Treatment of Seisure

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Uncontrolled or recurrent seizures affect a large number of children in the United United States. Compliance with medical therapy therapy is a crucial component to address when seizures recur. recur. The clinician should strive for seizure freedom or maximum reduction reduction of  recurrences balanced by the fewest adverse effects possible. If a child continues to have seizures and no other cause is identi fied, a rational treatment plan should be formulated. formulated. This may require further diagnostic testing.

Epilepsy and seizures affect at least 2.3 million people in the United United State States. s. The treatme treatment nt of febrile seizur seizures es (Chapterr 16,“Febrile Seizures”), (Chapte Seizures”), initial treatment of first unprovoked seizures  seizures  (Chapter 17, 17, “First Unprov Unprovoked oked Seizure”), and acute seizure emergencies (Chapter emergencies (Chapter 78, “Status Epilepticus”) are discussed discussed elsewhere. elsewhere. Once the seizure type or epilepsy syndrome has been classified, therapy may be initiated. Antiepileptic drugs (AEDs) are the primary primary form form of treat treatment. ment. Ho Howeve wever, r, 25 to to 30% of  children with epilepsy continue to have recurrent seizures. seizur es. In addition, addition, man manyy patients experien experience ce significant adverse adverse drug effects. effects. Children with epilepsy epilepsy characterized by uncontrolled uncontrolled seizures face a variety of risks, includingg higher includin higher mortality rates, higher rates of accidents and and injuries, injuries, a higher higher incidence incidence of cogn cognitiv itivee and psychiatric psych iatric impairments, impairments, poor self-esteem, self-esteem, highe higherr level levelss of anxie anxiety ty and depression depression,, and social social stigmatizatio stigmatization n or isolation. Thus, effective treatment to to control control seizures is fundamental to improving improving overall outcome. outcome. When the first-choice AED is prescribed, less than 50% of children are initially initially seizure-free. seizure-free. Wit With h adjustments adjustments in dose, this percentag perc entagee improves. improves. If the child has failed failed initial AED AED therapy (see Chapter Chapter 21, “First-Ch “First-Choice oice Antiepileptic Antiepileptic Drugs”), all treatment options  options  (Table 24-1)  24-1)  should be considered and a treatment plan developed. With all the treatment treat ment options options currently available, available, the clinician should strive for freedom from seizures or maximum

TABLE reatment ent Opti Options ons in Pedi Pediatric atric Epile Epilepsy psy TABLE 24-1. Treatm

reduction of recurrences balanced by the fewest adverse adverse effects possible.

as having one of these etiologies, etiologies,the the physician physician can describe the typical natural history history and prognosis of the epilepsy for

Current Management in Child Neurology, Third Edition   © 2005 Bernard Bern ard L. Maria, All Rights Reserved BC Decker Inc

Antiepileptic drug therapy (standard and new antiepileptic drugs) Vagus nerve stimulation Epilepsy surgery Ketogenic diet

Causes Caus es of Rec Recurre urrent nt Seizures Seizures The initial step in the treatment treatment of epilepsy involves involves corcorrectly identifying the event (seizure type) and associated conditionss that define the epilepsy condition epilepsy syndrome. syndrome. Etiology  should be established from the history, history, physica physicall examination, and selective selective laboratory tests. tests. All children with recurrecurrent afebrile seizures should have an electroencephalogram (EEG) performed while they are awake and asleep and a magnetic magnet ic resonance resonance imaging (MRI) (MRI) study of the brain. Children in the first 2 years of life may require special special MRI sequences and serial MRI scans to identify abnormalities during early brain development development.. This work-up will allow  classification classificatio n of the seizures seizures and epilepsy epilepsy syndrome. syndrome. Some seizure types (ie, (ie, absence, benign centrote centrotemporal mporal epilepsy  epilepsy  of childhoo childhood, d, geneti geneticc epilepsies) epilepsies) are are well contro controlled lled with initial therapy therapy.. How However ever,, some seizure seizure types, epilepsy synsyndromes, and specific etiologies are known known to be treatment resistant and typically lead to recurrent or intractable seizures (Tables seizures  (Tables 24-2 and and 24-3).  24-3). Once a child is identified

Recurrent Seizures

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140 /   / The Office Visit: Seizures and Epilepsy 140 TABLE TABL E 2424-2. 2. Sei Seizur zure e Type Typess and Epile Epilepsy psy Syndr Syndrome omess Associated with Recurrent Seizures

TABL ABLE E 2424-4. 4. Pre Predic dictor torss of Medica Medically lly Intra Intracta ctable ble Childhood Epilepsy

Simple partial seizures Complex partial seizures Myoclonic seizures Atonic seizures Tonic seizures Severe myoclonic epilepsy in infancy (Dravet syndrome) Ohtahara syndrome Infantile spasms (West’s syndrome) Lennox-Gastaut syndrome

Seizure onset in infancy Symptomatic etiology (organic brain disease–cerebral palsy, mental retardation) Seizure type (see type (see Table 24-2) Presence of multiple seizure types High seizure frequency Long duration of uncontrolled seizures Failure of previous medical treatment

the family. family. This prognosis includes the likelihood likelihood that the child will respond to certain treatment options, options, allowing a logical, sequentia sequentiall treatment plan to be formulated. In addition to the epilepsy type and the etiology, etiology, other factors are important in predicting medically refractory  childhood epilepsy  (Table   (Table 24-4). Ons Onset et in infancy infancy,, evidence of organi organicc brain disease, multiple seizure types (especially tonic tonic and atonic seizures), clustering of seizures, a persistently abnormal EEG, and a long duration of  epilepsy are dire prognostic indicators. A number of factors are responsible for for inadequate control of seizu seizures. res. Inco Incorrect rrect identifica identification tion of the seizure seizure type results in faulty diagnosis  diagnosis  (Table 24-5). The inability to distinguish between absence seizures and complex partial seizures may lead to use of inappropriate medication. This may result in a choice of medication that has the potential potential to exacerbate the underlying seizure type (Table type (Table 24-6). The clinicia clin ician n should should be awar awaree of thi thiss possibil possibility ity,, and if thi thiss appears to be occurring, occurring, therapy should be changed. The epileptic seizure must be distinguished from other nonepileptic events, events, as this can often lead lead to incorrect treatment or overmedication. overmedication. This is especially important in children with other neurologic neurologic abnormalities (ie, cerebral palsy, palsy, autism, and mental retardat retardation) ion) for which video-EEG monitoring may be necessary necessar y to correctly identify all the events. events. Failure to recognize recognize underlying disease TABLE TABL E 2424-3. 3. Syn Syndro dromes mes of of Intrac Intractab table le Child Childhoo hood d Epilepsy Neurocutaneous Sturge-Weber syndrome Tuberous sclerosis complex

Dysplasias Focal pachygyria Focal cortical dysplasia Band heterotopia Lissencephaly Hemimegalencephaly Hypothalamic hamartoma Rasmussen’s syndrome

Current Management in Child Neurology Neurology,, Third Edition   © 2005 Bernard Berna rd L. Maria , All Rights Reserved BC Decker Inc

processes, such as porphyri processes, porphyria, a, hypo hypoglyc glycemia, emia, or hypocal hypocal-cemia, may lead lead to apparent recurrent recurrent seizures. seizures. Failure to recognize precipitating factors (ie, reflex epilepsies, sleep deprivation, other medicines) that should be eliminated may lead to to lack of seizure control. control. Faulty treatment may cause recurrent seizures  seizures  (Table 24-7). Some specific seizure etiologies are known to be medically unresponsive and may be best treated with the ketogen ket ogenic ic diet, diet, vagu vaguss nerve nerve stimula stimulation tion,, or epileps epilepsy  y  surgery. Additionally Additionally,, certain medications may may exacerbate seizures. Drug interactions between AEDs or an AED and another drug may may lower the the efficacy of the AED, AED, resulting in increased seizure activity. activity. For children, children, especially in the the first 2 years years of life, the drug dose dose may may need to be be signifisignificantly higher on a mg-per-kg basis than the dose for adolescents or adults to achieve the same serum level. Children aged 2 to 10 years typically require 50% higher doses, whereas infants (aged 2 to 24 months) may require up to 100 to 200% higher doses on a mg-per-kg basis than the dose for for adults. adults. Serum blood blood levels, levels, along with clinical clinical response, respon se, help guide dosing dosing decisions, as a set maintenance maintenance dose may lead to an inadequate trial of the AED. AED. Patient factors may contribute to recurrent seizures (Table 24-8). One of the most most common common causes is partial partial compliance. This may be improved improved by patient education and use of an AED formulatio formulation n that allows allows twice-daily  twice-daily  dosing. dosin g. No Nonav navoidan oidance ce of preci precipitat pitating ing factors factors,, includ including ing sleep deprivation, emotional stress, and other medicines, may lead to continuation continuation of of seizures that might otherwise otherwise be controlled. Classic antihistamines may lower the seizure threshold in preschool children and promote apparent intractability. New research research suggests suggests several inherent inherent patient factors may predispose some children to recurrent seizures. Unfo Unfortunately rtunately,, there is currently no way to screen screen for these or to to modify treatment. treatment. Perhaps in the the future, magnetic resonance spectroscopy or another technology  may allow insights into a given patient’s brain neurochemistry and help guide treatment decisions.

Managementt of Recurren Managemen Recurrentt Seizures The treatment oftepilepsy requires the physician phy to determine the drug dr ug of firs first choice (see choice  (see Chapte Chapters rs sician 21, “First-Cho “First-Choice ice

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Recurrent Seizures / 141

TAB ABLE LE 2424-5. 5. Re Recur curren rentt Seizures Seizures:: Faulty Faulty Diagno Diagnosis sis

TABLE TA BLE 24-7. Recu Recurren rrentt Seizu Seizures: res: Faulty Tr Treatme eatment nt

Incorrect identification of seizure type or epilepsy syndrome Failure to correctly identify the event Failure to recognize underlying disease state Failure to recognize precipitating factors

Failure to use all available treatment options (see options  (see Table 24-1) Inappropriate medicine or therapy Drug interactions Polypharmacy Inadequate drug dosage

Antiepileptic tic Drugs” Drugs”and and 30,  30, “Curre “Current nt Pharmacotherapy for Antiepilep Pediatric Pedia tric Seizures and Epilepsy” and Table 24-9) and use it to its maximum effectiveness by increasing dosage up to the limit of tolera tolerability bility.. Effect Effectiven iveness ess is defined defined as a measure measure encompassing encompa ssing both efficacy (ie, seizure control) and tolerability.. If the first drug is unsuccessful, bility unsuccessful, an alternative alternative medication should be prescribed (Figure prescribed (Figure 24-1). This decision may  be influenced by other other factors (eg,dose (eg, dose formulation, formulation, comorbidity,, other medicines, pharmacokin bidity pharmacokinetics) etics) (Table  (Table 24-10). Use of of a single drug reduces the chance for potential potential side effects or drug interactions and often allows the best quality quali ty of life. Wh When en changing changing from from the first to a second second drug, the medicines medicines usually overlap overlap to prevent prevent a withdrawal or rebound increase in seizures. This allows time for the second drug to be increased in dosage to achieve efficacy.. When seizures continue cacy continue to recur, recur, a small number (10

AEDs appears to be better tolerated and accompanied by  fewer pharmacokinetic pharmacokinetic interactions interactions than was was true of the AEDs available prior to 1993 1993 (standard AEDs). AEDs). Also, a new  option, combining an AED AED with vagus nerve stimulation (see Chapt Chapter er 28, 28, “Epil “Epilepsy epsy Surge Surgery ry and Cortical Cortical Stimulation”), allows patients to have improved seizure control without the neurotoxicity neurotoxicity of polypharmacy polypharmacy.. Children who have failed two to three AEDs require more intensive intensive diagnostic effort. This typically consists of  video-EEG monitoring monitoring with scalp electrodes, electrodes, a highquality MRI with a specific epilepsy protocol, protocol, and possibly  other laboratory studies to search for an underlying etiology. Refe Referral rral to a compreh comprehensive ensive pediatric epilepsy program is recommended. This information is used to assess the risks, risk s, ben benefi efits, ts, and expect expected ed outcom outcomee of all treatm treatment ent

to 20%) of patients may benefit from from treatment with two AEDs. Strategies include combining combining drugs with different mechanisms of action (rational polypharmacy) polypharmacy) or drug combinations felt felt to be synergistic (eg, valproate [VPA] [VPA] and lamotrigine lamotrigine [LTG] [LTG],, VP VPA A and ethosuximide). ethosuximide). In the past, the teaching was to “change “change only one thing at a time” to learn as much as possible about which drug is most effective. effect ive.For For example, example, if seizure seizuress recurred despite despite maximal maximal dosingg of carbam dosin carbamazep azepine ine (CBZ), (CBZ), it was customary customary to add VPA without simultaneously decreasing the CBZ doses. Although it is still the case that a combination combination of of drugs may be effective when no single agent provides satisfactory  seizure control, control, there has been a shift in practice, whereby  drugs are increasingly used sequentially as monotherapy 

options (see Table 24-1) f or options (see or the child’s epilepsy type or syndrome.. A plan is formulate drome formulated, d, and a sequenc sequencee of treat treatment ment steps, based on respon response se to to therapy therapy,, is outlined outlined.. This is communicated commu nicated to the local pediatric neuro neurologist. logist. If the child’s seizures continue, periodic reevaluation is suggested at the comprehensive comprehensive pediatric epilepsy center. This allows review of the treatment treatment plan and and the use of newe newerr diagnostic tests or treatments. Currently,, many children continue Currently continue to have have recurrent seizures despite despite the use of all available treatment treatment options. options. Following the approach outlined above allows the best seizure control control and subsequent subsequent quality of life for each child with epilepsy. Since 1993, several new AEDs have have been released in the the

rather than in combination. This practice has evolved because of the ready ready availability of of new effective effective AEDs AEDs and recognition that polypharmacy is associated with significant toxicity toxicity.. Ho However wever,, polypharmacy with the newer

United States. As a group,these group, these newer drugs differ from from the established or first-choice first-choice drugs in terms of their pharmacokinetics (T cokinetics  (Table able 24-11), interaction potential, and adverse adverse effects. effect s. In addition, addition, the newer newer drugs may may achieve achieve seizure seizure

TAB ABLE LE 2424-6. 6. Re Recur curren rentt Seizures Seizures:: Antiepi Antiepilep leptic tic Drug Drug Associated with Seizure Exacerbation

TABL ABLE E 2424-8. 8. Re Recur curren rentt Seizures Seizures:: Patient Patient Fact Factors ors

Antiepileptic Drug

Seizure Type Exacerbated

Carbamazepine Oxcarbazepine Phenytoin Phenobarbital Vigabatrin Tiagabine Gabapentin

Absence, atonic, myoclonic Absence, atonic, myoclonic Absence, atonic, myoclonic Absence, atonic Absence, myoclonic Absence, myoclonic Myoclonic



Current Management in Child Neurology, Third Edition   © 2005 Bernard Bern ard L. Maria, All Rights Reserved BC Decker Inc

Partial compliance with AED therapy Nonavoidance of precipitating factors Use of other drugs—lower seizure threshold or altered AED levels Possible patient brain factors: MDR1 overexpression Low brain GABA levels or abnormal GABA receptor EAAT3 dysfunction Alteration in drug-binding at the Na + channel AED = antiepileptic drug; EAAT3 = excitatory amino acid transporter; GABA = γ -aminobutyric -aminobutyric acid; MDRI = multiple drug resistance gene.

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142 /   / The Office Visit: Seizures and Epilepsy 142 TABLE BLE 24-9. Recu Recurrent rrent Seizur Seizures: es: AED AED Treatm Treatment ent Options Options TA for Epilepsies and Epilepsy Syndromes Cryptogenic or symptomatic generalized epilepsies Infantile spasms First choice: ACTH, vigabatrin, nitrazepam Second choice: zonisamide, valproate Lennox-Gastaut syndrome Valproate, topiramate, lamotrigine, felbamate, zonisamide, vigabatrin Generalized idiopathic epilepsies Benign myoclonic epilepsy of infancy Valproate, topiramate, lamotrigine, zonisamide Childhood absence epilepsy Ethosuximide, valproate, lamotrigine Juvenile absence epilepsy Valproate, lamotrigine Juvenile myoclonic epilepsy Valproate, lamotrigine, topiramate, levetiracetam, zonisamide Epilepsy with GTC seizures on awakening Valproate, lamotrigine, topiramate Localization—related (partial) epilepsies Benign childhood epilepsy with centrotemporal spikes Gabapentin, oxcarbazepine, carbamazepine (extended release), phenytoin Partiall seizures ± second Partia secondary ary GTC Carbamazepine (extended-release), phenytoin, valproate, gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide ACTH = adrenocorticotropic hormone; AED = antiepileptic drug; GTC = generalized tonic-clonic.

control or improved tolerability in situations in which an established establis hed drug had had not. Ho Howeve wever, r, the availabili availability ty of  new AEDs represents a therapeutic dilemma for the clinician because optimal optimal use of these drugs has not yet yet been established. There is little information on the comparable bene benefits fits of new AED AEDs. s. In the nex nextt sectio section n of of this chapter chapt er,, the clinical clinical pharmaco pharmacology logy of the newer newer AEDs AEDs and seizure types or epilepsy epi lepsy syndromes for which each is useful will be discussed, with the realization realization that with

FBM due to to the emergence emergence of of reports of aplastic anemia anemia and hepatic failure. Unco Uncontrolled ntrolled reports suggest that FBM might be efficacious against absence absence seizures, infantile spasms, Doose syndrome, syndrome, juven juvenile ile myoclonic epilepsy, epilepsy, and acquired epileptic aphasia. Eve Even n with its broad broad spectrum of activity activity,, FBM’s main indication is in children with Lennox-Gastaut syndrome who have failed to respond to other treatments (eg,, VP (eg VPA, A, to topira piramat matee [T [TPM PM], ], LTG TG,, ket ketoge ogenic nic diet, diet, vag vagus us nerve stimulation) or as a third-line option in children with refractory partial-onset seizures. Nausea, Nau sea, vom vomiting iting,, anor anorexia exia,, weigh weightt loss, dizzin dizziness, ess, insom insom-nia, headache, headache,and and somnolence were were the most commonly commonly recognized side effects effects of FBM. FBM.Anore Anorexia xia and weight loss were the the most prominent and can be significantly worsened by cotreatment with other drugs sharing these side effects (eg,stimulant (eg, stimulant medication medic ation,, TPM, zoni zonisamid samidee [ZNS]). One year after FBM’s FBM’s release,it release, it became evident that FBM was associated associated with aplastic anemia, and the drug came close to being removed from the market.Additionally,, cases of severe hepatot market.Additionally hepatotoxicity oxicity,, some with fatal outcome,were outcome, were reported.Although reported. Although severe hypotoxicity hypotoxicity has occurred occu rred in children, children, no cases of aplast aplastic ic anemia anemia have been been reported in children children under the age of 13 years.Kno years. Known wn risk factors for FBM toxicity toxicity include a history of allergy or cytopenia with other AEDs and evidence of a concomitant immune immune disorder.. These should be sought by careful history-taking before order beginning therapy with FBM. Baseline hematologic and liver liver function tests should be performed and families informed of  potential poten tial risks. Cautio Cautious us introduction introduction of FBM reduces reduces the occurrence of early adverse adverse events. events. Therapy is typically initiated at 15 mg/kg/d (maximum of 1,200 mg) mg) and increased increased weekly by by 15 mg/kg/d mg/kg/d to

more experience, experience, this may change.

Clinical Pharmacology Pharmacology and and Use Use of New  Antiepileptic Drugs Felbamate

Felbamate (FBM) was released in the United States in 1993. FBM was tested tested in the the first-ever double-blind, placebocontrolled study in patients with Lennox-Gastaut syndrome. A decrease in total seizure number was significant for FBM, and FBM was particularly particular ly effective in reducing the frequency  of drop attacks. attacks. Effica Efficacy cy for monothera monotherapy py and adjunctiv adjunctivee treatment of of partial-onset seizures seizures was established established in adolescents anmarked d adults, but pediatric sttion stopped opped because ofand restrictions on thestudies use andwere promo promotion of  Current Management in Child Neurology Neurology,, Third Edition   © 2005 Bernard Berna rd L. Maria , All Rights Reserved BC Decker Inc

FIGURE 24-1.

Treatment of recurrent seizures. AED = antiepileptic drug.

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Recurrent Seizures / 143

TAB ABLE LE 2424-10. 10. Con Consid sidera eratio tions ns in the the Selec Selectio tion n of Antiepileptic Drug Therapy Efficacy for seizure type, epilepsy syndrome Safety Side effect profile Mechanism of action Drug interactions Need for laboratory monitoring Dosing requirements/drug formulations Cost

45 mg/kg/d (maximum 3,600 mg). Some children tolerate much more rapid dose escalation or benefit from doses up to 60 to 90 mg/kg/d (5,000 to 6,000 mg/d). mg/d). Serum levels and clinical response response guide dosing decisions. It is our policy to continue FBM only when seizure control is dramatic. Typically, intermittent hematology and liver function tests are checked the first 6 to 12 months and later as clinically  indicated. Comedications may need adjustment because of  of  known interactions. interactions. Obtaining baseline and follow-up follow-up serum levels of all AEDs assists in these these decisions. Gabapentin

Gabapentin (GBP) was marketed in the United States in 1994.. GBP is a niche 1994 niche AED AED, showin showingg efficacy efficacy against against only  partial and secondary generalized seizures. Pediatric studies showed efficacy efficacy in the treatment of partial seizures, whether refractory refracto ry or benign. GBP was studied in children as adjunctive therapy in refractory partial seizures s eizures and as monotherapy in benign centrot centrotempo emporal ral epilepsy of childh childhood. ood. Two double-blind studies of GBP in childhood childhood absence epilepsy  failed to demonstrate demonstrate efficacy. efficacy. A single placebo-controlled study of GBP in patients patients with generalized generalized tonic-clonic tonic-clonic seizures did not show efficacy over placebo. GBP was the first AED to be introduced that was excreted excret ed entirely by the the kidney. kidney. This infers a significant clinical advantage because GBP is neither the cause nor the

object of pharmacokinetic interactions. interactions.Addition Additionally, ally,GBP GBP is not bound to to serum proteins, proteins, so it is not displaced displaced by  other drugs. The main side effects during controlled trials were somnolence, somno lence, dizzine dizziness, ss, and ataxia ataxia.. Infre Infrequentl quentlyy (< 5%), aggressive behavior may may occur, occur, especially if there is a prior history of hyperactivity hyperactivity,, mental retardatio retardation, n, or underlying behavior disorder. disorder. These are readily reversible upon discontinuatio conti nuation n of GBP GBP.. Incre Increased ased appetite appetite and subsequent weight gain gain can be bothers bothersome. ome. How However ever,, idiosyn idiosyncratic cratic fatal side effects have not been attributed to GBP use, making it one one of the safest safest AEDs. We presently use GBP as initial therapy in the treatment of benign centrot centrotemporal emporal epilepsy epilepsy in childhood childhood and as adjunctive therapy for children with refractory partialonset seizures. seizures. The drug’s drug’s lack of pharmaco pharmacokinetic kinetic interacinteractions, outstanding safety profile, profile, and ability to rapidly titrate titrate make it one of the new AEDs used early early on in the treatment of partial seizures seizures in children. children. GBP is initiated initiated at 10 to 20 mg/kg/d,, given three mg/kg/d three times daily, daily, and the dose is increased by the same amount every 3 to 7 days to achieve a total daily  dose of of 35 to 45 45 mg/kg/d mg/kg/d.. If seiz seizure uress persist, persist, the GBP GBP dose can be increased to 60 to to 80 mg/kg/d as tolerated. Children  younger  young er than 4 years of age may benefit benefit from doses up to 100 mg/kg/d owing to their higher renal clearance of GBP GBP.. Adolescents are titrated up to doses of 1,800 to 2,400 mg/d as the first plateau and may be increased to 3,600 to 4,800 mg/d, mg/ d, if nee needed, ded, to achiev achievee maximal maximal benefit. benefit. Lamotrigine

LTG has been available in the United States since 1995. LTG was demonstrated to be effective, even as monotherapy,, in the treatment apy treatment of partial seizure seizuress in adults. Doub Doubleleblind monotherapy monotherapy trials compared compared treatment treatment of newonset partial seizures ± secondary generalization with LTG, LTG, CBZ, or phenytoin phenytoin.. No differe difference nce in efficacy efficacy was noted noted between betwee n the three AEDs, AEDs, but different different side effects were

TAB ABLE LE 2424-11. 11. Pha Pharma rmacok cokine inetic ticss of New New AED AEDss

Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Monohydroxy derivative Tiagabine Topiramate Vigabatrin Zonisamide

F (%)

Tmax (h)

VD (L/kg)

Protein Binding

1 T ⁄  2 (h)

Tss (d)

Therapeutic Range (mg/L)

Dose (mg/kg/d)

> 90 35 –60 > 90 100 > 95 — > 90 > 80 80 82– 88

2–6 2–3 1–3 0.6 –1.3 1–2 3 –5 1–2 1–4 0.5 –2 2–5

0.75 0.85 1.0 0.5 – 0.7 — 0.75 1.4 0.65 0.8 1.5

25 0 55 < 10 — 40 96 15 0 40

14–23 5 –9 15 –60 7 2 10 –15 2–9 12–30 5 –7 50 –70

4 1–2 3 –10 2 — 2 1–2 3 –5 2 10 –15

30 –100 4–20 3 –20 5 –5 0 — 10 –35 5 –70 2–25 — 10 –30

15 –60 30 –90 1–15 20 –60 15 –45 — 0.25 –1.25 2–20 40 –150 4–10


AED = antiepileptic drug; F = bioavailability; Protein binding = fraction bound to serum proteins; T  ⁄ 2 = elimination half-life; Tmax = time interval between ingestion and maximal serum concentration; Tss = steady-state time; VD = volume of distribution.

Current Management in Child Neurology, Third Edition   © 2005 Bernard Bern ard L. Maria, All Rights Reserved BC Decker Inc

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144 /   / The Office Visit: Seizures and Epilepsy 144

encountered. Controlled studies in children encountered. children have shown shown efficacy in treatment-resista treatment-resistant nt partial seizures, Lenno LennoxxGastaut syndrome, syndrome, and childhood childhood absence epilepsy epilepsy.. Uncontrolled series have suggested its efficacy against a broad range range of seizure types and and epilepsy syndrome syndromes, s, including generalized tonic-clonic seizures, juvenile myoclonic myoclon ic epilepsy, epilepsy, infantile spasms, and seizures seizures associated with Rett syndrome and juvenile neuronal ceroid lipofuscinosis. LTG is less effective against myoclonic seizures and, rarely rarely,, may worsen the myoclon myoclonus. us. Adverse Adv erse effect effectss consist consist mainly of of two types: types: (1) dosedoserelated central nervous system (CNS) toxicity and (2) rashes. Commo Common n side effects include somnolence somnolence,, dizziness, dizzine ss, headac headache, he, diplopia diplopia,, nausea nausea,, vom vomiting, iting,and, and, rarely rarely,, insomnia. LTG may have a brightening or energizing energizi ng effect in some childr children. en. In childre children n with an underlyi underlying ng encephalopathy, encephalopath y, this may present as acting-out behavior behavior and require require disconti discontinuat nuation ion of the drug. Seriou Seriouss rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, are the primary concern associated with LTG LTG therapy thera py.. Ove Overall, rall, rashe rashess occur occur in up to to 10% 10% of patie patients, nts, usuallyy during the first usuall first 8 weeks. weeks. In children children,, coa coadminis dminis-tration with VPA and rapid dose escalation increase the risk of rash. As a result, result, the titration titration schedul schedulee for LTG LTG use has been revised a couple of of times, slowing the rate rate of dose escalation, and this has resulted in a marked decrease in the incidence incid ence of of serio serious us rashes. rashes. The initial initial titratio titration n rates rates resulted in an estimated 1:100 to 1:200 children being at risk for serious skin rashes, and although no data are availavailable in the United United States, postmarketing experience experience in other countries shows that this appears to be decreased several-fold with the current dose schedule (Table schedule (Table 24-12). In the United United States, it is recommended that LTG LTG be stopped stop ped in the presenc presencee of a rash, unles unlesss another another specific etiology can be identified with certainty (eg, chickenpo chickenpox). x). Rechallenge with LTG in patients who developed a rash after the first exposure has been successful in some

all other treatment options have have been exhausted. LTG is predominantly metabolized metabolized by the liver and has pharmacokinetic interactions with other AEDs,resulting AEDs, resulting in a comcomplicated dosing schedule. With LTG LTG as monotherapy monotherapy in children, the elimination elimination half-life is 30 to 33 hours, 7.7 to 14 hours with LTG and enzyme-inducing AEDs (CBZ, phenytoin phen ytoin,, phen phenobarbi obarbital, tal, and primidone) primidone),, and 43 hours with LTG and VPA. LTG is a broad-spectrum AED that offers an alternative to VPA VPA monotherapy and can be b e effective as adjuvant therapy to prevent recurrent seizures.

TPM, the next broad-spectrum broad-spectrum AED, AED, was approved approved in the United Un ited States States in 1997. 1997. The efficacy efficacy of of TPM has has been demonstrated in double-blind, placebo-con placebo-controlled trolled studies in children with new-onset seizures (partial or generalized), ized ), intra intractabl ctablee partia partiall seiz seizures ures,, Len Lenno nox-Ga x-Gastau stautt syndrome,, primary generali drome generalized zed tonic-cl tonic-clonic onic seizure seizures, s, and  juvenile myoclo myoclonic nic epilepsy. epilepsy. A recent recent study showed equivalentt efficacy alen efficacy of TPM, CBZ, and VPA VPA when used as initial initial therapy for the treatment treatment of partial-onset or generalized generalized tonic-clonic seizures seizures in childhood. childhood. Unco Uncontrolled ntrolled studies suggest its efficacy in the treatment treatment of infantile spasms, severe myoclonic myoclonic epilepsy epilepsy in infancy, infancy, and childhood absence seizures. Over 50% of of TPM is excreted excreted unchanged unchanged by the kidneys. The clearance is higher in children children than in adults, leading to the need for higher relative daily doses on a mgper-kg basis. The most common side effects are CNSrelated and include somnolence and fatigue, impaired concentration, centra tion, word word-findin -findingg difficul difficulties, ties, and conf confusion. usion. All the CNS side effects can be significantly minimized minimi zed by slow  dose titration or by use of TPM as monotherapy monotherapy.. The non-CNS side effects effects consist primarily of anorexia and wei weight ght los loss, s, par parest esthes hesias ias,, dy dysge sgeusi usia, a, and and,, rar rarely ely,, nephrolithiasis. The last three side effects are related to

patients, although the authors authors do not advocate this unless

TPM’ss weak carbonic anhydrase inhibition, TPM’ inhibition, which is prob-


TABL TA BLE E 2424-12. 12. Lamo Lamotri trigin gine e Dos Dosing ing A. Lamotrigine added to an AED regimen containing VPA: VPA: Weeks 1 and 2: Weeks 3 and 4:

0.15 mg/kg/d in one or two divided doses, rounded down to the nearest whole tablet 0.3 mg/kg/d in one or two divided doses, rounded down to the nearest whole tablet

May then increase by 0.3 mg/kg/d every 1 to 2 weeks administered twice daily. Usual maintenance dose 1 to 5 mg/kg/d. B. Lamotrigine added to EIAEDs (without VPA): Weeks 1 and 2: Weeks 3 and 4:

0.6 mg/kg/d in two divided doses, rounded down to the nearest whole tablet 1.2 mg/kg/d in two divided doses, rounded down to the nearest whole tablet

May then increase by 1.2 mg/kg/d every 1 to 2 weeks. Usual maintenance dose 5 to 15 mg/kg/d. C. Lamotrigine added to AEDs other than EIAEDs and VPA. Use VPA schedule (A) above; maintenance dose will fall between those with and without VPA above. AED = antiepileptic drug; EIAED = enzyme-inducing antiepileptic drug; VPA = valproate.

Current Management in Child Neurology Neurology,, Third Edition   © 2005 Bernard Berna rd L. Maria , All Rights Reserved BC Decker Inc

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ably also responsible for the asymptomatic metabolic acidosis commonly seen on on routine serum chemistries. TPM should cautiously be coadministered to children on acetazolam zo lamide ide,, ZNS ZNS,, or the the keto ketogen genic ic diet diet becau because se of of the increased risk of nephrolithiasis and metabolic metabolic acidosis. Rarely,, children may experience Rarely experience hyperthermia and oligohydros hy drosis. is. If olig oligohy ohydrosi drosiss occurs, the clinician clinician and family  family  will have to decide if the degree of seizure control control justifies

noted in clinical trials were all related to the CNS and include dizzin dizziness, ess, tremo tremor, r, inatt inattentio ention, n, nervo nervousness usness,, somnol som nolenc ence, e, asth astheni enia, a, and wea weakne kness. ss. Aga Again, in, the side effects of TGB are all minimized minimized by slow dose escalation, escalation, intake inta ke with with food food,, and use use as mon monoth otherap erapyy. TG TGB, B, lik likee vigabatrin (VGB), (VGB), elevates synaptic GABA GABA levels, levels, raising concerns about the the possibility of visual field defects. However,, the mechanisms for elevating synaptic GABA However

the lifestyle lifestyle alterations alteration s (ie, limiti limiting ng duration duratio n of expo exposure sure to warm weather). Encouraging good fluid intake can help minimize the the risk of nephrolithiasis. With extensiv extensivee experience, to date, no severe or life-threatening life-threatening adverse events events have been attributed to TPM. TPM is used as initial therapy in children with newonset seizures, seizures, and as a broad-spectrum broad-spectrum AED, AED, especially in  young children, in whom greater concerns of VP VPA A side effects exist. exist. It is a potent AED in the the treatment treatment of refractory partial seizures. seizures. Although it is typically introduced slowly to minimize CNS adverse adverse effects, the author has rapidly titrated TPM in some children without significant problems. Initial monotherapy monotherapy doses are 25 mg/d given at bedtime, with weekly increases of the same amount to to an initial plateau of 50 mg twice daily (or (or start at 0.5 mg/kg/d and increase by 0.5 mg/kg/d weekly to 2 to 2.5 mg/kg/d given twice daily). daily). Most children children on monotherapy monotherapy are maintained on 100 to 200 mg/d (2.0 to to 4.5 mg/kg/d). Initial adjunct doses in children are typically 0.5 to 1.0 mg/kg/d divided two or three times daily, daily, with weekly increases to 6 mg/kg/d. mg/kg/d. Children < 6 years of of age have have tolerated doses up to 20 to 30 mg/kg/d, mg/kg/d, although the typical dose is 12 mg/kg/d given three times daily in this age group. Children aged 6 to 12 years usually achieve maintenance doses as adjunctive adjunctive therapy of 6 to 9 mg/kg/d and may may tolerate twice-daily administration. TPM has joined VPA VPA and LTG as a broad-spectrum agent to be used in children with mixed seizure disorders.

levels are completely complete ly different, and this explain the retinal problems encountered withmay VGB have why  not occurred with TGB. The authors prescribe TGB as adjunctive therapy in the child with partial seizures and spasticity (eg, in cerebral palsy). Dosing begins in children at 0.1 0.1 mg/kg/d and is increased by this amount weekly to 0.4 to 0.6 mg/kg/d in children who are not taking enzyme-inducing AEDs. Children taking enzyme-inducing AEDs may require doses up to 1.0 mg/kg/d, mg/kg/d, typicall typicallyy divided three three times daily daily. In  young children (age < 24 months) doses up to 3.0 mg/kg/d have been used.

Tiagabine Tiagabine (TGB) was approved in the United States in the fall of 199 1997. 7. This is the the first licensed licensed AED in the the United United States that was was based on our modern modern knowledge of of brain neurochemistry. TGB is a nipecotic acid derivative that increases extracellul extracellular ar γ -aminobutyric -aminobutyric acid (GABA) by  inhibiting reuptake reuptake of GABA by the neurons neurons and glia. Double-blind and open-label studies have documented the efficacy efficacy of TG TGB B in the treatment treatment of refr refracto actory ry partialonset seizures in children. Unco Uncontrolled ntrolled studies suggest suggest efficacy as monotherapy in partial-onset seizures and in improvement improv ement of spasticity. The GABA-e GABA-ergic rgic effect effect of TGB may exacerbate absence seizures. Although patient exposure is still limited (about

requirements are approximately 50% higher for OXC than for CBZ, and many patients patients tolerate conve conversion rsion from one drug to the other. The adverse effects of OX OXC C in children are somnolence, dizzine dizz iness, ss, hea headach dache, e, and, and,rare rarely ly,, rash rash.. The incidenc incidencee of rash is less common common than with CBZ, and the cross-allergy  cross-allergy  between CBZ and OXC OXC was found in only about 1 of 3 children.. Hyp dren Hyponat onatrem remia, ia, alth although ough rare rare,, occu occurs rs more more comcommonly with OXC OXC than with CBZ, but hematologic changes changes associated with CBZ have not been seen with OXC. Treatment with OXC is usually initiated at 5 to 10 mg/kg/d, mg/kg/d, divide divided d in two doses, doses, and increased increased by by this amount weekly to 20 to 30 mg/kg/d. mg/kg/d. Some children may  may  benefit from further dose escalation to 40 to 50 mg/kg/d.

100,0 100,000 00effects patients), patients), no attributed potentially potentia llyto TGB. lifelife-threat ening adverse have been have T GB.threatening Side effects

Rec Recentl entlyy, to a slower slowe r initial initia l dose of 5 mg/kg/d mg/kg/d has been been suggested minimize CNS side effects.

Current Management in Child Neurology, Third Edition   © 2005 Bernard Bern ard L. Maria, All Rights Reserved BC Decker Inc


Oxcarbazepine (OXC) was approved in the spring of  2000 in the the United United States for for the treatment treatment of partialonset seizures with or without w ithout secondary generalization. Since then, it has received monotherapy monotherapy approval for the treatment treat ment of partial partial-onse -onsett seizures in children over over 4 years years of age. OXC is a keto-a keto-analog nalogue ue of CBZ and and can be thought thought of as a prodrug prodrug because it is rapidly conconverted to the monohydroxy monohydroxy derivative. derivative. This derivative is responsible respo nsible for the antiepilepti antiepilepticc effect. This design avoids the epoxide epoxide metabolite of CBZ, which was shown shown to be linked to neuroto neurotoxicity, xicity, especially when CBZ was used with other AEDs. AEDs. Comp Comparison, arison, double double-blind -blind trials have evaluated OXC versus CBZ or phenytoin or VPA in the treatment treatment of of pediatric partial seizures. No significant significant difference differe nce in efficacy was noted noted for any any agent. Dose

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146 /   / The Office Visit: Seizures and Epilepsy 146



ZNS has been available in the United States since the spring of 2000 but for 10 years years prior to that in Japan. Japan. As a result, more information is available than we have for the other recent AEDs. AEDs. Efficacy in partial seizures has been found in several controlled controlled studies. studies. Efficacy in infantile spasms, spasms, Ohtahara syndrome, Lenno Lennox-Gastaut x-Gastaut syndrome, absence seizures, seizure s, genera generalized lized tonic-cl tonic-clonic onic seizures, seizures, and the the pro-

VGB is not approved approved by the U.S. Food and Drug Drug Administration but is used in the Unite United d States. This is the drug of choice for for treating treating infantile infantile spasms secondary to tuberous sclerosis complex and may benefit children with infantile spasms due to other etiologies. Controlled studies have also shown its efficacy in the treatment treat ment of partialpartial-onset onset seizures, seizures, but potential potential visual

gressive myoclonic myoclonic epilepsies has been reported. The most common common adverse adverse effects of of ZNS are somnosomnolence, len ce, ata ataxia xia,, ano anore rexia xia,, and wei weight ght los loss. s. ZNS ZNS,, lik likee TPM TPM,, inhibits carbonic anhydrase anhydrase and may cause renal stones,dysstones, dysgeusia, geusi a, oligo oligohy hydros drosis, is, and hype hypertherm rthermia. ia. Po Poten tentiall tiallyy, thes thesee side effects could be worsened by coadministration with TPM or acetazolamide. acetazolamide. This drug is also contraindicated in patientss on the ketogenic patient ketogenic diet. Simult Simultaneous aneous use of ZNS with stimulant medication may have a synergistic effect on appetite suppression. suppression. Serious rashes rarely occur occur.. ZNS has a sulfonamide moiety and should not be used in a child with a prior history of allergic rash to sulfonamide sulfonamide antibiotics. antibiotics. Therapy with ZNS is initiated at 1 mg/kg/d and increased by this amount amount weekly to 6 to 8 mg/kg/d, mg/kg/d, typi-

field defects defects will relegate relegate VGB VGB to a treatment treatment of last choice in this this seizure type. Anecdotal evidence suggests its efficacy in Lennox-Gastaut syndrome and generalized tonic-clonic seizures. VGB’s VGB ’s entry into the U.S. U.S. market has been delayed because of concerns over over visual field field constriction associated with its use. This defect predomina predominantly ntly affects affects the nasal field field bilaterally bilaterally,, is usually asymptoma asymptomatic, tic, and may  may  persist even even after discontin discontinuation uation of VGB. As a result, the fundamental issue when prescribing VGB is the evaluation of the risk-benefit risk-benefit ratio. ratio. Whe When n treating treating infantile infantile spasms, this side effect may be a modest price to pay for seizure control and the potential for a better developmental outcome. Other adverse adverse effects reported are hyperactivity hyperactivity,,

cally twice daily. dailyto . Children under age 2 levels years may administered tolerate dose increases 15 mg/kg/d. Serum and clinical response may help guide dosing decisions, especially in young children. There is currently no no commercial dose formulation that may be easily given to young children. This may be accomplished accomplished by placing placing the contentss of one 100 tent 100 mg capsule capsule in 30 30 cc of apple juice. juice. This is stable for 48 hours when refrigerated and should be shaken well before each dose is administered.

weight gain, drowsiness, drow siness, ataxia, and somnol somnolence. When treating infantile spasms, VGB isence. initiated at 50 mg/kg/d, given twice daily, daily, and the dose is increased by  the same amount after after 1 week to a total of 100 mg/kg/d. Some children may benefit from doses up to 200 mg/kg/d. Doses used in the treatment treatment of partial-o partial-onset nset seizures seizures are typically typic ally 20 mg/kg mg/kg/d, /d, adm adminis inister tered ed twice daily daily,, and increased by this amount weekly to 40 to 60 mg/kg/d. After the decision to to use VGB VGB has been made, a plan should be in place for visual field testing before starting the medicine. This will serve as a baseline to evaluate possible changes during VGB VGB treatment.In treatment. In older children, children, this may consist of  a complete ophthalmologic evaluation and formal visual field testing testing every every 4 to 6 months. months. In the the infant, infant, formal ophthalmologic ophthalmo logic evaluation,visual evaluation, visual evoked potentials, potentials, and an electroretinogram electrore tinogram may need to be performed periodically. periodically. A set protocol for monitoring visual field defects has yet to be developed.


The United States approved levetiracetam (LEV) in 2000. Approvall was based on multicenter, Approva multicenter, double-blind studies in adults with partial epilepsy. Pediatric studies evaluating the efficacy in partial seizures are are completed, completed, and results are pending. Although the overall overall exposure is limited, limited, to date LEV has a good safety profile. The most common adverse adverse effects are asthe asthenia, nia, somn somnole olence nce,, dizz dizzine iness, ss, and nervou nervousnes sness. s. Hostility, anger, anger,or or aggressive behavior occurs in some children, especially if they have have an underlying encephalopath encephalopathy  y  or history history of beha behavior vior disorders disorders.. This is reversibl reversiblee upon discontinuation of the drug. Currently, the authors use LEV as adjunctive treatment for partial-onset seizures. It may benefit some patients with symptomatic generalized seizures or juvenile myoclonic epilepsy. Therapy is initiated at 10 to to 20 mg/kg/d and increased by this amount weekly. weekly. Maint Maintenance enance doses are typically 40 to 60 mg/kg/d, although some children children tolerate doses up to 80 or 100 mg/kg/d. mg/kg/d. This is administered administered as a two- or three-times-daily dosing. Current Management in Child Neurology Neurology,, Third Edition   © 2005 Bernard Berna rd L. Maria , All Rights Reserved BC Decker Inc

Conclusion Uncontrolled or recurrent seizures affect a large number of  Uncontrolled children in the United United States. Compliance with medical therapy is a critical component that needs to be addressed when initiating therapy  (see   (see Chapter 25, 25, “Discont “Discontinuing inuing AntiAntiepileptic Drugs in Children” Children”). ). If the child continues continues to have have seizures and no other cause is identified, a rational treatment plan should be formulated. formulated. This may require require further diagnostic nost ic testing. testing. If this is done done and all availab available le treatmen treatmentt opinions are pursued, the child and the family will achieve the best possible seizure control and quality of life.

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Recurrent Seizures / 147

Suggested Readings Berg AT, Levy SR, No Novotn votnyy EJ, EJ, et al. al. Pre Predict dictors ors of intra intractab ctable le epilepsy epile psy in child childhood: hood: a case-con case-control trol study study.. Epile Epilepsia psia 1996;37:24–30. Bergin AM, Conn Bergin Connolly olly M. New antiepil antiepileptic eptic drug drug therapies. therapies. Neurol Clin 2002;20:1163 2002;20:1163–82. –82. Bourgeois BF. BF. New antiepileptic antiepileptic drugs in children: which ones for which seizures? Clin Neuropharmacol 2000;23:119–32. 2000;23:119–32. Jarrar RG, RG, Buchhalter JR. Therapeutics in pediatric epilepsy, epilepsy, Part 1: the new antiepileptic drugs drugs and the ketogenic ketogenic diet. Mayo Clin Proc 2003;78:359– 2003;78:359–70. 70. Loscher W, Loscher W, Po Potschk tschkaa H. Role of multi multidrug drug transporters transporters in pharmacoresistance to antiepileptic antiepileptic drugs. J Pharmacol Exp Ther 2002;301:7–14. Sillanpaa M, Jala Sillanpaa Jalava va M, Kalev Kalevaa O, O, Shinna Shinnarr S. Long-t Long-term erm prognoprognosis of of seiz seizures ures with onset onset in in childhood childhood.. N Engl J Med Med 1998;338:1715–22. Wheless JW, Wheless JW, Venkat enkataraman araman V. V. New formulati formulations ons of drugs in epilepsy. Expert Opin Pharmacother 1999;1:49–60. 1999;1:49–60. Wheless JW,Baumgartner J, Ghanbari C. Vagus nerve stimulation Wheless and the ketogenic diet. Neurol Clin 2001;19:371–407. 2001;19:371–407.

Practitioner and Patient Resources Epilepsy Foundation 4351 Garden City Drive, Suite 406 Landover,, MD 20789 Landover Phone: (800 (800)) 332332-1000 1000 The Epilepsy Foundation is the nonprofit organization representing patients with epilepsy in the United States. Local chapters provide patient education, education, job training, and advocacy advocacy.. The Epilepsy Foundation recommends these books:

Reisner H, edit Reisner editor or.. Child Children ren with with epileps epilepsyy. A parents parents’’ guid guide. e. Bethesda Bethes da (MD): Woodbi oodbine ne Hous House; e; 1988 1988.. The Epilepsy Research Foundation PO Box 3004 London W4 1XT Phone: 020 8995 8995 4781 E-mail:: [email protected] E-mail [email protected]  uk  The Epilepsyresearch Researchfor Foundation is devoted solely to sponsoring effective all who now suffer from epilepsy. H.O.P.E. Mentorin H.O.P.E. Mentoringg Program Phone: (877) HOPE 4 YOU YOU (877-467-3496) H.O.P.E., H.O.P .E., a part of the Epilepsy Foundation, was created to allow  people who live with epilepsy to educate others and to share their experiences. H.O.P H.O.P.E. .E. trains people with epilepsy to be “patient educators”” throughout the epilepsy and neurologic communities. educators communities. Epilepsy Information Service (EIS) Department Departme nt of Neu Neurology  rology  Wake Forest University University School of Medicine Medical Center Blvd. Winston-Salem, NC 27157 Phone: (800)) 642(800 642-0500 0500 html The EIS is a nonprofit resource center that offers a nationwide toll-free information line for people with epilepsy and their families, profe profession ssionals, als, and the public. public. Free educational educational packets packets are available to all callers.

Freeman J,J, Vini Freeman Vining ng E, Pillas D, editor editors. s. Seizu Seizures res and epilepsy epilepsy in childho chi ldhood: od: a guide guide for parents parents.. Balt Baltimor imoree (MD): (MD): The Johns Johns 11911 Freedom Drive #730 Reston, VA 20190 Phone: (703 (703)) 437437-9720 9720 is an online resource provided by The Epilepsy  Project, a nonprofit nonprofit organization organization that supports research. Epilepsy.c Epileps om provides provides information information for children children,, parents, and

Hopkins University University Press; Press; 1990.


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