Chapter 562. Epilepsy Treatment: Antiepileptic Drug Therapy

Although other treatment modalities, such as the ketogenic diet, epilepsy surgery, and the vagus nerve stimulator, are appropriate options at some point for certain patients, antiepileptic drugs (AEDs) represent almost invariably the first and, in the great majority of patients, the only treatment in patients diagnosed with epilepsy. Until 1993, 4 AEDs represented more than 90% of all prescriptions for epilepsy: phenobarbital, phenytoin, carbamazepine, and valproate. These drugs are now referred to as the “older” AEDs. Adrenocorticotropic hormone (ACTH) was available but was used only for limited specific indications. Since 1993, many “newer” AEDs have become available. As a group, most of these newer drugs offer welcome alternatives with less or different side effects, fewer or no pharmacokinetic interactions, and a spectrum of efficacy that covers a wider range of different seizure types. However, despite the availability of these newer drugs, the percentage of patients whose seizures can never be fully controlled by medication has not been reduced and remains around 25% to 30% of all patients diagnosed with epilepsy. With so many AEDs to choose from, the challenge of matching the best possible drug to a given patient has grown substantially. The first goal of therapy is to find as rapidly as possible the AED that will provide the best possible seizure control while maximizing tolerability and safety. The currently available evidence-based guidelines address only a small proportion of the seizure types and syndromes, and selecting the most appropriate drug will also involve clinical experience and art.1,2 Often the choice will have to be tailored for a given patient, and in addition to seizure type and epilepsy syndrome, personal characteristics of the patient will have to be taken into account, such as gender, age, comorbid conditions, other medications, and lifestyle.

How Does Epilepsy Differ in Children?

Compared to practice in adults, the drug treatment of epilepsy in children differs in many ways. Children have seizure types, epilepsy syndromes, and underlying etiologies that cover a much broader spectrum. As the brain matures, seizures in children may evolve over time. The decision to initiate treatment after a first or even second seizure may differ in children, due to factors such as prognosis and impact of seizures on lifestyle. Antiepileptic therapy in children occurs in a context of growing, learning, and developing. Children may receive therapies that are only exceptionally used in adults, such as adrenocorticotropic hormone (ACTH), steroids, or the ketogenic diet. Often, antiepileptic drugs (AEDs) are used off label in children, either based on age or based on seizure type. Certain side effects of medications are more likely to occur in the pediatric age range, whereas others are more likely to occur in adults. Because children need to develop and learn, possible cognitive side effects of AEDs are a particular concern in this age group.3 Children’s pharmacokinetics differ, because they have invariably shorter drug elimination half-lives and higher clearances, which translate into substantially higher dosage requirements (in mg/kg/day). A subgroup of children has epilepsies that are likely to remit, and children as a group are less likely to experience seizure relapse when AEDs are tapered and discontinued following successful treatment. All these differences can determine drug choice, dosage, and monitoring of therapy. Also, the goal of AED therapy is to fully control seizures with no or minimal side effects, but the goal of epilepsy treatment is broader, because it is to help the child and the family to deal not only with the seizures, but also with their medical and psychosocial consequences, and with the patient’s other possible neurological comorbidities. Examples of comorbid conditions include mental retardation, cerebral palsy, attention deficit, depression, hydrocephalus, and metabolic disorder. Over the past decades, the treatment of epilepsy has evolved from a seizure control emphasis to a quality of life emphasis.

Decision to Initiate or Withhold Prophylactic Treatment

In a child with a single or several new-onset unprovoked epileptic seizures, the first task is to determine whether daily prophylactic AED therapy is the best option, or whether it would be preferable to withhold treatment for the time being. The following questions should be addressed: What is the risk of seizure recurrence? What would be the likely or possible consequences of a seizure recurrence? Does early treatment influence outcome? What are the risks associated with treatment? What are the patient’s age, occupation, and preference? The question of the risk of seizure recurrence in children following a first unprovoked seizure has been addressed in many studies, and a meta-analysis of 16 studies provides very useful numbers4:

Risk of Recurrence at 2 Years

The risk of recurrence at 2 years is as follows:

• Overall: 42%
• Idiopathic seizure, normal electroencephalogram (EEG): 24%
• Remote symptomatic, epileptiform EEG: 65%

Remote symptomatic means that the seizure is presumably due to a remote brain abnormality or insult. Thus, based on a history, neuroimaging, and an EEG, it may be possible to distinguish between a risk of seizure recurrence that can be as low as 1 in 4 or as high as 2 in 3. There is little doubt that such a distinction may significantly impact the decision to treat. Also, additional risk factors for seizure recurrence have been identified, such as partial (focal onset) seizure, prior acute symptomatic seizure (ie, history of a seizure during an acute neurological disease or insult), the first seizure represents status epilepticus, or the seizure was followed by a Todd’s paralysis. Treatment is often withheld initially in certain forms of epilepsy, such as benign childhood epilepsy with centrotemporal spikes (rolandic epilepsy) or benign occipital epilepsy. Inversely, AED treatment is often initiated in certain conditions associated with rare seizures or no seizures, such as acquired epileptic aphasia (Landau-Kleffner syndrome) or the syndrome of electrical status epilepticus of sleep (ESES).

Selecting the Medication and Starting Treatment

Once the decision to initiate prophylactic treatment has been reached, and before selecting an AED of first choice in monotherapy, every attempt should be made to reach the most accurate diagnosis of the seizure type and, if applicable, of the epilepsy syndrome. The same seizure type may respond to therapy differently, depending on the syndrome in which it occurs. When there is uncertainty about the seizure type or syndrome diagnosis, it is always better to select a drug with a relatively broad spectrum of efficacy. As a general rule, when various drugs have been found to be effective against a given seizure type, it has usually never been demonstrated that one is more effective than the others. Therefore, among the drugs that are considered to be most effective against the patient’s seizure type or syndrome, the drug of choice will be selected predominantly on the basis of its anticipated adverse effect profile in the individual patient, as well as on pharmacokinetic properties, including the possibility of interactions with other medications that the patient may already be taking. In addition to lack of interactions, desirable pharmacokinetic properties include constant bioavailability, a long half-life, low protein binding, and linear kinetics. When considering side effects, it is important to separate the drugs into those that are very unlikely and those that are likely to cause severe, irreversible, or potentially life-threatening side effects. All things being otherwise equal, the latter drugs should not be chosen as first-line therapy. Age or gender of the patient may also be a consideration when the side-effect profile is analyzed. For example, fatal liver failure as a complication of treatment with valproate has been shown to have a much higher incidence in young children (less than 3 years) who took valproate in combination with other AEDs.5 Also, the risk of a severe skin reaction to lamotrigine is higher in children than in adults. The risk of rash with lamotrigine is higher among those who already developed a rash with another AED. Inversely, fatal aplastic anemia related to treatment with felbamate was never reported in anyone less than 18 years old, and hyponatremia with oxcarbazepine is more common in adults and in elderly patients than in children. Also, certain underlying conditions may represent a contraindication for certain drugs, such as valproate in mitochondrial disorders. Gender may also be an issue when the impact of AED side effects is assessed, such as polycystic ovary syndrome with valproate, hirsutism with phenytoin, or teratogenicity with various AEDs. Before prescribing any AED, it is imperative to discuss all common and all potentially serious side effects of the drug with the parents or with the patient. It is also good practice to document what information has been provided. Recently, the FDA alerted the medical community that AEDs in general have been found to be associated with an increased risk of depression and suicidality. Finally, among the adverse effects of AEDs that must be weighed when selecting a drug of choice, one has to take into account the evidence that some drugs can aggravate seizures or cause new seizure types in patients with certain seizure types or epileptic syndromes.6 For instance, it has been shown that carbamazepine, phenytoin, and lamotrigine7,8 can exacerbate myoclonic seizures in patients with juvenile myoclonic epilepsy. It appears that drugs with a broader spectrum are less likely to do so.

After selection of what is considered to be the best drug for the patient, it should be introduced as monotherapy. There is virtually never a good reason to start a patient on more than one AED. An exception may be the temporary addition of a drug with rapid onset of action to a drug that needs to be introduced slowly. Most newer drugs must be introduced gradually, with the goal of achieving the initial target dose after about 2 to 6 weeks. There is only one optimal final dose in a given patient: as much as necessary and as little as possible. The goal of the therapy should always remain the same: no seizures and no side effects. Before switching to another AED or adding a second drug, the dose of the first drug should be increased gradually until either the seizures are controlled, or the patient’s maximal tolerated dose is reached. Combination of two or more drugs should only be considered if there is convincing evidence that the combination works better than either drug alone.

Blood levels of the drugs should only be measured if there is a specific question that might be answered by knowing the blood level. According to recent guidelines, “situations in which AED measurements are most likely to be of benefit include (1) when a person has attained the desired clinical outcome, to establish an individual therapeutic concentration which can be used at subsequent times to assess potential reasons for a change in drug response; (2) as an aid in the diagnosis of clinical toxicity; (3) to assess compliance, particularly in patients with uncontrolled seizures or breakthrough seizures; (4) to guide dosage adjustment in situations associated with increased pharmacokinetic variability (eg, children, the elderly, patients with associated diseases, drug formulation changes); (5) when a potentially important pharmacokinetic change is anticipated (eg, in pregnancy, or when an interacting drug is added or removed); (6) to guide dose adjustments for AEDs with dose-dependent pharmacokinetics, particularly phenytoin.”9 According to common practice, laboratory tests such as complete blood count and transaminases are ordered before introduction of certain drugs and periodically thereafter. This is done only for certain drugs, whereas other drugs generally do not require any routine blood monitoring.

Decision to Discontinue Treatment

It is a widely accepted practice to treat a child with seizures for 2 years after the last seizure. At that point, discontinuation can be discussed with the child and the parents. It is common practice to record an electroencephalogram (EEG) before discontinuing the medications. In certain cases, one may choose to continue the treatment beyond 2 years without seizure. This is based on an assessment of the risk of seizure recurrence if the drugs are stopped. Overall, the risk of seizure recurrence is lower in children (about 20% to 30%) than in adults (about 40% to 50%). In a meta-analysis of 25 studies,10 the risk of relapse was 25% at 1 year and 29% at 2 years. Risk factors associated with higher rates of seizure recurrence include remote symptomatic etiology (ie, preexisting underlying neurological abnormality), seizure onset after the age of 12 years, family history of epilepsy, slowing on the EEG, a history of atypical febrile seizures, and an IQ of less than 50.11 One may also be more hesitant to taper the medication of the patient has a history of status epilepticus. The drug must always be tapered slowly, over a period of about 2 to 3 months. In case of seizure recurrence, the last drug is reintroduced in most instances. Parents and patients often express the concern that the drug may not work again after it has been stopped. This is very uncommon.

Dosages of antiepileptic drugs (AEDs) are provided in Table 562-1 and their spectrum of efficacy, indications and main adverse effects are shown in Table 562-2. Specific dosage recommendations for lamotrigine are provided in Table 562-3. Further discussion of each antiepileptic drug, including their pharmacokinetics, common drug interactions is provided in electronic text.

Older Antiepileptic Drugs

Phenobarbital (PB)

There is still widespread use of PB worldwide. Despite its sedative and cognitive side effects, it is effective, easy to use, and inexpensive. PB had some efficacy against most seizure types, except for absence seizures. It remains the drug of first choice for the treatment of neonatal seizures, and the drug of second choice in the treatment of status epilepticus. Although PB is effective against febrile seizures, prophylactic treatment in this condition is now used only exceptionally.

The half-life of PB is long, about 1.5 days in children. Consequently, it only needs to be given once daily, and the dose does not need to be titrated because the steady-state level is reached only after several days. PB is a strong inducer of some hepatic enzymes and accelerates the elimination of several other AEDs, such as carbamazepine, valproic acid, ethosuximide, lamotrigine, topiramate, tiagabine, and zonisamide. This enzymatic induction can decrease the efficacy of vitamin D, resulting in osteomalacia and hypocalcemia. The main side effects of PB consist of its impact on cognition and behavior. Paradoxical hyperactivity and decreased attention span are not unusual. An allergic rash may occur, but organ toxicity is exceptional.

Phenytoin (PHT)

PHT is not a broad-spectrum drug, but it remains popular because it can be rapidly administered intravenously and remains a drug of choice in the treatment of status epilepticus, after the administration of lorazepam. PHT is effective against partial onset seizures with or without secondary generalization. It is also effective against primarily generalized tonic-clonic seizures, and is used as a drug of second choice in neonatal seizures. PHT can aggravate certain seizure types, in particular, absence seizures and myoclonic seizures.

The pharmacokinetics of PHT are unique among AEDs, due to saturable enzyme kinetics. This results in a disproportionate increase in steady-state levels as the maintenance dose is increased. In some children, very small alterations in the daily dose can result in extensive changes in the steady-state level. PHT is also a strong inducer of some hepatic enzymes, and it accelerates the elimination of several other AEDs, as listed under PB. It can also decrease the efficacy of vitamin D, resulting in osteomalacia and hypocalcemia. Adverse effects of PHT include hypersensitivity reactions, including Stevens-Johnson syndrome, ataxia, drowsiness, lethargy, sedation, gingival hyperplasia, hirsutism, and mild facial dysmorphism. Rare problems include hematological and hepatic toxicity, as well as cerebellar atrophy. PHT remains one of the less sedative AEDs.

Ethosuximide (ESM)

ESM retains a prominent role in the treatment of pediatric epilepsy because of its selective efficacy against absence seizures, and its excellent safety profile. It is not effective against generalized tonic-clonic seizures. In patients with childhood absence epilepsy who have not experienced generalized tonic-clonic seizures, ESM can be considered as the drug of first choice. ESM may have some efficacy against myoclonic seizures and drop attacks. The elimination half-life of ESM is relatively long, about 30 hours in children. This half-life may be shortened by enzyme-inducing drugs such as PB, PHT, and carbamazepine, while VPA tends to prolong the half-life. ESM does not seem to cause any pharmacokinetic interaction. By far the most common adverse effects of ESM are gastrointestinal, such as upset stomach and hiccups. ESM should be taken preferably after meals. ESM is not sedative. Rare adverse reactions include leukopenia, aplastic anemia, thrombocytopenia, skin rash, and psychosis.

Carbamazepine (CBZ)

Like PHT, CBZ is not a broad-spectrum drug. It is effective against partial-onset seizures with or without secondary generalization. It is also effective against primarily generalized tonic-clonic seizures. It cannot be administered intravenously and is not used in the treatment of status epilepticus. Like PHT, CBZ can aggravate certain seizure types, in particular, absence seizures and myoclonic seizures. For many years, CBZ has been used as the drug of first choice against partial onset seizures.

CBZ has a relatively short half-life, about 10 to 15 hours (shorter in children and in the presence of an inducing drug such as PHT or PB). CBZ is converted to an active metabolite, CBZ-epoxide, which can accumulate to clinically relevant plasma levels. The metabolism of CBZ is unique, because it accelerates its own elimination rate during the first few weeks of treatment, a phenomenon called autoinduction. As a consequence, a plasma level during the first week at a given dose will be much higher than a level 1 month later at the same daily dose. Therefore, the dose of CBZ must be increased gradually during the first 3 to 4 weeks of treatment. CBZ is also a strong inducer of some hepatic enzymes, and it accelerates the elimination of several other AEDs, as listed under PB. It too can decrease the efficacy of vitamin D, resulting in osteomalacia and hypocalcemia. CBZ levels are increased by certain drugs that inhibit hepatic microsomal enzymes, such as erythromycin and propoxyphene. Addition of these drugs to CBZ treatment can result in toxic levels of CBZ within 2 to 3 days.

Valproic Acid (Valproate, VPA)

Among the older AEDs, VPA was the first true broad-spectrum drug. It has either some or even good efficacy against all seizure types. It is considered a drug of first choice in the treatment of the idiopathic generalized epilepsies, with good efficacy against all seizures occurring in these epilepsies, generalized tonic-clonic, myoclonic, and absence seizures. VPA also has documented efficacy against partial onset seizures and may be effective against infantile spasms and in the Lennox-Gastaut syndrome. Although it can be administered intravenously, the role of VPA in the treatment of status epilepticus is not well established. It is not used against neonatal seizures because of the frequent occurrence of hyperammonemia.

VPA has a short half-life, especially in the presence of enzyme-inducing drugs. Inversely, VPA may act as an enzyme inhibitor, significantly prolonging the half-life of other AEDs such as PB, ESM, and lamotrigine. VPA is extensively bound to serum protein and can significantly displace PHT and benzodiazepines, increasing their free fraction. This interferes with the interpretation of total levels of PHT, and may require the measurement of free levels of PHT.

Although it is usually not sedative, VPA does have a number of side effects, some of them being potentially serious. Tremor and thrombocytopenia are typically dose related. Other common side effects include excessive weight gain, thinning or transient loss of hair, benign hyperammonemia, increased bruising, and decreased coagulation (independent from thrombocytopenia). Hemorrhagic pancreatitis is rare but serious.12,13 The most feared adverse effect is the potentially fatal acute or subacute liver failure. The high risk is in infants less than 3 years of age who are receiving other AEDs, have a congenital metabolic disorder, or have organic brain disease. The incidence in this group has been found to be 1 in 600. In contrast, older children on monotherapy with VPA were found to have an incidence of fatal liver failure of about 1 in 16,000 or less.

Benzodiazepines (BDZ)

As a group, BDZs have their own niche in the treatment of epilepsy. Their main advantages are their broad spectrum of activity, rapid onset of action, and absence of serious adverse effects or organ toxicity (other than respiratory suppression at high doses). Main disadvantages are their pronounced sedative effect, even at therapeutic doses, and their tendency to lose their efficacy after a relatively short time (tolerance to BDZ develops within weeks to months). Accordingly, BDZs have a role in the acute, temporary, or intermittent treatment of epilepsy. Because of a pronounced sedative effect to which tolerance develops within days, the initial dose of BDZs should be lower than the maintenance doses suggested in Table 562-1. Diazepam is used orally for transient exacerbations of seizures or for the prophylaxis of febrile seizures (during febrile episodes only). Rectal diazepam, applied outside of the hospital setting by caregivers, is currently the treatment of choice for acute repetitive or prolonged seizures. Lorazepam is currently the first-line drug in the treatment of status epilepticus, whereas midazolam is used as an infusion for refractory status epilepticus. Clonazepam is used for more prolonged treatment as an adjunctive drug. Clobazam seems to be less sedative than other BDZs and seems to have a fairly broad spectrum of efficacy in pediatric patients, including the more severe and refractory generalized epilepsies, such as Lennox-Gastaut syndrome and myoclonic astatic epilepsy (Doose syndrome).

Newer Antiepileptic Drugs

Felbamate (FBM)

FBM has documented efficacy against partial onset seizures and in the treatment of the Lennox-Gastaut syndrome. Its elimination half-life in children was found to be about 16 hours. Within a year of its marketing, it became evident that FBM was significantly associated with 2 life-threatening adverse effects, aplastic anemia and liver failure, and the drug came close to being withdrawn from the market. However, fatal aplastic anemia was never reported in children, and the risk of fatal liver failure, which seems to be similar across ages, is less than that of VPA. Other side effects of FBM include anorexia, weight loss, and insomnia. When introducing FBM, it is very important to obtain baseline complete blood count and serum transaminase levels and to repeat these tests at monthly intervals during the first few months, then at least every 3 months.

Gabapentin (GBP)

Gabapentin is a narrow-spectrum antiepileptic drugs (AED). It is effective against partial onset and secondarily generalized seizures. It is not effective against absence seizures14 or generalized tonic-clonic seizures in generalized epilepsies. It may be effective in benign rolandic epilepsy. GBP has a half-life of only a few hours. Since the introduction of bromide, GBP was the first AED to be eliminated entirely by the kidneys and to be involved in no pharmacokinetic interaction. The absorption of GBP has the unique characteristic of being saturable; thus, the percentage of a single dose that is absorbed after an oral dose may decrease as the dose is increased, from a maximum of about 60% to 70% to as little as 30%. Side effects of GBP include somnolence, dizziness, ataxia, behavioral problems, excessive weight gain, and rarely, involuntary movements.

Lamotrigine (LTG)

LTG can definitely be ranked among the broad-spectrum drugs. It has documented efficacy against partial onset seizures, primary generalized tonic-clonic seizures,15 absence seizures,16 and the Lennox-Gastaut syndrome.17 LTG may aggravate myoclonic seizures, particularly those occurring in patients with juvenile myoclonic epilepsy. LTG is largely metabolized by the liver, a process that is subject to acceleration by the enzyme-inducing drugs and inhibition by VPA. Accordingly, the initial dosage and titration can vary by a factor of 4, depending on whether the patient takes no other AED or a noninteracting AED, or takes an enzyme-inducing AED, or takes VPA18 (see Table 562-3).

Occasional dose-related adverse effects of LTG are dizziness, sedation, headache, diplopia, and ataxia. LTG has virtually no toxicity to organs such as liver, bone marrow, or kidneys. The main concern with LTG is the possibility of a rash (about 10%), which can evolve into Stevens-Johnson syndrome. This seems to be more likely to occur in children. The risk of rash is higher among those who had already developed a rash with another AED. There is also good evidence that the likelihood of a rash increases with faster titration rates, especially in the presence of VPA. This observation has led to the current recommendation for very slow titration, which should be applied rigorously (Table 562-3). It is not uncommon for the slow titration to be a limiting factor for the use of LTG, particularly when fast seizure control is required; this may require the use of a “bridge” medication such as clonazepam until a therapeutic dose is achieved.

Topiramate (TPM)

TPM is also recognized as a broad-spectrum AED. It is indicated in the treatmentof partial onsetseizures, primarily generalized tonic-clonic seizures, and drop attacks associated with Lennox-Gastaut syndrome. There is also evidence that it may potentially be useful in the treatment of juvenile myoclonic epilepsy19 and infantile spasms. TPM is a weak carbonic anhydrase inhibitor, although this property probably does not contribute significantly to its efficacy but may be responsible for some of the adverse effects, such as metabolic acidosis, hypohydrosis (decreased sweating), nephrolithiasis, and paresthesias. The half-life of TPM varies according to age (less than 10 hours in children, and longer than 10 hours in adults). Inducing drugs shorten the half-life ofTPM.

The most common adverse effects of TPM in children include somnolence and fatigue, problems with concentration and word finding, decreased appetite, and weight loss. TPM may frequently induce or aggravate metabolic acidosis and should be administered with caution and under monitoring in patients with renal disease and those on the ketogenic diet or zonisamide. Nephrolithiasis has occurred in 1.5% of patients. Hypohydrosis can lead to hyperthermia.

Tiagabine (TGB)

TGB is indicated only in the treatment of partial onset seizures. It is extensively metabolized by the liver. The elimination half-life of TGB is only 5 to 8 hours, and it is shortened further to about 3 hours by inducing drugs. TGB does not seem to affect the kinetics of other drugs. TGB as add-on therapy was implicated in the development of nonconvulsive status epilepticus. So far, the recognized adverse effects of TGB are mostly dose-related effects on the central nervous system, such as dizziness, asthenia, and tremor. Buckling of the knees has been associated with TGB and may represent a negative myoclonus. There have been no significant laboratory abnormalities or dangerous idiosyncratic reactions.

Vigabatrin (VGB)

Studies of VGB in adults have clearly demonstrated its efficacy against partial seizures, with little or no efficacy against other seizure types. However, VGB has emerged as a first-choice AED against infantile spasms, particularly in patients with tuberous sclerosis. The pharmacokinetic properties of VGB are similar to those of GBP, including the renal excretion and the lack of pharmacokinetic interactions. Although the elimination half-life of VGB is quite short, its pharmacodynamic action after a single dose can be demonstrated for several days. The most common adverse effects of VGB in children include fatigue, headache, drowsiness, dizziness, ataxia, tremor, depression, weight gain, and hyperactivity. The main concern is the occurrence of irreversible visual field constriction, with bilateral optic disc pallor, and subtle peripheral retinal atrophy. This has prompted the recommendation of initial and periodic ophthalmologic examinations (approximately every 3 months) and electroretinograms in patients treated with VGB. The use of VGB in the pediatric population should be limited to the treatment of infantile spasms.

Oxcarbazepine (OXC)

OXC is closely related to carbamazepine (CBZ), and their efficacy and adverse effect profiles do not differ appreciably. OXC is indicated for the treatment of partial onset seizures. There is also evidence that OXC is effective for the treatment of generalized tonic-clonic seizures although, like CBZ, it is contraindicated in idiopathic generalized epilepsies because of the potential for seizure aggravation. OXC is a prodrug, the active compound being the 10-mono-hydroxy derivative (MHD). Pharmacokinetic differences between OXC and CBZ include the absence of enzymatic autoinduction with OXC, and weaker enzymatic induction with OXC than with CBZ. In children younger than 8 years, clearance of OXC is 30% to 40% higher than in older children.

OXC has a relatively favorable adverse effect profile in children.20 Potentially serious dermatologic reactions and multiorgan hypersensitivity reactions can occur. Cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in children and adults. In terms of cross-hypersensitivity reactions, one quarter to one third of patients with a reaction to CBZ will experience one when CBZ is replaced by OXC. Hyponatremia is another known side effect OXC, but it has been reported in less than 1% of children. Routine monitoring of serum sodium concentrations does not appear to be necessary in children.

Levetiracetam (LEV)

LEV is emerging as another broad-spectrum AED. It is indicated for the treatmentof partial onset seizures and has been also approved for the treatment of myoclonic seizures in juvenile myoclonic epilepsy and generalized tonic-clonic seizures in idiopathic generalized epilepsies. LEV can also suppress generalized spike-wave complexes in the EEG. Approximately one third of a LEV dose is metabolized in blood by hydrolysis, and the remainder is excreted directly in the urine. LEV has no significant pharmacokinetic interactions with other AEDs. It is usually well tolerated and has a rather benign adverse effect profile. Behavioral changes such as mood changes and irritability, as well as occasional psychosis, are the main concerns.

Zonisamide (ZNS)

ZNS is indicated in the treatment of partial onset seizures. Experience suggests that it is effective in children with Lennox-Gastaut syndrome and against both partial and generalized seizures, particularly in myoclonic epilepsies. Like TPM, ZNS is a weak inhibitor of carbonic anhydrase. It has a long half-life (60 to 80 hours). Enzyme-inducing drugs, suchas CBZ and PHT, increase the clearance of ZNS. Common adverse effects of ZNS include sleepiness, cognitive impairment, loss of appetite, weight loss, and ataxia. Oligohydrosis (decreased sweating) and hyperthermia have been reported in pediatric patients. Hence, children receiving ZNS should be monitored in that respect, especially in warm or hot weather. Kidney stones and allergic rashes may also occur with ZNS.

Pregabalin (PGB)

PGB was approved as adjunctive therapy for partial onset seizures in adults only. Neither its safety nor its efficacy or pharmacokinetic properties have been studied in children. There is evidence that PGB can induce myoclonic seizures even in patients with focal seizures. PGB is structurally related to GBP. It has a favorable pharmacokinetic profile, with similarities to GBP, including virtual absence of protein binding and minimal metabolism. Unlike GBP, PGB has high and nonsaturable bioavailability (> 90%). Hepatic enzyme induction and drug-drug interactions do not occur. In clinical trials, the side effect profile of PGB was similar to that of GBP. The most common adverse effects included dizziness, sleepiness, difficulty concentrating, ataxia, and weight gain. PGB can also cause or exacerbate myoclonic seizures.21

Table 562-4 represents an attempt to rank antiepileptic drugs (AEDs) as first and second choices for various seizure types and epilepsy syndromes occurring in the pediatric age group. Because scientific evidence alone cannot be used to establish such rankings, the choices have to be based on a combination of published evidence of efficacy, side effect and safety considerations, published and personal uncontrolled observations, and comfort factor. Accordingly, such rankings may appear somewhat arbitrary and are open to debate and to change over time (Table 562-4).

Partial Seizures

Overall, most AEDs have documented efficacy against partial seizures, and none could be shown to be more effective than any other. Therefore, choices should be based mainly on side effect profile and overall accumulated experience with the different AEDs. Accordingly, carbamazepine (CBZ), oxcarbazepine (OXC), and levetiracetam (LEV) could be considered as drugs of first choice.

Generalized Tonic-Clonic Seizures (GTCS)

GTCS may occur in the context of an idiopathic generalized epilepsy, in undetermined epilepsies without evidence of focality, or in focal epilepsies with rapid secondary generalization. Considering this heterogeneity, the treatment of GTCS as the only seizure type may be challenging. The choice of medication for GTCS may depend on whether the patient is experiencing a nonfocal GTCS in the context of idiopathic generalized epilepsy. If this is the case, the drugs of choice would be valproic acid (VPA), lamotrigine (LTG), levetiracetam (LEV), or topiramate (TPM) because of the available evidence. Carbamazepine (CBZ), phenytoin (PHT), or zonisamide (ZNS), which are potentially effective, could be considered as further choices, but CBZ and PHT should be avoided if an idiopathic generalized epilepsy is suspected.

Absence Epilepsies: Childhood and Juvenile Absence Epilepsy (CAE and JAE)

Children with absence seizures may be divided into 2 age categories: those under the age of 10 years and those above the age of 10 years. There are at least 3 reasons for this: (1) concomitant GTCS are more likely to occur after the age of 10 years in patients diagnosed with CAE, and are common in JAE; (2) the incidence of VPA-induced fatal hepatotoxicity is highest in infants and young children, especially in combination therapy; and (3) the incidence of severe hypersensitivity reaction associated with LTG also appears to be inversely age related. Consequently, Ethosuximide (ESM) may still represent the drug of first choice in patients younger than 10 years old who have only absence seizures, as is usually the case in CAE. In any child older than 10 years with absence seizures, when an AED needs to be introduced or changed, the choice would be valproic acid (VPA). It is quite safe in monotherapy at this age and highly effective against GTCS, whereas ESM offers no such protection. LTG, which is also effective against absence seizures and GTCS, is quite safe in this age group and is a valuable alternative to VPA, especially in adolescent girls. Methsuximide and acetazolamide also may be effective against absence seizures, and TPM has been found to have some efficacy. GBP, CBZ, PHT, and TGB appear to have no role in the treatment of absence seizures, and the efficacy of LEV and ZNS has yet to be assessed.

Juvenile Myoclonic Epilepsy (JME)

Valproic acid (VPA) remains a drug of choice for JME. However, the side-effect profile of VPA is a concern, especially in women of childbearing age (weight gain, teratogenicity, the possibility of polycystic ovary syndrome, and cognitive impairment in a child exposed to VPA in utero). For a potentially lifelong condition such as JME, an alternative drug would be desirable, such as LTG that has a much lower incidence of severe idiosyncratic reactions in adults than in children, and has few other side effects. Lamotrigine (LTG) is quite effective against GTCS, but it may aggravate myoclonic seizures. There is growing evidence that levetiracetam (LEV) is effective in all seizure types of IGE and is another promising alternative to VPA. Clonazepam is very effective against the myoclonic seizures but less effective against the GTCS. TPM has been shown to be effective against the GTCS in JME,19 but its role against myoclonic seizures remains to be established. FBM also appears to be effective, but it should be considered only in unusually refractory cases because of its side-effect profile.

Benign Rolandic Epilepsy with Centrotemporal Spikes (BRECTS)

BRECTS is usually associated with excellent prognosis and outcome, although there is growing evidence that it may at times have a substantial impact on the child’s behavior or cognition. In many cases, treatment is not necessary. Many AEDs were reported efficacious, including oxcarbazepine (OXC) and clonazepam (CZP). However, randomized trials have been performed with only gabapentin (GBP) and sulthiame22; the latter was also reported to normalize the EEG.23

Infantile Spasms

Adrenocorticotropic hormone (ACTH) and vigabatrin (VGB) are the most effective agents in the treatment of infantile spasms, but concerns remain about the risk/benefit profiles of these drugs.24 In addition, both treatments have potentially severe and at times irreversible side effects. Particular attention should be paid to the irreversible restriction of visual fields associated with VGB.

Lennox-Gastaut Syndrome (LGS)

Three drugs have been shown in double-blind, controlled trials to be superior to placebo in the treatment of LGS: topiramate (TPM), lamotrigine (LTG), and felbamate (FBM). Among these 3, TPM and LTG are now commonly used as the drugs of first choice. FBM may be one of the most effective drugs in patients with LGS, but its side effect profile makes it a drug of third choice. Valproic acid (VPA) can still be considered as a drug of second choice in these patients. Because the age of onset is after 2 to 3 years, the risk of hepatic failure from VPA is relatively low in these patients, especially in monotherapy. Benzodiazepines are also effective against all types of seizures, including tonic seizures, but they can at times cause tonic status epilepticus. CBZ, PHT, GBP, and TGB have little or no role in the treatment of LGS. The role of ZNS and LEV remains to be established. In patients who failed 2 or 3 initial drug trials, it is now common to try the ketogenic diet (see Chapter 563). In a recently reported double-blind add-on trial, rufinamide, a newly developed AED, was shown to have good responder rates for astatic seizures in patients with LGS.

Neonatal Seizures

The current standard of treatment has been applied for several decades. Phenobarbital (PB) and phenytoin (PHT), 2 of the oldest AEDs, together with a benzodiazepine, remain the first-line choices.25 Interestingly, none of the newer AEDs has been evaluated in a systematic manner in this fragile population, and only anecdotal reports can be found. Currently, acute symptomatic seizures in newborns are only treated for a relatively short time. When neonatal seizures remain intractable, specific metabolic underlying etiologies requiring special treatment should be considered. Examples include pyridoxine-dependent seizures, folinic acid–dependent seizures, or the glucose transporter defect (see Chapter 557) that may respond to the ketogenic diet (see Chapter 563).