23% to 30%)

Remote (16% to 39%)

• Cerebral migrational disorders (lissencephaly or schizencephaly)

• Cerebral dysgenesis

• Perinatal hypoxic-ischemic encephalopathy

• Progressive neurodegenerative disorders

Idiopathic/cryptogenic (5% to 19%)

CNS Central nervous system. Adapted from reference [3]

The present guideline paper addresses CSE in children and infants older than one month of age. It replaces the statement published in 1996 [4].

2 | EMERGENCY MANAGEMENT OF THE PAEDIATRIC PATIENT WITH GENERALIZED CONVULSIVE STATUS EPILEPTICUS

Protocols and guidelines

There is limited evidence in paediatrics on which to base a ‘gold standard’ protocol for the management of CSE. There are many different variations of guidelines, protocols and algorithms endorsed by organizations and institutions around the world, based on a combination of evidence, consensus opinion, local experience and drug availability [2]-[10]. Despite the minor variations in detail, in many ways they are quite similar.

In the highly stressed setting of this type of medical emergency, a familiar standardized protocol of recommended management saves time, prevents errors and facilitates care. Although the outcome is mainly determined by its cause, the duration of CSE is very important. A timely approach may be more important than the exact individual pharmacological interventions. Particular local expertise or resource limitations may provide legitimate reasons to adapt or adjust the recommended protocol. For individual children, who are known to respond well to specific medications, a more tailored approach may be more appropriate.

The objectives for the acute management of CSE are as follows:

1. Maintenance of adequate airway, breathing and circulation (ABCs).

2. Termination of the seizure and prevention of recurrence.

3. Diagnosis and initial therapy of life-threatening causes of CSE (eg, hypoglycemia, meningitis and cerebral space-occupying lesions).

4. Arrangement of appropriate referral for ongoing care or transport to a secondary or tertiary care centre.

5. Management of refractory status epilepticus (RSE).

1. Maintenance of adequate ABCS

Inability to maintain the airway is the most important immediate risk to the patient with CSE. Factors responsible for the

airway and ventilation being at risk include a clenched jaw, poorly coordinated respirations, and production of secretions and vomitus. Hypoxia is frequently present. Management of the airway includes positioning the child on his/her side and suctioning the easily accessible secretions. The teeth should not be pried apart. After suctioning, the patient should be repositioned on his/her back and a chin lift or jaw thrust should be applied, if necessary, to help open the airway. Oxygen (100%) should be given by face mask, and cardiorespiratory and oxygen saturation monitors should be used. Breathing should be carefully monitored. Assisted ventilation should be considered if the child shows signs of respiratory depression or if oxygen saturations remain low despite receiving 100% oxygen by face mask.

Increased heart rate and blood pressure (BP) are usually observed in the convulsing patient. They should return to normal when the seizure stops. Bradycardia, hypotension and poor perfusion are ominous signs. They imply severe hypoxia and an immediate need to establish the airway and ventilate the patient, either by bag-valve mask ventilation or intubation. Intravenous (IV) access should be obtained immediately (two large-bore IV lines if possible) and the bedside blood glucose level should be checked. Further testing should be considered once the ABCs have been stabilized.

2. Termination of the seizure and prevention of recurrence

Principles of treatment and monitoringThe major goal of treatment is to stop the seizure and, in doing so, prevent brain injury. In animal models, ischemic and excitotoxic neuronal cell loss starts to occur after 30 min of seizure activity. Seizures that last longer than 5 min to 10 min are at high risk of continuing for at least 30 min, so early treatment is associated with the best outcome. This is the rationale behind assuming that any child who arrives in the emergency department with acute tonic-clonic generalized convulsions is in early CSE, which should immediately trigger the first-line treatment with benzodiazepines as per the management protocol (Figure 1)



TABLE 2Anticonvulsant drug therapies for convulsive status epilepticus

Drug and route Dose Maximum Rate Repeat Risks Comments

First-line treatments

Lorazepam(IV, IO, buccal, PR)

0.1 mg/kg 4 mg <2 mg/min(IV over 0.5–1 min)

Every 5 min ×2

Hypotension, respiratory depression, sedation

Use sublingual tablets for buccal route.For PR route, dilute injection to 2 mg/mL in D5W or NS

Midazolam


Buccal 0.5 mg/kg 10 mg Every 5 min ×2


Intranasal 0.2 mg/kg 5 mg/nostril

IM 0.2 mg/kg

IV 0.1 mg/kg

Diazepam

IV 0.3 mg/kg 5 mg(<5 yrs)

10 mg(≥5 yrs)

<2 mg/min(IV over 2 min)

Every 5 min ×2


PR 0.5 mg/kg 20 mg

Second-line treatments

Fosphenytoin(IV, IM)

20 mg/kg phenytoin equivalents

1000 mg IV over 5–10 min(in NS or D5W)

Decreased risks compared with phenytoin

Expensive

Phenytoin* (IV) 20 mg/kg 1000 mg 1 mg/kg/min(over 20 min in NS)

Hypotension, bradycardia, arrhythmia

Must be given in nonglucose-containing solution

Phenobarbital†(IV, IO)

20 mg/kg 1000 mg 1 mg/kg/min(over 20 min in NS or D5W)

Respiratory depression (especially if benzodiazepine has been used), hypotension, sedation

First choice in neonates, or if on phenytoin maintenance

Paraldehyde‡ (PR) 400 mg(0.4 mL/kg/dose)

10 g(10 mL/dose)

Mucosal irritation Dilute 1/1 in oil in glass syringe

*If a patient is already receiving phenytoin, a partial loading dose of 5 mg/kg may be given. Subsequent doses may be given based on anticonvulsant levels; †If a patient is already on phenobarbital, a dose of 5 mg/kg may be given. Subsequent doses may be given based on anticonvulsant levels; ‡Paraldehyde is available through Health Canada's Special Access Programme but, currently, is only used in certain regions of Canada. D5W 5% dextrose water; IM Intramuscular; IO Intraosseous; IV Intravenous; NS Normal saline; PR Per rectum; yrs Years

Anticonvulsant drug therapies for CSE are listed in Table 2and Figure 1. If IV access is unavailable, then other routes (eg, buccal, intranasal and rectal) should be used while efforts to establish access continue. Consideration should be given to starting an intraosseous (IO) line if IV access is not possible and the seizure is prolonged or the patient is decompensating.

Because of the time required to administer many of the second-line treatments (eg, phenytoin and phenobarbital), preparations to give these should start at the same time as administering the first dose of benzodiazepine. Regardless of the particular institutional protocol being followed, some of the frequent problems encountered include the following [5]:

• Inadequate doses of benzodiazepines.


• Treating with more than two doses of benzodiazepines and a delay in initiating second-line treatment (usually fosphenytoin/phenytoin or phenobarbital).

• Delay in initiating the RSE treatments (usually rapid sequence induction/intubation and initiation of midazolam infusion).

It is important to obtain a brief history including any history of seizure disorder, other symptoms (eg, fever), medication usage and allergies to medications. This can be completed by a designated person not immediately involved in the acute resuscitation. This history will allow a simultaneous search for cause (Table 1) and focused physical examination to be completed while termination of the seizure is undertaken.

A bedside glucose determination will establish the need for a bolus of dextrose. If the blood glucose level is 2.6 mmol/L or lower, then the recommended management is 2 mL/kg to 4 mL/kg of 25% dextrose water or 5 mL/kg of 10% dextrose water (0.5 g/kg) by IV. If the patient is hypoglycemic, the bedside glucose level should be rechecked 3 min to 5 min postbolus, and a repeat bolus should be given as necessary. Increased intracranial pressure (ICP) or sepsis should be suspected and treated as needed.

During the administration of medications, pulse rate, respiratory rate, BP, cardiac monitoring and oxygen saturation via pulse oximeter should be followed on a regular basis. Anticonvulsant medications may cause loss of airway reflexes, respiratory depression, hypotension and cardiac arrhythmias. Monitor the child’s temperature and aim for normothermia using acetaminophen and ibuprofen as appropriate.

First-line treatmentFirst-line treatment usually begins outside the hospital. It has been shown that prehospital treatment of children reduces seizure length but often is not utilized [11]. Benzodiazepines are the first-line drugs of choice in the treatment of CSE. If used within the first 20 min of seizure onset, termination rates of seizures can be as high as 70% to 85% [5]. Because IV administration results in more rapid onset of action and improved bioavailability and efficacy, IV access should be obtained as soon as possible.

Prehospital: Treatment varies depending on local practices and availability, but options include the following: buccal or rectal lorazepam; buccal or intranasal midazolam; and rectal diazepam (for dosing details see Table 2). Buccal midazolam has been shown to control seizures in 56% of children compared with rectal diazepam (27%) [12]. Two further studies [13]

[14] showed a 70% to 75% response to buccal midazolam compared with a 57% to 59% response to rectal diazepam. In one trial [15], intranasal midazolam (88%) was shown to be as effective as IV lorazepam (92%) in the treatment of prolonged febrile convulsions of at least 10 min. If available, some

would consider buccal [16] or intranasal midazolam [2] to be the first-line management in children without IV access.

In hospital: IV lorazepam is usually the first-line treatment. It has a longer-lasting anticonvulsant activity and causes less respiratory depression than diazepam [17]. It has been shown to be more effective than diazepam or phenytoin in stopping seizures [18]. Note that repeat doses are much less likely to be effective (17% versus 85% for the first dose [12]). If children have received benzodiazepines in the prehospital setting, one repeat IV dose may be adequate [5] before moving to second-line treatments if necessary. Because timing is critically important, if no IV access is available, a second dose of benzodiazepine (lorazepam, midazolam or diazepam) should be given through the buccal, intranasal, rectal or intramuscular (IM) route while IV access is being obtained. Treatment with more than two doses of benzodiazepines is associated with respiratory depression [11].

Second-line treatmentFosphenytoin/phenytoin is generally preferred over phenobarbital because it is less likely to cause respiratory depression and alter the level of consciousness of the child [3], which can complicate the assessment. If no IV access is available, then IM fosphenytoin, IO phenytoin or rectal paraldehyde are alternative options. Note that evidence for the safety and efficacy of IO phenytoin or phenobarbital is scant.

Phenytoin and fosphenytoin: Phenytoin has been shown to control 60% to 80% of seizures with a 20 mg/kg dose [19]. It must be administered in normal saline (NS) because it precipitates in glucose-containing solutions. It is infused over approximately 20 min. Because of its high pH, extravasation of phenytoin can result in severe subcutaneous irritation (‘purple glove syndrome’) characterized by edema, discolouration and pain distal to the site of administration. This side effect does not occur with fosphenytoin (20 mg/kg/dose), which is a water-soluble prodrug of phenytoin. In addition to more rapid IV infusion, fosphenytoin may be given by IM injection, but it is more expensive and is not universally available [5]. Side effects of both phenytoin and fosphenytoin include cardiac arrhythmias, bradycardia and hypotension, so continuous BP and electrocardiogram monitoring is recommended during infusion.

Phenobarbital: Early trials suggest that phenobarbital has similar anticonvulsant activity to phenytoin, but a greater incidence of respiratory depression, especially when used in conjunction with benzodiazepines. The mechanism of action is similar to benzodiazepines, so it may be less effective in treating seizures refractory to these drugs [5]. It is still routinely used for the treatment of neonatal seizures, as well as for children who are already on phenytoin maintenance. The loading dose is 20 mg/kg in NS or 5% dextrose water over 20 min. Side effects include sedation, respiratory depression and


hypotension, especially if a benzodiazepine has already been given.

Paraldehyde: The mechanism of action is unknown. In the only published randomized controlled trial [20] to date, IM paraldehyde was found to be inferior to intranasal lorazepam as a first-line treatment in sub-Saharan Africa. In a prospective observational study [11], children who received IV phenytoin were nine times more likely to stop seizing than those who received rectal paraldehyde. There are, however, case series showing benefit in a minority of cases for which other anticonvulsant drugs have failed. Because of side effects reported with IV and IM use (eg, cyanosis, cough, hypotension and pulmonary edema), only the rectal route with dilution in oil is recommended. A dose of 0.4 mL/kg is mixed in an equal amount of oil to a maximum total volume of 20 mL [5]. Paraldehyde is available through Health Canada’s Special Access Programme but, currently, is only used in certain regions of Canada. Many authorities no longer recommend paraldehyde use, while others incorporate it only in cases for which there is no IV access.

Sodium valproate: There is increasing interest in the use of IV sodium valproate as a second- or third-line treatment. Initial open-label randomized trials look promising, with similar efficacy to phenytoin, fewer adverse effects and, specifically, no respiratory or cardiovascular compromise [3]. The IV loading dose is 30 mg/kg over 5 min, followed by a 10 mg/kg bolus if needed. The maintenance dose is 10 mg/kg by IV every 8 h [9]. Its role as a second-line treatment requires further investigation in well-controlled paediatric trials.

Pyridoxine: For children younger than 18 months of age in whom seizures may be caused by an undiagnosed metabolic disorder such as pyridoxine-dependent epilepsy, a trial of pyridoxine (vitamin B6) 100 mg by IV initially and then 50 mg IV or by mouth twice a day, should be considered [9].

3. Diagnosis and initial therapy of life-threatening causes of CSE

Investigations should be individualized according to the clinical scenario (Table 1). The most common cause of CSE is a prolonged febrile seizure. Children experiencing this type of seizure may not require an extensive workup. The same may apply to children with a known seizure disorder who are already on anticonvulsant therapy. However, a full clinical assessment should involve a search for precipitating causes, focusing on signs of infection, meningeal irritation, trauma, focal neurological deficits and intoxication. It is important not to mistake decorticate or decerebrate posturing for seizures.

When the etiology of the seizure is unclear, the following investigations should be considered [1]: blood for electrolytes,

glucose (to verify earlier bedside determination), complete blood count and differential, cultures (if sepsis is suspected), and capillary or arterial gas (perfusion must be adequate for capillary gas). Anticonvulsant levels should be measured for patients on long-term anticonvulsant therapy. Urine and blood can be sent for toxicology screening. Serum calcium, blood urea nitrogen, magnesium, liver enzymes, lactate and ammonia may be required in selected cases. A decision regarding the need for lumbar puncture (LP) should be deferred until the patient’s vital signs are stable, there is no suspicion of increased ICP and the convulsion has stopped. If sepsis is believed to be likely, IV antibiotics may be given immediately after blood cultures without waiting to perform the LP. Prolonged attempts at obtaining cultures should not delay treatment.

A history of trauma, evidence of increased ICP, focal neurological signs, unexplained loss of consciousness or suspicion of cerebral herniation are some of the indications for a computed tomography (CT) scan of the head. Head CT may be performed after the ABCs have been stabilized and the convulsion has terminated [1].

If there are clinical indications of raised intracranial pressure or herniation, these must be treated immediately before further investigation. A normal CT scan does not exclude significantly increased ICP. LP must be deferred if clinical or radiological signs of increased ICP are present.

Intoxication should always be considered as a possibility. If intoxication is proven or strongly suspected, and the convulsive activity has stopped, the use of activated charcoal may be considered once the airway is protected, either through intubation or after the child has woken up sufficiently to protect his own airway.

Non-CSEIf the child’s level of consciousness does not recover as expected after the convulsion has stopped, or if neuromuscular paralysis is being used, then an electroencephalogram (EEG) should be performed to exclude non-CSE. If an EEG cannot be obtained, then empirical treatment for non-CSE may be indicated [10].

4. Arrangement of appropriate referral for ongoing care or transport to a secondary or tertiary care centre

Children without a previous history of epilepsy or febrile seizures who present with CSE should be referred to either a secondary or tertiary care hospital for further treatment and investigation. Unstable vital signs or continuing CSE require transport to a paediatric intensive care unit. Stabilization of


the child before transport must be discussed with a physician skilled in paediatric emergency medicine or critical care.

5. Management of RSE

CSE that is unresponsive to two different antiepileptic medications (eg, a benzodiazepine and phenytoin) is considered to be refractory, although some authorities have added a duration criterion such as longer than 30 min or longer than 60 min [3][21]. Studies in children have indicated that CSE lasts longer than 1 h in 26% to 45% of patients [21]. These children are unlikely to respond to other second-line anticonvulsants. Therefore, escalation to anesthetic support with subspecialist and intensive care consultation and initiation of a midazolam infusion should be considered within 20 min to 30 min of starting the CSE algorithm (Figure 1).

It is recognized that paralysis may aid ventilation and prevent the motor manifestations of seizures, but it does not terminate the seizure activity in the brain. At this point, the patient’s care is beyond the scope of the usual emergency department setting, and transfer to a paediatric intensive care unit with neurological consultation for further management will be necessary. Management will depend on the previous experience in the individual centre involved, and may include intermittent or constant EEG monitoring.

Pharmacotherapy in RSE(Figure 1)

There are currently no published controlled trials examining different treatment options for RSE in children. A number of Canadian hospital guidelines have incorporated a continuous infusion of midazolam as the first step. If this fails, then anesthetizing doses of barbiturates should be considered. Most recently, the use of topiramate and levetiracetam has been suggested, but the role of these drugs remains unclear at the present time.

Midazolam: Midazolam is a fast-acting benzodiazepine with a short half-life. It is believed to be effective in the management of RSE and is administered by IV access with a bolus dose followed by continuous infusion. A loading dose of 0.15 mg/kg (maximum 8 mg) is followed by an infusion rate of 2 µg/kg/min. This can be titrated up by increasing by 2 µg/kg/min every 5 min until seizure control is achieved or a maximum of 24 µg/kg/min is reached [9][10]. Side effects include hypotension [21]. Therefore, BP should be monitored judiciously, and low BP should be treated by giving 20 mL/kg IV boluses of NS.

Barbiturates (thiopental and pentobarbital): Thiopental is dosed at 2 mg/kg to 4 mg/kg bolus followed by 2 mg/kg/h to 4 mg/kg/h. Increases of 1 mg/kg/h can be used every 30 min as needed, with a 2 mg/kg bolus with each increase in the in

fusion rate to a maximum of 6 mg/kg/h. If midazolam and phenobarbital are currently being used, they should be discontinued, whereas phenytoin should be maintained at therapeutic serum levels. Once seizures are controlled for 48 h, the infusion rate of thiopental is decreased by 25% every 3 h; phenobarbital is restarted while tapering [9].

If pentobarbital is used, it can be administered as a 10 mg/kg bolus, followed by a continuous infusion at 0.5 mg/kg/h to 1 mg/kg/h [10]. Studies in children reported an efficacy for pentobarbital of 74% to 100% and a high incidence of hypotension [21].

Other pharmacotherapy: Other options include propofol [10], topiramate [9] and levetiracetam [3][21]. These drugs may be useful in the management of RSE, but should be used by specialists with experience in their use.

Conclusion

There have been a number of changes in the emergency management of CSE over the past 15 years based on the emergence of new evidence and medications. It is important for all those involved in the acute medical management of children to have an up-to-date, evidence-based approach to the emergency management of children with CSE.

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ACUTE CARE COMMITTEEMembers: Adam Cheng MD; Catherine Farrell MD; Jeremy N Friedman MD; Marie Gauthier MD (board representative); Angelo Mikrogianakis MD (chair); Oliva Ortiz-Alvarez MDLiaisons: Claudette Bardin MD, Hospital Paediatrics Sec-tion, Canadian Paediatric Society; Laurel Chauvin-Kimoff MD, Paediatric Emergency Medicine Section, Canadian Pae-diatric Society; Dawn Hartfield MD, Hospital Paediatrics Sec-tion, Canadian Paediatric SocietyPrincipal author: Jeremy N Friedman MD

Also available at www.cps.ca/en© Canadian Paediatric Society 2014

The Canadian Paediatric Society gives permission to print single copies of this document from our website. For permission to reprint or reproduce multiple copies, please see our copyright policy.

Disclaimer: The recommendations in this position statement do not indicate an exclusive course of treatment or procedure to be followed. Variations, taking into account individual circumstances, may be appropriate. Internet addresses are current at time of publication.

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