CHAPTER 24

RECURRENT SEIZURES
JAMES W. WHELESS, MD DAVE F. CLARKE, MD

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

Epilepsy and seizures affect at least 2.3 million people in the United States. The treatment of febrile seizures (Chapter 16, Febrile Seizures), initial treatment of first unprovoked seizures (Chapter 17, First Unprovoked Seizure), and acute seizure emergencies (Chapter 78, Status Epilepticus) are discussed elsewhere. Once the seizure type or epilepsy syndrome has been classified, therapy may be initiated. Antiepileptic drugs (AEDs) are the primary form of treatment. However, 25 to 30% of children with epilepsy continue to have recurrent seizures. In addition, many patients experience significant adverse drug effects. Children with epilepsy characterized by uncontrolled seizures face a variety of risks, including higher mortality rates, higher rates of accidents and injuries, a higher incidence of cognitive and psychiatric impairments, poor self-esteem, higher levels of anxiety and depression, and social stigmatization or isolation. Thus, effective treatment to control seizures is fundamental to improving overall outcome. When the first-choice AED is prescribed, less than 50% of children are initially seizure-free. With adjustments in dose, this percentage improves. If the child has failed initial AED therapy (see Chapter 21, First-Choice Antiepileptic Drugs), all treatment options (Table 24-1) should be considered and a treatment plan developed. With all the treatment options currently available, the clinician should strive for freedom from seizures or maximum reduction of recurrences balanced by the fewest adverse effects possible.
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TABLE 24-1. Treatment Options in Pediatric Epilepsy

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

Causes of Recurrent Seizures

The initial step in the treatment of epilepsy involves correctly identifying the event (seizure type) and associated conditions that define the epilepsy syndrome. Etiology should be established from the history, physical examination, and selective laboratory tests. All children with recurrent afebrile seizures should have an electroencephalogram (EEG) performed while they are awake and asleep and a magnetic resonance imaging (MRI) study of the brain. Children in the rst 2 years of life may require special MRI sequences and serial MRI scans to identify abnormalities during early brain development. This work-up will allow classication of the seizures and epilepsy syndrome. Some seizure types (ie, absence, benign centrotemporal epilepsy of childhood, genetic epilepsies) are well controlled with initial therapy. However, some seizure types, epilepsy syndromes, and specic etiologies are known to be treatment resistant and typically lead to recurrent or intractable seizures (Tables 24-2 and 24-3). Once a child is identied as having one of these etiologies, the physician can describe the typical natural history and prognosis of the epilepsy for

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140 / The Ofce Visit: Seizures and Epilepsy TABLE 24-2. Seizure Types and Epilepsy Syndromes Associated with Recurrent Seizures
Simple partial seizures Complex partial seizures Myoclonic seizures Atonic seizures Tonic seizures Severe myoclonic epilepsy in infancy (Dravet syndrome) Ohtahara syndrome Infantile spasms (Wests syndrome) Lennox-Gastaut syndrome

TABLE 24-4. Predictors of Medically Intractable Childhood Epilepsy

Seizure onset in infancy Symptomatic etiology (organic brain diseasecerebral palsy, mental retardation) Seizure 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. This prognosis includes the likelihood that the child will respond to certain treatment options, allowing a logical, sequential treatment plan to be formulated. In addition to the epilepsy type and the etiology, other factors are important in predicting medically refractory childhood epilepsy (Table 24-4). Onset in infancy, evidence of organic brain disease, multiple seizure types (especially 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 inadequate control of seizures. Incorrect identication of the seizure type results in faulty 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 to exacerbate the underlying seizure type (Table 24-6). The clinician should be aware of this possibility, and if this appears to be occurring, therapy should be changed. The epileptic seizure must be distinguished from other nonepileptic events, as this can often lead to incorrect treatment or overmedication. This is especially important in children with other neurologic abnormalities (ie, cerebral palsy, autism, and mental retardation) for which video-EEG monitoring may be necessary to correctly identify all the events. Failure to recognize underlying disease
TABLE 24-3. Syndromes of Intractable Childhood Epilepsy
Neurocutaneous Sturge-Weber syndrome Tuberous sclerosis complex Dysplasias Focal pachygyria Focal cortical dysplasia Band heterotopia Lissencephaly Hemimegalencephaly Hypothalamic hamartoma Rasmussens syndrome

processes, such as porphyria, hypoglycemia, or hypocalcemia, may lead to apparent recurrent seizures. Failure to recognize precipitating factors (ie, reex epilepsies, sleep deprivation, other medicines) that should be eliminated may lead to lack of seizure control. Faulty treatment may cause recurrent seizures (Table 24-7). Some specic seizure etiologies are known to be medically unresponsive and may be best treated with the ketogenic diet, vagus nerve stimulation, or epilepsy surgery. Additionally, certain medications may exacerbate seizures. Drug interactions between AEDs or an AED and another drug may lower the efcacy of the AED, resulting in increased seizure activity. For children, especially in the rst 2 years of life, the drug dose may need to be signicantly 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 adults. Serum blood levels, along with clinical response, help guide dosing decisions, as a set maintenance dose may lead to an inadequate trial of the AED. Patient factors may contribute to recurrent seizures (Table 24-8). One of the most common causes is partial compliance. This may be improved by patient education and use of an AED formulation that allows twice-daily dosing. Nonavoidance of precipitating factors, including sleep deprivation, emotional stress, and other medicines, may lead to continuation of seizures that might otherwise be controlled. Classic antihistamines may lower the seizure threshold in preschool children and promote apparent intractability. New research suggests several inherent patient factors may predispose some children to recurrent seizures. Unfortunately, there is currently no way to screen for these or to modify treatment. Perhaps in the future, magnetic resonance spectroscopy or another technology may allow insights into a given patients brain neurochemistry and help guide treatment decisions.

Management of Recurrent Seizures

The treatment of epilepsy requires the physician to determine the drug of first choice (see Chapters 21, First-Choice

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Recurrent Seizures / 141 TABLE 24-5. Recurrent Seizures: Faulty Diagnosis

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

TABLE 24-7. Recurrent Seizures: Faulty Treatment

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

Antiepileptic Drugs and 30,Current Pharmacotherapy for Pediatric Seizures and Epilepsy and Table 24-9) and use it to its maximum effectiveness by increasing dosage up to the limit of tolerability. Effectiveness is dened as a measure encompassing both efcacy (ie, seizure control) and tolerability. If the rst drug is unsuccessful, an alternative medication should be prescribed (Figure 24-1). This decision may be inuenced by other factors (eg, dose formulation, comorbidity, other medicines, pharmacokinetics) (Table 24-10). Use of a single drug reduces the chance for potential side effects or drug interactions and often allows the best quality of life. When changing from the rst to a second drug, the medicines usually overlap to prevent a withdrawal or rebound increase in seizures. This allows time for the second drug to be increased in dosage to achieve efcacy. When seizures continue to recur, a small number (10 to 20%) of patients may benet from treatment with two AEDs. Strategies include combining drugs with different mechanisms of action (rational polypharmacy) or drug combinations felt to be synergistic (eg, valproate [VPA] and lamotrigine [LTG], VPA and ethosuximide). In the past, the teaching was to change only one thing at a time to learn as much as possible about which drug is most effective. For example, if seizures recurred despite maximal dosing of carbamazepine (CBZ), it was customary to add VPA without simultaneously decreasing the CBZ doses. Although it is still the case that a combination of drugs may be effective when no single agent provides satisfactory seizure control, there has been a shift in practice, whereby drugs are increasingly used sequentially as monotherapy rather than in combination. This practice has evolved because of the ready availability of new effective AEDs and recognition that polypharmacy is associated with signicant toxicity. However, polypharmacy with the newer
TABLE 24-6. Recurrent Seizures: Antiepileptic Drug Associated with Seizure Exacerbation
Antiepileptic Drug Carbamazepine Oxcarbazepine Phenytoin Phenobarbital Vigabatrin Tiagabine Gabapentin Lamotrigine Seizure Type Exacerbated Absence, atonic, myoclonic Absence, atonic, myoclonic Absence, atonic, myoclonic Absence, atonic Absence, myoclonic Absence, myoclonic Myoclonic Myoclonic

AEDs appears to be better tolerated and accompanied by fewer pharmacokinetic interactions than was true of the AEDs available prior to 1993 (standard AEDs). Also, a new option, combining an AED with vagus nerve stimulation (see Chapter 28, Epilepsy Surgery and Cortical Stimulation), allows patients to have improved seizure control without the neurotoxicity of polypharmacy. Children who have failed two to three AEDs require more intensive diagnostic effort. This typically consists of video-EEG monitoring with scalp electrodes, a highquality MRI with a specic epilepsy protocol, and possibly other laboratory studies to search for an underlying etiology. Referral to a comprehensive pediatric epilepsy program is recommended. This information is used to assess the risks, benefits, and expected outcome of all treatment options (see Table 24-1) for the childs epilepsy type or syndrome. A plan is formulated, and a sequence of treatment steps, based on response to therapy, is outlined. This is communicated to the local pediatric neurologist. If the childs seizures continue, periodic reevaluation is suggested at the comprehensive pediatric epilepsy center. This allows review of the treatment plan and the use of newer diagnostic tests or treatments. Currently, many children continue to have recurrent seizures despite the use of all available treatment options. Following the approach outlined above allows the best seizure control and subsequent quality of life for each child with epilepsy. Since 1993, several new AEDs have been released in the United States. As a group, these newer drugs differ from the established or rst-choice drugs in terms of their pharmacokinetics (Table 24-11), interaction potential, and adverse effects. In addition, the newer drugs may achieve seizure
TABLE 24-8. Recurrent Seizures: Patient Factors
Partial compliance with AED therapy Nonavoidance of precipitating factors Use of other drugslower 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 = -aminobutyric acid; MDRI = multiple drug resistance gene.

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142 / The Ofce Visit: Seizures and Epilepsy TABLE 24-9. Recurrent Seizures: AED Treatment Options 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 Localizationrelated (partial) epilepsies Benign childhood epilepsy with centrotemporal spikes Gabapentin, oxcarbazepine, carbamazepine (extended release), phenytoin Partial seizures secondary 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 drug had not. However, the availability of new AEDs represents a therapeutic dilemma for the clinician because optimal use of these drugs has not yet been established. There is little information on the comparable benefits of new AEDs. In the next section of this chapter, the clinical pharmacology of the newer AEDs and seizure types or epilepsy syndromes for which each is useful will be discussed, with the realization that with more experience, this may change.

FBM due to the emergence of reports of aplastic anemia and hepatic failure. Uncontrolled reports suggest that FBM might be efcacious against absence seizures, infantile spasms, Doose syndrome, juvenile myoclonic epilepsy, and acquired epileptic aphasia. Even with its broad spectrum of activity, FBMs main indication is in children with Lennox-Gastaut syndrome who have failed to respond to other treatments (eg, VPA, topiramate [TPM], LTG, ketogenic diet, vagus nerve stimulation) or as a third-line option in children with refractory partial-onset seizures. Nausea, vomiting, anorexia, weight loss, dizziness, insomnia, headache, and somnolence were the most commonly recognized side effects of FBM.Anorexia and weight loss were the most prominent and can be signicantly worsened by cotreatment with other drugs sharing these side effects (eg, stimulant medication, TPM, zonisamide [ZNS]). One year after FBMs release, it became evident that FBM was associated with aplastic anemia,and the drug came close to being removed from the market.Additionally, cases of severe hepatotoxicity, some with fatal outcome,were reported.Although severe hypotoxicity has occurred in children, no cases of aplastic anemia have been reported in children under the age of 13 years. Known risk factors for FBM toxicity include a history of allergy or cytopenia with other AEDs and evidence of a concomitant immune disorder. These should be sought by careful history-taking before beginning therapy with FBM. Baseline hematologic and liver function tests should be performed and families informed of potential risks. Cautious introduction of FBM reduces the occurrence of early adverse events. Therapy is typically initiated at 15 mg/kg/d (maximum of 1,200 mg) and increased weekly by 15 mg/kg/d to

Clinical Pharmacology and Use of New Antiepileptic Drugs

Felbamate Felbamate (FBM) was released in the United States in 1993. FBM was tested in the rst-ever double-blind, placebocontrolled study in patients with Lennox-Gastaut syndrome. A decrease in total seizure number was signicant for FBM, and FBM was particularly effective in reducing the frequency of drop attacks. Efcacy for monotherapy and adjunctive treatment of partial-onset seizures was established in adolescents and adults, but pediatric studies were stopped because of marked restrictions on the use and promotion of
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FIGURE 24-1. Treatment of recurrent seizures. AED = antiepileptic drug.

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Recurrent Seizures / 143 TABLE 24-10. Considerations in the Selection of Antiepileptic Drug Therapy
Efcacy for seizure type, epilepsy syndrome Safety Side effect prole 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 benet from doses up to 60 to 90 mg/kg/d (5,000 to 6,000 mg/d). Serum levels and clinical 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 rst 6 to 12 months and later as clinically indicated. Comedications may need adjustment because of known interactions. Obtaining baseline and follow-up serum levels of all AEDs assists in these decisions. Gabapentin Gabapentin (GBP) was marketed in the United States in 1994. GBP is a niche AED, showing efcacy against only partial and secondary generalized seizures. Pediatric studies showed efcacy in the treatment of partial seizures, whether refractory or benign. GBP was studied in children as adjunctive therapy in refractory partial seizures and as monotherapy in benign centrotemporal epilepsy of childhood. Two double-blind studies of GBP in childhood absence epilepsy failed to demonstrate efcacy. A single placebo-controlled study of GBP in patients with generalized tonic-clonic seizures did not show efcacy over placebo. GBP was the first AED to be introduced that was excreted entirely by the kidney. This infers a signicant clinical advantage because GBP is neither the cause nor the

object of pharmacokinetic interactions. Additionally, GBP is not bound to serum proteins, so it is not displaced by other drugs. The main side effects during controlled trials were somnolence, dizziness, and ataxia. Infrequently (< 5%), aggressive behavior may occur, especially if there is a prior history of hyperactivity, mental retardation, or underlying behavior disorder. These are readily reversible upon discontinuation of GBP. Increased appetite and subsequent weight gain can be bothersome. However, idiosyncratic fatal side effects have not been attributed to GBP use, making it one of the safest AEDs. We presently use GBP as initial therapy in the treatment of benign centrotemporal epilepsy in childhood and as adjunctive therapy for children with refractory partialonset seizures. The drugs lack of pharmacokinetic interactions, outstanding safety prole, and ability to rapidly titrate make it one of the new AEDs used early on in the treatment of partial seizures in children. GBP is initiated at 10 to 20 mg/kg/d, given three times daily, and the dose is increased by the same amount every 3 to 7 days to achieve a total daily dose of 35 to 45 mg/kg/d. If seizures persist, the GBP dose can be increased to 60 to 80 mg/kg/d as tolerated. Children younger than 4 years of age may benet from doses up to 100 mg/kg/d owing to their higher renal clearance of GBP. Adolescents are titrated up to doses of 1,800 to 2,400 mg/d as the rst plateau and may be increased to 3,600 to 4,800 mg/d, if needed, to achieve maximal benet. Lamotrigine LTG has been available in the United States since 1995. LTG was demonstrated to be effective, even as monotherapy, in the treatment of partial seizures in adults. Doubleblind monotherapy trials compared treatment of newonset partial seizures secondary generalization with LTG, CBZ, or phenytoin. No difference in efcacy was noted between the three AEDs, but different side effects were

TABLE 24-11. Pharmacokinetics of New AEDs

F (%) Felbamate Gabapentin Lamotrigine Levetiracetam Oxcarbazepine Monohydroxy derivative Tiagabine Topiramate Vigabatrin Zonisamide > 90 3560 > 90 100 > 95 > 90 > 80 80 8288 Tmax (h) 26 23 13 0.61.3 12 35 12 14 0.52 25 VD (L/kg) 0.75 0.85 1.0 0.50.7 0.75 1.4 0.65 0.8 1.5 Protein Binding 25 0 55 < 10 40 96 15 0 40 T12 (h) 1423 59 1560 7 2 1015 29 1230 57 5070 Tss (d) 4 12 310 2 2 12 35 2 1015 Therapeutic Range (mg/L) 30100 420 320 550 1035 570 225 1030 Dose (mg/kg/d) 1560 3090 115 2060 1545 0.251.25 220 40150 410

AED = antiepileptic drug; F = bioavailability; Protein binding = fraction bound to serum proteins; T12 = elimination half-life; Tmax = time interval between ingestion and maximal serum concentration; Tss = steady-state time; VD = volume of distribution.

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encountered. Controlled studies in children have shown efficacy in treatment-resistant partial seizures, LennoxGastaut syndrome, and childhood absence epilepsy. Uncontrolled series have suggested its efcacy against a broad range of seizure types and epilepsy syndromes, including generalized tonic-clonic seizures, juvenile myoclonic epilepsy, infantile spasms, and seizures associated with Rett syndrome and juvenile neuronal ceroid lipofuscinosis. LTG is less effective against myoclonic seizures and, rarely, may worsen the myoclonus. Adverse effects consist mainly of two types: (1) doserelated central nervous system (CNS) toxicity and (2) rashes. Common side effects include somnolence, dizziness, headache, diplopia, nausea, vomiting, and, rarely, insomnia. LTG may have a brightening or energizing effect in some children. In children with an underlying encephalopathy, this may present as acting-out behavior and require discontinuation of the drug. Serious rashes, including Stevens-Johnson syndrome and toxic epidermal necrolysis, are the primary concern associated with LTG therapy. Overall, rashes occur in up to 10% of patients, usually during the rst 8 weeks. In children, coadministration with VPA and rapid dose escalation increase the risk of rash. As a result, the titration schedule for LTG use has been revised a couple of times, slowing the rate of dose escalation, and this has resulted in a marked decrease in the incidence of serious rashes. The initial titration rates resulted in an estimated 1:100 to 1:200 children being at risk for serious skin rashes, and although no data are available in the United States, postmarketing experience in other countries shows that this appears to be decreased several-fold with the current dose schedule (Table 24-12). In the United States, it is recommended that LTG be stopped in the presence of a rash, unless another specic etiology can be identied with certainty (eg, chickenpox). Rechallenge with LTG in patients who developed a rash after the first exposure has been successful in some patients, although the authors do not advocate this unless
TABLE 24-12. Lamotrigine Dosing
A. Lamotrigine added to an AED regimen containing VPA: Weeks 1 and 2: Weeks 3 and 4:

all other treatment options have been exhausted. LTG is predominantly metabolized by the liver and has pharmacokinetic interactions with other AEDs, resulting in a complicated dosing schedule. With LTG as monotherapy in children, the elimination half-life is 30 to 33 hours, 7.7 to 14 hours with LTG and enzyme-inducing AEDs (CBZ, phenytoin, phenobarbital, and primidone), and 43 hours with LTG and VPA. LTG is a broad-spectrum AED that offers an alternative to VPA monotherapy and can be effective as adjuvant therapy to prevent recurrent seizures. Topiramate TPM, the next broad-spectrum AED, was approved in the United States in 1997. The efficacy of TPM has been demonstrated in double-blind, placebo-controlled studies in children with new-onset seizures (partial or generalized), intractable partial seizures, Lennox-Gastaut syndrome, primary generalized tonic-clonic seizures, and juvenile myoclonic epilepsy. A recent study showed equivalent efcacy of TPM, CBZ, and VPA when used as initial therapy for the treatment of partial-onset or generalized tonic-clonic seizures in childhood. Uncontrolled studies suggest its efcacy in the treatment of infantile spasms, severe myoclonic epilepsy in infancy, and childhood absence seizures. Over 50% of TPM is excreted unchanged by the kidneys. The clearance is higher in 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, word-nding difculties, and confusion. All the CNS side effects can be signicantly minimized by slow dose titration or by use of TPM as monotherapy. The non-CNS side effects consist primarily of anorexia and weight loss, paresthesias, dysgeusia, and, rarely, nephrolithiasis. The last three side effects are related to TPMs weak carbonic anhydrase inhibition, which is prob-

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.

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ably also responsible for the asymptomatic metabolic acidosis commonly seen on routine serum chemistries. TPM should cautiously be coadministered to children on acetazolamide, ZNS, or the ketogenic diet because of the increased risk of nephrolithiasis and metabolic acidosis. Rarely, children may experience hyperthermia and oligohydrosis. If oligohydrosis occurs, the clinician and family will have to decide if the degree of seizure control justies the lifestyle alterations (ie, limiting duration of exposure to warm weather). Encouraging good uid intake can help minimize the risk of nephrolithiasis. With extensive experience, to date, no severe or life-threatening adverse events have been attributed to TPM. TPM is used as initial therapy in children with newonset seizures, and as a broad-spectrum AED, especially in young children, in whom greater concerns of VPA side effects exist. It is a potent AED in the treatment of refractory partial seizures. Although it is typically introduced slowly to minimize CNS adverse effects, the author has rapidly titrated TPM in some children without signicant problems. Initial monotherapy doses are 25 mg/d given at bedtime, with weekly increases of the same amount to an initial plateau of 50 mg twice daily (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). Most children on monotherapy are maintained on 100 to 200 mg/d (2.0 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, with weekly increases to 6 mg/kg/d. Children < 6 years of age have tolerated doses up to 20 to 30 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 therapy of 6 to 9 mg/kg/d and may tolerate twice-daily administration. TPM has joined VPA and LTG as a broad-spectrum agent to be used in children with mixed seizure disorders. Tiagabine Tiagabine (TGB) was approved in the United States in the fall of 1997. This is the rst licensed AED in the United States that was based on our modern knowledge of brain neurochemistry. TGB is a nipecotic acid derivative that increases extracellular -aminobutyric acid (GABA) by inhibiting reuptake of GABA by the neurons and glia. Double-blind and open-label studies have documented the efcacy of TGB in the treatment of refractory partialonset seizures in children. Uncontrolled studies suggest efcacy as monotherapy in partial-onset seizures and in improvement of spasticity. The GABA-ergic effect of TGB may exacerbate absence seizures. Although patient exposure is still limited (about 100,000 patients), no potentially life-threatening adverse effects have been attributed to TGB. Side effects
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noted in clinical trials were all related to the CNS and include dizziness, tremor, inattention, nervousness, somnolence, asthenia, and weakness. Again, the side effects of TGB are all minimized by slow dose escalation, intake with food, and use as monotherapy. TGB, like vigabatrin (VGB), elevates synaptic GABA levels, raising concerns about the possibility of visual field defects. However, the mechanisms for elevating synaptic GABA levels are completely different, and this may explain why the retinal problems encountered with VGB have 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 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, typically divided three times daily. In young children (age < 24 months) doses up to 3.0 mg/kg/d have been used. Oxcarbazepine Oxcarbazepine (OXC) was approved in the spring of 2000 in the United States for the treatment of partialonset seizures with or without secondary generalization. Since then, it has received monotherapy approval for the treatment of partial-onset seizures in children over 4 years of age. OXC is a keto-analogue of CBZ and can be thought of as a prodrug because it is rapidly converted to the monohydroxy derivative. This derivative is responsible for the antiepileptic effect. This design avoids the epoxide metabolite of CBZ, which was shown to be linked to neurotoxicity, especially when CBZ was used with other AEDs. Comparison, double-blind trials have evaluated OXC versus CBZ or phenytoin or VPA in the treatment of pediatric partial seizures. No significant difference in efficacy was noted for any agent. Dose requirements are approximately 50% higher for OXC than for CBZ, and many patients tolerate conversion from one drug to the other. The adverse effects of OXC in children are somnolence, dizziness, headache, and, rarely, rash. The incidence of rash is less common than with CBZ, and the cross-allergy between CBZ and OXC was found in only about 1 of 3 children. Hyponatremia, although rare, occurs more commonly with OXC than with CBZ, but hematologic changes associated with CBZ have not been seen with OXC. Treatment with OXC is usually initiated at 5 to 10 mg/kg/d, divided in two doses, and increased by this amount weekly to 20 to 30 mg/kg/d. Some children may benet from further dose escalation to 40 to 50 mg/kg/d. Recently, a slower initial dose of 5 mg/kg/d has been suggested to minimize CNS side effects.

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Zonisamide ZNS has been available in the United States since the spring of 2000 but for 10 years prior to that in Japan. As a result, more information is available than we have for the other recent AEDs. Efcacy in partial seizures has been found in several controlled studies. Efficacy in infantile spasms, Ohtahara syndrome, Lennox-Gastaut syndrome, absence seizures, generalized tonic-clonic seizures, and the progressive myoclonic epilepsies has been reported. The most common adverse effects of ZNS are somnolence, ataxia, anorexia, and weight loss. ZNS, like TPM, inhibits carbonic anhydrase and may cause renal stones, dysgeusia, oligohydrosis, and hyperthermia. Potentially, these side effects could be worsened by coadministration with TPM or acetazolamide. This drug is also contraindicated in patients on the ketogenic diet. Simultaneous use of ZNS with stimulant medication may have a synergistic effect on appetite suppression. Serious rashes rarely occur. ZNS has a sulfonamide moiety and should not be used in a child with a prior history of allergic rash to sulfonamide antibiotics. Therapy with ZNS is initiated at 1 mg/kg/d and increased by this amount weekly to 6 to 8 mg/kg/d, typically administered twice daily. Children under age 2 years may tolerate dose increases to 15 mg/kg/d. Serum levels and clinical response may help guide dosing decisions, especially in young children. There is currently no commercial dose formulation that may be easily given to young children. This may be accomplished by placing the contents of one 100 mg capsule in 30 cc of apple juice. This is stable for 48 hours when refrigerated and should be shaken well before each dose is administered. Levetiracetam The United States approved levetiracetam (LEV) in 2000. Approval was based on multicenter, double-blind studies in adults with partial epilepsy. Pediatric studies evaluating the efcacy in partial seizures are completed, and results are pending. Although the overall exposure is limited, to date LEV has a good safety prole. The most common adverse effects are asthenia, somnolence, dizziness, and nervousness. Hostility, anger, or aggressive behavior occurs in some children, especially if they have an underlying encephalopathy or history of behavior disorders. This is reversible upon discontinuation of the drug. Currently, the authors use LEV as adjunctive treatment for partial-onset seizures. It may benet some patients with symptomatic generalized seizures or juvenile myoclonic epilepsy. Therapy is initiated at 10 to 20 mg/kg/d and increased by this amount weekly. Maintenance doses are typically 40 to 60 mg/kg/d, although some children tolerate doses up to 80 or 100 mg/kg/d. This is administered as a two- or three-times-daily dosing.
Current Management in Child Neurology, Third Edition 2005 Bernard L. Maria, All Rights Reserved BC Decker Inc

Vigabatrin VGB is not approved by the U.S. Food and Drug Administration but is used in the United States. This is the drug of choice for treating 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 of partial-onset seizures, but potential visual field defects will relegate VGB to a treatment of last choice in this seizure type. Anecdotal evidence suggests its efficacy in Lennox-Gastaut syndrome and generalized tonic-clonic seizures. VGBs entry into the U.S. market has been delayed because of concerns over visual eld constriction associated with its use. This defect predominantly affects the nasal eld bilaterally, is usually asymptomatic, and may persist even after discontinuation of VGB. As a result, the fundamental issue when prescribing VGB is the evaluation of the risk-benet ratio. When treating 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 effects reported are hyperactivity, weight gain, drowsiness, ataxia, and somnolence. When treating infantile spasms, VGB is initiated at 50 mg/kg/d, given twice daily, and the dose is increased by the same amount after 1 week to a total of 100 mg/kg/d. Some children may benet from doses up to 200 mg/kg/d. Doses used in the treatment of partial-onset seizures are typically 20 mg/kg/d, administered twice daily, and increased by this amount weekly to 40 to 60 mg/kg/d. After the decision to use VGB has been made, a plan should be in place for visual eld testing before starting the medicine. This will serve as a baseline to evaluate possible changes during VGB treatment. In older children, this may consist of a complete ophthalmologic evaluation and formal visual field testing every 4 to 6 months. In the infant, formal ophthalmologic evaluation, visual evoked potentials, and an electroretinogram may need to be performed periodically. A set protocol for monitoring visual eld defects has yet to be developed.

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

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Suggested Readings
Berg AT, Levy SR, Novotny EJ, et al. Predictors of intractable epilepsy in childhood: a case-control study. Epilepsia 1996;37:2430. Bergin AM, Connolly M. New antiepileptic drug therapies. Neurol Clin 2002;20:116382. Bourgeois BF. New antiepileptic drugs in children: which ones for which seizures? Clin Neuropharmacol 2000;23:11932. Jarrar RG, Buchhalter JR. Therapeutics in pediatric epilepsy, Part 1: the new antiepileptic drugs and the ketogenic diet. Mayo Clin Proc 2003;78:35970. Loscher W, Potschka H. Role of multidrug transporters in pharmacoresistance to antiepileptic drugs. J Pharmacol Exp Ther 2002;301:714. Sillanpaa M, Jalava M, Kaleva O, Shinnar S. Long-term prognosis of seizures with onset in childhood. N Engl J Med 1998;338:171522. Wheless JW, Venkataraman V. New formulations of drugs in epilepsy. Expert Opin Pharmacother 1999;1:4960. Wheless JW, Baumgartner J, Ghanbari C. Vagus nerve stimulation and the ketogenic diet. Neurol Clin 2001;19:371407.

Reisner H, editor. Children with epilepsy. A parents guide. Bethesda (MD): Woodbine House; 1988. The Epilepsy Research Foundation PO Box 3004 London W4 1XT Phone: 020 8995 4781 E-mail: info@erf.org.uk http://www.erf.org.uk The Epilepsy Research Foundation is devoted solely to sponsoring effective research for all who now suffer from epilepsy. H.O.P.E. Mentoring Program Phone: (877) HOPE 4 YOU (877-467-3496) http://www.epilepsyfoundation.org/services/hope.html 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.E. trains people with epilepsy to be patient educators throughout the epilepsy and neurologic communities. Epilepsy Information Service (EIS) Department of Neurology Wake Forest University School of Medicine Medical Center Blvd. Winston-Salem, NC 27157 Phone: (800) 642-0500 http://www.bgsm.edu/neurology/department/diagneuro/neuro1. html The EIS is a nonprot resource center that offers a nationwide toll-free information line for people with epilepsy and their families, professionals, and the public. Free educational packets are available to all callers. Epilepsy.com 11911 Freedom Drive #730 Reston, VA 20190 Phone: (703) 437-9720 http://www.epilepsy.com Epilepsy.com is an online resource provided by The Epilepsy Project, a nonprofit organization that supports research. Epilepsy.com provides information for children, parents, and professionals.

Practitioner and Patient Resources

Epilepsy Foundation 4351 Garden City Drive, Suite 406 Landover, MD 20789 Phone: (800) 332-1000 http://www.epilepsyfoundation.org/ The Epilepsy Foundation is the nonprot organization representing patients with epilepsy in the United States. Local chapters provide patient education, job training, and advocacy. The Epilepsy Foundation recommends these books: Freeman J, Vining E, Pillas D, editors. Seizures and epilepsy in childhood: a guide for parents. Baltimore (MD): The Johns Hopkins University Press; 1990.

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

Recurrent Seizures Pages 139147