Chapter 21: Pharmacotherapy of the Epilepsies

Apart from this epileptic seizure classification, an additional classification specifies epileptic syndromes, which refer to a cluster of symptoms frequently occurring together and include seizure types, etiology, age of onset, and other factors (Commission on Classification and Terminology, 1989). More than 50 distinct epileptic syndromes have been identified and categorized into partial versus generalized epilepsies. The partial epilepsies may consist of any of the partial seizure types (Table 21–1) and account for roughly 60% of all epilepsies. The etiology commonly consists of a lesion in some part of the cortex, such as a tumor, developmental malformation, or damage due to trauma or stroke. Such lesions often are evident on brain magnetic resonance imaging (MRI). Alternatively, the etiology may be genetic. The generalized epilepsies are characterized most commonly by one or more of the generalized seizure types listed in Table 21–1 and account for ~40% of all epilepsies. The etiology is usually genetic. The most common generalized epilepsy is referred to as juvenile myoclonic epilepsy, accounting for ~10% of all epileptic syndromes. The age of onset is in the early teens, and the condition is characterized by myoclonic, tonic-clonic, and often absence seizures. Like most of the generalized-onset epilepsies, juvenile myoclonic epilepsy is a complex genetic disorder that is probably due to inheritance of multiple susceptibility genes; there is a familial clustering of cases, but the pattern of inheritance is not mendelian. The classification of epileptic syndromes guides clinical assessment and management, and in some instances, selection of anti-seizure drugs.

Such studies support the idea that pharmacological regulation of synaptic function can regulate the propensity for seizures and provide a framework for electrophysiological analyses aimed at elucidating the role of both synaptic and nonsynaptic mechanisms in seizures and epilepsy. Progress in techniques has fostered the progressive refinement of the analysis of seizure mechanisms from the EEG to populations of neurons (field potentials) to individual neurons to individual synapses and individual ion channels on individual neurons. Beginning in the mid-1960s, cellular electrophysiological studies of epilepsy focused on elucidating the mechanisms underlying the depolarization shift (DS), the intracellular correlate of the "interictal spike" (Figure 21–1). The interictal (or between-seizures) spike is a sharp waveform recorded in the EEG of patients with epilepsy; it is asymptomatic in that it is accompanied by no overt change in the patient's behavior. The location of the interictal spike helps localize the brain region from which seizures originate in a given patient. The DS consists of a large depolarization of the neuronal membrane associated with a burst of action potentials. In most cortical neurons, the DS is generated by a large excitatory synaptic current that can be enhanced by activation of voltage-gated intrinsic membrane currents. Although the mechanisms generating the DS are increasingly understood, it remains unclear whether the interictal spike triggers a seizure, inhibits a seizure, or is an epiphenomenon with respect to seizure occurrence in an epileptic brain. While these questions remain unanswered, the study of the mechanisms of DS generation set the stage for inquiry into the cellular mechanisms of a seizure.

During the 1980s, various in vitro models of seizures were developed in isolated brain slice preparations, in which many synaptic connections are preserved. Electrographic events with features similar to those recorded during seizures in vivo have been produced in hippocampal slices by multiple methods, including altering ionic constituents of media bathing the brain slices (McNamara, 1994) such as low Ca²⁺, zero Mg²⁺, or elevated K⁺. The accessibility and experimental control provided by these preparations has permitted mechanistic investigations into the induction of seizures. Analyses of multiple in vitro models confirmed the importance of synaptic function for initiating a seizure, demonstrating that subtle (e.g., 20%) reductions of inhibitory synaptic function could lead to epileptiform activity and that activation of excitatory synapses could be pivotal in seizure initiation. Other important factors were identified, including the volume of the extracellular space as well as intrinsic properties of a neuron, such as voltage-gated ion channels (e.g., K⁺, Na⁺, and Ca²⁺ channels) (Traynelis and Dingledine, 1988). Identification of these diverse synaptic and nonsynaptic factors controlling seizures in vitro provides potential pharmacological targets for regulating seizure susceptibility in vivo.

One model, termed "kindling," is induced by periodic administration of brief, low-intensity electrical stimulation of the amygdala or other limbic structures. Initial stimulations evoke a brief electrical seizure recorded on the EEG without behavioral change, but repeated (e.g., 10-20) stimulations result in progressive intensification of seizures, culminating in tonic-clonic seizures. Once established, the enhanced sensitivity to electrical stimulation persists for the life of the animal. Despite the exquisite propensity to intense seizures, spontaneous seizures or a truly epileptic condition do not occur until 100-200 stimulations have been administered. The ease of control of kindling induction (i.e., stimulations administered at the investigator's convenience), its graded onset, and the ease of quantitating epileptogenesis (number of stimulations required to evoke tonic-clonic seizures) simplify experimental study. In mice, deletion of the gene encoding the receptor tyrosine kinase, TrkB, prevents epileptogenesis in the kindling model (He et al., 2004), which advances TrkB and its downstream signaling pathways as attractive targets for developing small molecule inhibitors for prevention of epilepsy or its progression.

Additional models are produced by induction of continuous seizures for hours ("status epilepticus"), with the inciting agent being a chemoconvulsant, such as kainic acid or pilocarpine, or sustained electrical stimulation. The fleeting episode of status epilepticus is followed weeks later by the onset of spontaneous seizures, an intriguing parallel to the scenario of complicated febrile seizures in young children preceding the emergence of spontaneous seizures years later. In contrast to the limited or absent neuronal loss characteristic of the kindling model, overt destruction of hippocampal neurons occurs in the status epilepticus models, reflecting aspects of hippocampal sclerosis observed in humans with severe limbic seizures. Indeed, the discovery that complicated febrile seizures precede and presumably are the cause of hippocampal sclerosis in young children (VanLandingham et al., 1998) establishes yet another commonality between these models and the human condition.

Several questions arise with respect to these models. What transpires during the latent period between status epilepticus and emergence of spontaneous seizures that causes the epilepsy? Might an anti-epileptogenic agent that was effective in one of these models be effective in other models?

The EEG hallmark of an absence seizure is generalized spike-and-wave discharges at a frequency of 3 per second (3 Hz). These bilaterally synchronous spike-and-wave discharges, recorded locally from electrodes in both the thalamus and the neocortex, represent oscillations between the thalamus and neocortex. A comparison of EEG and intracellular recordings reveals that the EEG spikes are associated with the firing of action potentials and the following slow wave with prolonged inhibition. These reverberatory, low-frequency rhythms are made possible by a combination of factors, including reciprocal excitatory synaptic connections between the neocortex and thalamus as well as intrinsic properties of neurons in the thalamus (Huguenard and McCormick, 2007). One intrinsic property of thalamic neurons that is pivotally involved in the generation of the 3-Hz spike-and-wave discharges is a particular type of Ca²⁺ current, the low threshold ("T-type") current. T-type Ca²⁺ channels are activated at a much more negative membrane potential (hence "low threshold") than most other voltage-gated Ca²⁺ channels expressed in the brain. T-type currents are much larger in many thalamic neurons compared to neurons outside the thalamus. Indeed, bursts of action potentials in thalamic neurons are mediated by activation of the T-type currents. T-type currents amplify thalamic membrane potential oscillations, with one oscillation being the 3-Hz spike-and-wave discharge of the absence seizure. Importantly, the principal mechanism by which anti–absence-seizure drugs (ethosuximide, valproic acid) are thought to act is by inhibition of the T-type Ca²⁺ channels (Figure 21–4) (Rogawski and Loscher, 2004). Thus, inhibiting voltage-gated ion channels is a common mechanism of action among anti-seizure drugs, with anti–partial-seizure drugs inhibiting voltage-activated Na⁺ channels and anti–absence-seizure drugs inhibiting voltage-activated Ca²⁺ channels.

Enormous progress has been made in understanding the genetics of mammalian epilepsy. Mutant genes have been identified for a number of symptomatic epilepsies, in which the epilepsy is a manifestation of the underlying neurodegenerative disease. Because most patients with epilepsy are neurologically normal, elucidating the mutant genes underlying familial epilepsy in otherwise normal individuals is of particular interest; this has led to the identification of 25 distinct genes implicated in distinct idiopathic epilepsy syndromes that account for < 1% of all of the human epilepsies. Interestingly, almost all of the mutant genes encode voltage- or ligand-gated ion channels (Reid et al., 2008). Mutations have been identified in Na⁺, K⁺, Ca²⁺, and Cl⁻ channels, in channels gated by GABA and acetylcholine, and most recently, in intracellular Ca²⁺ release channels (RyR2) activated by Ca²⁺. The genotype-phenotype correlations of these genetic syndromes are complex; the same mutation in one channel can be associated with divergent clinical syndromes ranging from simple febrile seizures to intractable seizures with intellectual decline. Conversely, clinically indistinguishable epilepsy syndromes have been associated with mutation of distinct genes. The implication of genes encoding ion channels in familial epilepsy is particularly interesting because episodic disorders involving other organs also result from mutations of these genes. For example, episodic disorders of the heart (cardiac arrhythmias), skeletal muscle (periodic paralyses), cerebellum (episodic ataxia), vasculature (familial hemiplegic migraine), and other organs all have been linked to mutations in genes encoding components of voltage-gated ion channels (Ptacek and Fu, 2001).

The cellular electrophysiological consequences of these mutations can inform on the mechanisms of seizures and anti-seizure drugs. For example, generalized epilepsy with febrile seizures (GEFS+) is caused by a point mutation in the β subunit of a voltage-gated Na⁺ channel (SCN1B). As described previously, several anti-seizure drugs act on Na⁺ channels to promote their inactivation; the phenotype of the mutated Na⁺ channel appears to involve defective inactivation (Wallace et al., 1998).

Spontaneous mutations in SCN1A (encoding the α subunit of the major voltage-gated Na⁺ channel in neurons) that result in truncations and presumed loss of Na⁺ channel function have been identified in a subset of infants with a catastrophic severe myoclonic epilepsy of infancy. An intriguing clue as to how this genotype may lead to an epileptic phenotype has emerged from the study of SCN1A knock-out mice (Yu et al., 2006). Heterozygote mice have only one functional allele and provide a mouse model of this epileptic syndrome. Because activation of voltage-gated Na⁺ channels depolarizes and activates a neuron, it seemed odd that a loss of function mutation of SCN1A would result in increased excitability of networks of neurons and epilepsy. This led to the discovery of impaired firing of inhibitory interneurons, but not excitatory principal neurons, in SCN1A heterozygous mice (Yu et al., 2006). These findings suggest that loss of function mutations of SCN1A may cause epilepsy as a consequence of reduced firing of inhibitory interneurons. Because interneurons effect inhibition by releasing GABA, this suggests that drugs acting to enhance GABA-mediated inhibition may be effective anticonvulsants in SCN1A mutant mice and infants with these mutations. Consistent with this hypothesis, preliminary findings reveal that an experimental anti-seizure drug that increases the duration of GABA_A receptor channel open times (Quilichini et al., 2006) was beneficial in children with severe myoclonic epilepsy of infancy (Chiron, 2007). If confirmed, this would provide the first instance of rational use of anti-seizure drugs in that insight into the cellular mechanism of the epilepsy would guide selection of drugs acting by a given mechanism.

History. The first anti-epileptic drug was bromide, which was used in the late 19th century. Phenobarbital was the first synthetic organic agent recognized as having anti-seizure activity. Its usefulness, however, was limited to generalized tonic-clonic seizures, and to a lesser degree, simple and complex partial seizures. It had no effect on absence seizures. Merritt and Putnam developed the electroshock seizure test in experimental animals to screen chemical agents for anti-seizure effectiveness; in the course of screening a variety of drugs, they discovered that diphenylhydantoin (later renamed phenytoin) suppressed seizures in the absence of sedative effects. The electroshock seizure test is extremely valuable, because drugs that are effective against tonic hind limb extension induced by electroshock generally have proven to be effective against partial and tonic-clonic seizures in humans. Another screening test, seizures induced by the chemoconvulsant pentylenetetrazol, is most useful in identifying drugs that are effective against myoclonic seizures in humans. These screening tests are still used. The chemical structures of most of the drugs introduced before 1965 were closely related to phenobarbital. These included the hydantoins and the succinimides. Between 1965 and 1990, the chemically distinct structures of the benzodiazepines, an iminostilbene (carbamazepine), and a branched-chain carboxylic acid (valproic acid) were introduced, followed in the 1990s by a phenyltriazine (lamotrigine), a cyclic analog of GABA (gabapentin), a sulfamate-substituted monosaccharide (topiramate), a nipecotic acid derivative (tiagabine), and a pyrrolidine derivative (levetiracetam).

History. Phenytoin was first synthesized in 1908 by Biltz, but its anticonvulsant activity was not discovered until 1938. In contrast to the earlier accidental discovery of the anti-seizure properties of bromide and phenobarbital, phenytoin was the product of a search among nonsedative structural relatives of phenobarbital for agents capable of suppressing electroshock convulsions in laboratory animals. It was introduced for the treatment of epilepsy in the same year. Since this agent is not a sedative in ordinary doses, it established that anti-seizure drugs need not induce drowsiness and encouraged the search for drugs with selective anti-seizure action.

Structure-Activity Relationship. A 5-phenyl or other aromatic substituent appears essential for activity against generalized tonic-clonic seizures. Alkyl substituents in position 5 contribute to sedation, a property absent in phenytoin. The carbon 5 position permits asymmetry, but there appears to be little difference in activity between isomers.

Mechanism of Action. Phenytoin limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord neurons maintained in vitro (McLean and Macdonald, 1986a). This effect is mediated by a slowing of the rate of recovery of voltage-activated Na⁺ channels from inactivation, an action that is both voltage- (greater effect if membrane is depolarized) and use-dependent. These effects of phenytoin are evident at concentrations in the range of therapeutic drug levels in cerebrospinal fluid (CSF) in humans, which correlate with the free (or unbound) concentration of phenytoin in the serum. At these concentrations, the effects on Na⁺ channels are selective, and no changes of spontaneous activity or responses to iontophoretically applied GABA or glutamate are detected. At concentrations 5- to 10-fold higher, multiple effects of phenytoin are evident, including reduction of spontaneous activity and enhancement of responses to GABA; these effects may underlie some of the unwanted toxicity associated with high levels of phenytoin.

The majority (95%) of phenytoin is metabolized in the hepatic endoplasmic reticulum by CYP2C9/10 and to a lesser extent CYP2C19 (Table 21–3). The principal metabolite, a parahydroxy-phenyl derivative, is inactive. Because its metabolism is saturable, other drugs that are metabolized by these enzymes can inhibit the metabolism of phenytoin and increase its plasma concentration. Conversely, the degradation rate of other drugs that are substrates for these enzymes can be inhibited by phenytoin; one such drug is warfarin, and addition of phenytoin to a patient receiving warfarin can lead to bleeding disorders (Chapter 30). An alternative mechanism of drug interactions arises from phenytoin's ability to induce diverse CYPs (Chapter 6); co-administration of phenytoin and medications metabolized by these enzymes can lead to an increased degradation of such medications. Of particular note in this regard are oral contraceptives, which are metabolized by CYP3A4; treatment with phenytoin can enhance the metabolism of oral contraceptives and lead to unplanned pregnancy. The potential teratogenic effects of phenytoin underscore the importance of attention to this interaction. Carbamazepine, oxcarbazepine, phenobarbital, and primidone also can induce CYP3A4 and likewise might increase degradation of oral contraceptives.

The low water solubility of phenytoin hindered its intravenous use and led to production of fosphenytoin, a water-soluble prodrug. Fosphenytoin (cerebyx, others) is converted into phenytoin by phosphatases in liver and red blood cells with a t_1/2 of 8-15 minutes. Fosphenytoin is extensively bound (95-99%) to human plasma proteins, primarily albumin. This binding is saturable and fosphenytoin displaces phenytoin from protein-binding sites. Fosphenytoin is useful for adults with partial or generalized seizures when intravenous or intramuscular administration is indicated.

When fosphenytoin, the water-soluble prodrug, is administered intravenously at an excessive rate in the emergency treatment of status epilepticus, the most notable toxic signs are cardiac arrhythmias with or without hypotension, and/or CNS depression. Although cardiac toxicity occurs more frequently in older patients and in those with known cardiac disease, it also can develop in young, healthy patients. These complications can be minimized by administering fosphenytoin at a rate of < 150 mg of phenytoin sodium equivalents per minute. Acute oral overdosage results primarily in signs referable to the cerebellum and vestibular system; high doses have been associated with marked cerebellar atrophy. Toxic effects associated with chronic treatment also are primarily dose-related cerebellar-vestibular effects but also include other CNS effects, behavioral changes, increased frequency of seizures, GI symptoms, gingival hyperplasia, osteomalacia, and megaloblastic anemia. Hirsutism is an annoying untoward effect in young females. Usually, these phenomena can be diminished by proper adjustment of dosage. Serious adverse effects, including those on the skin, bone marrow, and liver, probably are manifestations of drug allergy. Although rare, they necessitate withdrawal of the drug. Moderate elevation of the plasma concentrations of hepatic transaminases sometimes are observed; since these changes are transient and may result in part from induced synthesis of the enzymes, they do not necessitate withdrawal of the drug.

Gingival hyperplasia occurs in ~20% of all patients during chronic therapy and is probably the most common manifestation of phenytoin toxicity in children and young adolescents. It may be more frequent in those individuals who also develop coarsened facial features. The overgrowth of tissue appears to involve altered collagen metabolism. Toothless portions of the gums are not affected. The condition does not necessarily require withdrawal of medication and can be minimized by good oral hygiene.

A variety of endocrine effects have been reported. Inhibition of release of anti-diuretic hormone (ADH) has been observed in patients with inappropriate ADH secretion. Hyperglycemia and glycosuria appear to be due to inhibition of insulin secretion. Osteomalacia, with hypocalcemia and elevated alkaline phosphatase activity, has been attributed to both altered metabolism of vitamin D and the attendant inhibition of intestinal absorption of Ca²⁺. Phenytoin also increases the metabolism of vitamin K and reduces the concentration of vitamin K–dependent proteins that are important for normal Ca²⁺ metabolism in bone. This may explain why the osteomalacia is not always ameliorated by the administration of vitamin D.

Hypersensitivity reactions include morbilliform rash in 2-5% of patients and occasionally more serious skin reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis. Systemic lupus erythematosus and potentially fatal hepatic necrosis have been reported rarely. Hematological reactions include neutropenia and leukopenia. A few cases of red-cell aplasia, agranulocytosis, and mild thrombocytopenia also have been reported. Lymphadenopathy, resembling Hodgkin's disease and malignant lymphoma, is associated with reduced immunoglobulin A (IgA) production. Hypoprothrombinemia and hemorrhage have occurred in the newborns of mothers who received phenytoin during pregnancy; vitamin K is effective treatment or prophylaxis.

Plasma Drug Concentrations. A good correlation usually is observed between the total concentration of phenytoin in plasma and its clinical effect. Thus, control of seizures generally is obtained with total concentrations above 10 μg/mL, while toxic effects such as nystagmus develop at total concentrations around 20 μg/mL. Control of seizures generally is obtained with free phenytoin concentrations of 0.75-1.25 μg/mL.

Drug Interactions. Concurrent administration of any drug metabolized by CYP2C9 or CYP2C10 can increase the plasma concentration of phenytoin by decreasing its rate of metabolism (Table 21–3). Carbamazepine, which may enhance the metabolism of phenytoin, causes a well-documented decrease in phenytoin concentration. Conversely, phenytoin reduces the concentration of carbamazepine. Interaction between phenytoin and phenobarbital is variable.

Other Uses. Trigeminal and related neuralgias occasionally respond to phenytoin, but carbamazepine may be preferable. The use of phenytoin in the treatment of cardiac arrhythmias is discussed in Chapter 29.

Structure-Activity Relationship. The structural formula of phenobarbital (5-phenyl-5-ethylbarbituric acid) is shown in Chapter 17. The structure-activity relationships of the barbiturates have been studied extensively. Maximal anti-seizure activity is obtained when one substituent at carbon 5 position is a phenyl group. The 5,5-diphenyl derivative has less anti-seizure potency than does phenobarbital, but it is virtually devoid of hypnotic activity. By contrast, 5,5-dibenzyl barbituric acid causes convulsions.

Mechanism of Action. The mechanism by which phenobarbital inhibits seizures likely involves potentiation of synaptic inhibition through an action on the GABA_A receptor. Intracellular recordings of mouse cortical or spinal cord neurons demonstrated that phenobarbital enhances responses to iontophoretically applied GABA. These effects have been observed at therapeutically relevant concentrations of phenobarbital. Analyses of single channels in outside-out patches isolated from mouse spinal cord neurons demonstrated that phenobarbital increased the GABA_A receptor–mediated current by increasing the duration of bursts of GABA_A receptor–mediated currents without changing the frequency of bursts (Twyman et al., 1989). At levels exceeding therapeutic concentrations, phenobarbital also limits sustained repetitive firing; this may underlie some of the anti-seizure effects of higher concentrations of phenobarbital achieved during therapy of status epilepticus.

Pharmacokinetic Properties. Oral absorption of phenobarbital is complete but somewhat slow; peak concentrations in plasma occur several hours after a single dose. It is 40-60% bound to plasma proteins and bound to a similar extent in tissues, including brain. Up to 25% of a dose is eliminated by pH-dependent renal excretion of the unchanged drug; the remainder is inactivated by hepatic microsomal enzymes, principally CYP2C9, with minor metabolism by CYP2C19 and CYP2E1. Phenobarbital induces uridine diphosphate-glucuronosyltransferase (UGT) enzymes as well as the CYP2C and CYP3A subfamilies. Drugs metabolized by these enzymes can be more rapidly degraded when co-administered with phenobarbital; importantly, oral contraceptives are metabolized by CYP3A4.

Scarlatiniform or morbilliform rash, possibly with other manifestations of drug allergy, occurs in 1-2% of patients. Exfoliative dermatitis is rare. Hypoprothrombinemia with hemorrhage has been observed in the newborns of mothers who have received phenobarbital during pregnancy; vitamin K is effective for treatment or prophylaxis. As with phenytoin, megaloblastic anemia that responds to folate and osteomalacia that responds to high doses of vitamin D occur during chronic phenobarbital therapy of epilepsy. Other adverse effects of phenobarbital are discussed in Chapter 17.

Plasma Drug Concentrations. During long-term therapy in adults, the plasma concentration of phenobarbital averages 10 μg/mL per daily dose of 1 mg/kg; in children, the value is 5-7 μg/mL per 1 mg/kg. Although a precise relationship between therapeutic results and concentration of drug in plasma does not exist, plasma concentrations of 10-35 μg/mL are usually recommended for control of seizures.

The relationship between plasma concentration of phenobarbital and adverse effects varies with the development of tolerance. Sedation, nystagmus, and ataxia usually are absent at concentrations below 30 μg/mL during long-term therapy, but adverse effects may be apparent for several days at lower concentrations when therapy is initiated or whenever the dosage is increased. Concentrations > 60 μg/mL may be associated with marked intoxication in the nontolerant individual.

Since significant behavioral toxicity may be present despite the absence of overt signs of toxicity, the tendency to maintain patients, particularly children, on excessively high doses of phenobarbital should be resisted. The plasma phenobarbital concentration should be increased above 30-40 μg/mL only if the increment is adequately tolerated and only if it contributes significantly to control of seizures.

Chemistry. Carbamazepine is related chemically to the tricyclic antidepressants. It is a derivative of iminostilbene with a carbamyl group at the 5 position; this moiety is essential for potent anti-seizure activity.

Pharmacological Effects. Although the effects of carbamazepine in animals and humans resemble those of phenytoin in many ways, the two drugs exhibit important differences. Carbamazepine has been found to produce therapeutic responses in manic-depressive patients, including some in whom lithium carbonate is not effective. Further, carbamazepine has anti-diuretic effects that are sometimes associated with increased concentrations of anti-diuretic hormone (ADH) in plasma. The mechanisms responsible for these effects of carbamazepine are not clearly understood.

Mechanism of Action. Like phenytoin, carbamazepine limits the repetitive firing of action potentials evoked by a sustained depolarization of mouse spinal cord or cortical neurons maintained in vitro (McLean and Macdonald, 1986a). This appears to be mediated by a slowing of the rate of recovery of voltage-activated Na⁺ channels from inactivation. These effects of carbamazepine are evident at concentrations in the range of therapeutic drug levels in CSF in humans. The effects of carbamazepine are selective at these concentrations, in that there are no effects on spontaneous activity or on responses to iontophoretically applied GABA or glutamate. The carbamazepine metabolite, 10,11-epoxycarbamazepine, also limits sustained repetitive firing at therapeutically relevant concentrations, suggesting that this metabolite may contribute to the anti-seizure efficacy of carbamazepine.

The predominant pathway of metabolism in humans involves conversion to the 10,11-epoxide. This metabolite is as active as the parent compound in various animals, and its concentrations in plasma and brain may reach 50% of those of carbamazepine, especially during the concurrent administration of phenytoin or phenobarbital. The 10,11-epoxide is metabolized further to inactive compounds, which are excreted in the urine principally as glucuronides. Carbamazepine also is inactivated by conjugation and hydroxylation. Hepatic CYP3A4 is primarily responsible for biotransformation of carbamazepine. Carbamazepine induces CYP2C, CYP3A, and UGT, thus enhancing the metabolism of drugs degraded by these enzymes. Of particular importance in this regard are oral contraceptives, which are also metabolized by CYP3A4.

Some tolerance develops to the neurotoxic effects of carbamazepine, and they can be minimized by gradual increase in dosage or adjustment of maintenance dosage. Various hepatic or pancreatic abnormalities have been reported during therapy with carbamazepine, most commonly a transient elevation of hepatic transaminases in plasma in 5-10% of patients. A transient, mild leukopenia occurs in ~10% of patients during initiation of therapy and usually resolves within the first 4 months of continued treatment; transient thrombocytopenia also has been noted. In ~2% of patients, a persistent leukopenia may develop that requires withdrawal of the drug. The initial concern that aplastic anemia might be a frequent complication of long-term therapy with carbamazepine has not materialized. In most cases, the administration of multiple drugs or the presence of another underlying disease has made it difficult to establish a causal relationship. The prevalence of aplastic anemia appears to be ~1 in 200,000 patients who are treated with the drug. It is not clear whether monitoring of hematological function can avert the development of irreversible aplastic anemia. Although carbamazepine is carcinogenic in rats, it is not known to be carcinogenic in humans. Possible teratogenic effects are discussed later in the chapter.

Carbamazepine is the primary agent for treatment of trigeminal and glossopharyngeal neuralgias. It is also effective for lightning-type ("tabetic") pain associated with bodily wasting. Most patients with neuralgia benefit initially, but only 70% obtain continuing relief. Adverse effects require discontinuation of medication in 5-20% of patients. The therapeutic range of plasma concentrations for anti-seizure therapy serves as a guideline for its use in neuralgia. Carbamazepine is also used in the treatment of bipolar affective disorders, as discussed further in Chapter 16.

Its mechanism of action is similar to that of carbamazepine. Oxcarbazepine is a less potent enzyme inducer than carbamazepine. Substitution of oxcarbazepine for carbamazepine is associated with increased levels of phenytoin and valproic acid, presumably because of reduced induction of hepatic enzymes. Oxcarbazepine does not induce the hepatic enzymes involved in its own degradation. Although oxcarbazepine does not appear to reduce the anticoagulant effect of warfarin, it does induce CYP3A and thus reduces plasma levels of steroid oral contraceptives. It has been approved for monotherapy or adjunct therapy for partial seizures in adults, as monotherapy for partial seizures in children ages 4-16, and as adjunctive therapy in children 2 years of age and older with epilepsy.

Structure-Activity Relationship. The structure-activity relationship of the succinimides is in accord with that for other anti-seizure classes. Methsuximide (celontin) has phenyl substituents and is more active against maximal electroshock seizures. It is no longer in common use. Discussion of its properties can be found in previous editions of this book. Ethosuximide, with alkyl substituents, is the most active of the succinimides against seizures induced by pentylenetetrazol and is the most selective for absence seizures.

Pharmacological Effects. The most prominent characteristic of ethosuximide at nontoxic doses is protection against clonic motor seizures induced by pentylenetetrazol. By contrast, at nontoxic doses ethosuximide does not inhibit tonic hind limb extension of electroshock seizures or kindled seizures. This profile correlates with efficacy against absence seizures in humans.

Mechanism of Action. Ethosuximide reduces low threshold Ca²⁺ currents (T-type currents) in thalamic neurons (Coulter et al., 1989). The thalamus plays an important role in generation of 3-Hz spike-and-wave rhythms typical of absence seizures (Huguenard and McCormick, 2007). Neurons in the thalamus exhibit large-amplitude T-type currents that underlie bursts of action potentials and likely play an important role in thalamic oscillatory activity such as 3-Hz spike-and-wave activity. At clinically relevant concentrations, ethosuximide inhibits the T-type current, as is evident in voltage-clamp recordings of acutely isolated, ventrobasal thalamic neurons from rats and guinea pigs. Ethosuximide reduces this current without modifying the voltage dependence of steady-state inactivation or the time course of recovery from inactivation. By contrast, succinimide derivatives with convulsant properties do not inhibit this current. Ethosuximide does not inhibit sustained repetitive firing or enhance GABA responses at clinically relevant concentrations. Inhibition of T-type currents likely is the mechanism by which ethosuximide inhibits absence seizures.

Pharmacokinetic Properties. Absorption of ethosuximide appears to be complete, with peak concentrations in plasma within ~3 hours after a single oral dose. Ethosuximide is not significantly bound to plasma proteins; during long-term therapy, its concentration in the CSF is similar to that in plasma. The apparent volume of distribution averages 0.7 L/kg.

Approximately 25% of the drug is excreted unchanged in the urine. The remainder is metabolized by hepatic microsomal enzymes, but whether CYPs are responsible is unknown. The major metabolite, the hydroxyethyl derivative, accounts for ~40% of administered drug, is inactive, and is excreted as such and as the glucuronide in the urine. The plasma t_1/2 of ethosuximide averages between 40 and 50 hours in adults and ~30 hours in children.

Toxicity. The most common dose-related side effects are gastrointestinal complaints (nausea, vomiting, and anorexia) and CNS effects (drowsiness, lethargy, euphoria, dizziness, headache, and hiccough). Some tolerance to these effects develops. Parkinson-like symptoms and photophobia also have been reported. Restlessness, agitation, anxiety, aggressiveness, inability to concentrate, and other behavioral effects have occurred primarily in patients with a prior history of psychiatric disturbance.

Urticaria and other skin reactions, including Stevens-Johnson syndrome, as well as systemic lupus erythematosus, eosinophilia, leukopenia, thrombocytopenia, pancytopenia, and aplastic anemia also have been attributed to the drug. The leukopenia may be transient despite continuation of the drug, but several deaths have resulted from bone marrow depression. Renal or hepatic toxicity has not been reported.

Plasma Drug Concentrations. During long-term therapy, the plasma concentration of ethosuximide averages ~2 μg/mL per daily dose of 1 mg/kg. A plasma concentration of 40-100 μg/mL usually is required for satisfactory control of absence seizures.

Therapeutic Uses. Ethosuximide is effective against absence seizures but not tonic-clonic seizures.

An initial daily dose of 250 mg in children (3-6 years old) and 500 mg in older children and adults is increased by 250-mg increments at weekly intervals until seizures are adequately controlled or toxicity intervenes. Divided dosage is required occasionally to prevent nausea or drowsiness associated with once-daily dosing. The usual maintenance dose is 20 mg/kg per day. Increased caution is required if the daily dose exceeds 1500 mg in adults or 750-1000 mg in children. The therapeutic use of ethosuximide is discussed further at the end of the chapter.

Chemistry. Valproic acid (n-dipropylacetic acid) is a simple branched-chain carboxylic acid. Certain other branched-chain carboxylic acids have potencies similar to that of valproic acid in antagonizing pentylenetetrazol-induced convulsions. However, increasing the number of carbon atoms to nine introduces marked sedative properties. Straight-chain carboxylic acids have little or no activity.

Mechanism of Action. Valproic acid produces effects on isolated neurons similar to those of phenytoin and ethosuximide (Table 21–2). At therapeutically relevant concentrations, valproate inhibits sustained repetitive firing induced by depolarization of mouse cortical or spinal cord neurons (McLean and Macdonald, 1986b). The action is similar to that of both phenytoin and carbamazepine and appears to be mediated by a prolonged recovery of voltage-activated Na⁺ channels from inactivation. Valproic acid does not modify neuronal responses to iontophoretically applied GABA. In neurons isolated from the nodose ganglion, valproate also produces small reductions of T-type Ca²⁺ currents (Kelly et al., 1990) at clinically relevant but slightly higher concentrations than those that limit sustained repetitive firing; this effect on T-type currents is similar to that of ethosuximide in thalamic neurons (Coulter et al., 1989). Together, these actions of limiting sustained repetitive firing and reducingT-type currents may contribute to the effectiveness of valproic acid against partial and tonic-clonic seizures and absence seizures, respectively.

Another potential mechanism that may contribute to valproate's anti-seizure actions involves metabolism of GABA. Although valproate has no effect on responses to GABA, it does increase the amount of GABA that can be recovered from the brain after the drug is administered to animals. In vitro, valproate can stimulate the activity of the GABA synthetic enzyme, glutamic acid decarboxylase, and inhibit GABA degradative enzymes, GABA transaminase and succinic semialdehyde dehydrogenase. Thus far it has been difficult to relate the increased GABA levels to the anti-seizure activity of valproate.

The apparent volume of distribution for valproate is ~0.2 L/kg. Its extent of binding to plasma proteins is usually ~90%, but the fraction bound is reduced as the total concentration of valproate is increased through the therapeutic range. Although concentrations of valproate in CSF suggest equilibration with free drug in the blood, there is evidence for carrier-mediated transport of valproate both into and out of the CSF.

The vast majority of valproate (95%) undergoes hepatic metabolism, with < 5% excreted unchanged in urine. Its hepatic metabolism occurs mainly by UGT enzymes and β-oxidation. Valproate is a substrate for CYP2C9 and CYP2C19, but metabolism by these enzymes accounts for a relatively minor portion of its elimination. Some of the drug's metabolites, notably 2-propyl-2-pentenoic acid and 2-propyl-4-pentenoic acid, are nearly as potent anti-seizure agents as the parent compound; however, only the former (2-en-valproic acid) accumulates in plasma and brain to a potentially significant extent. The t_1/2 of valproate is ~15 hours but is reduced in patients taking other anti-epileptic drugs.

A rare complication is a fulminant hepatitis that is frequently fatal (Dreifuss et al., 1989). Pathological examination reveals a microvesicular steatosis without evidence of inflammation or hypersensitivity reaction. Children below 2 years of age with other medical conditions who were given multiple anti-seizure agents were especially likely to suffer fatal hepatic injury. At the other extreme, there were no deaths reported for patients over the age of 10 years who received only valproate. Acute pancreatitis and hyperammonemia also have been frequently associated with the use of valproic acid. Valproic acid can also produce teratogenic effects such as neural tube defects.

Plasma Drug Concentrations. Valproate plasma concentrations associated with therapeutic effects are ~30-100 μg/mL. However, there is a poor correlation between the plasma concentration and efficacy. There appears to be a threshold at ~30-50 μg/mL; this is the concentration at which binding sites on plasma albumin begin to become saturated.

Drug Interactions. Valproate primarily inhibits the metabolism of drugs that are substrates for CYP2C9, including phenytoin and phenobarbital. Valproate also inhibits UGT and thus inhibits the metabolism of lamotrigine and lorazepam. A high proportion of valproate is bound to albumin, and the high molar concentrations of valproate in the clinical setting result in valproate's displacing phenytoin and other drugs from albumin. With respect to phenytoin in particular, valproate's inhibition of the drug's metabolism is exacerbated by displacement of phenytoin from albumin. The concurrent administration of valproate and clonazepam has been associated with the development of absence status epilepticus; however, this complication appears to be rare.

Anti-Seizure Properties. In animal models, inhibition of pentylenetetrazol-induced seizures by the benzodiazepines is much more prominent than is their modification of the maximal electroshock seizure pattern. Clonazepam is unusually potent in antagonizing the effects of pentylenetetrazol, but it is almost without action on seizures induced by maximal electroshock. Benzodiazepines, including clonazepam, suppress the spread of kindled seizures and generalized convulsions produced by stimulation of the amygdala, but do not abolish the abnormal discharge at the site of stimulation.

Mechanism of Action. The anti-seizure actions of the benzodiazepines, as well as other effects that occur at nonsedating doses, result in large part from their ability to enhance GABA-mediated synaptic inhibition. Molecular cloning and study of recombinant receptors have demonstrated that the benzodiazepine receptor is an integral part of the GABA_A receptor (Chapter 17). At therapeutically relevant concentrations, benzodiazepines act at subsets of GABA_A receptors and increase the frequency, but not duration, of openings at GABA-activated Cl⁻ channels (Twyman et al., 1989). At higher concentrations, diazepam and many other benzodiazepines can reduce sustained high-frequency firing of neurons, similar to the effects of phenytoin, carbamazepine, and valproate. Although these concentrations correspond to concentrations achieved in patients during treatment of status epilepticus with diazepam, they are considerably higher than those associated with anti-seizure or anxiolytic effects in ambulatory patients.

Pharmacokinetic Properties. Benzodiazepines are well absorbed after oral administration, and concentrations in plasma are usually maximal within 1-4 hours. After intravenous administration, they are redistributed in a manner typical of that for highly lipid-soluble agents. Central effects develop promptly, but wane rapidly as the drugs move to other tissues. Diazepam is redistributed especially rapidly, with a t_1/2 of redistribution of ~1 hour. The extent of binding of benzodiazepines to plasma proteins correlates with lipid solubility, ranging from ~99% for diazepam to ~85% for clonazepam (Appendix II).

The major metabolite of diazepam, N-desmethyl-diazepam, is somewhat less active than the parent drug and may behave as a partial agonist. This metabolite also is produced by the rapid decarboxylation of clorazepate following its ingestion. Both diazepam and N-desmethyl-diazepam are slowly hydroxylated to other active metabolites, such as oxazepam. The t_1/2 of diazepam in plasma is between 1 and 2 days, while that of N-desmethyl-diazepam is ~60 hours. Clonazepam is metabolized principally by reduction of the nitro group to produce inactive 7-amino derivatives. Less than 1% of the drug is recovered unchanged in the urine. The t_1/2 of clonazepam in plasma is ~23 hours. Lorazepam is metabolized chiefly by conjugation with glucuronic acid; its t_1/2 in plasma is ~14 hours.

Other side effects include hypotonia, dysarthria, and dizziness. Behavioral disturbances, especially in children, can be very troublesome; these include aggression, hyperactivity, irritability, and difficulty in concentration. Both anorexia and hyperphagia have been reported. Increased salivary and bronchial secretions may cause difficulties in children. Seizures are sometimes exacerbated, and status epilepticus may be precipitated if the drug is discontinued abruptly. Other aspects of the toxicity of the benzodiazepines are discussed in Chapter 17. Cardiovascular and respiratory depression may occur after the intravenous administration of diazepam, clonazepam, or lorazepam, particularly if other anti-seizure agents or central depressants have been administered previously.

Plasma Drug Concentrations. Because tolerance affects the relationship between drug concentration and drug anti-seizure effect, plasma concentrations of benzodiazepines are of limited value.

Therapeutic Uses. Clonazepam is useful in the therapy of absence seizures as well as myoclonic seizures in children. However, tolerance to its anti-seizure effects usually develops after 1-6 months of administration, after which some patients will no longer respond to clonazepam at any dosage. The initial dose of clonazepam for adults should not exceed 1.5 mg per day and for children 0.01-0.03 mg/kg per day. The dose-dependent side effects are reduced if two or three divided doses are given each day. The dose may be increased every 3 days in amounts of 0.25-0.5 mg per day in children and 0.5-1 mg per day in adults. The maximal recommended dose is 20 mg per day for adults and 0.2 mg/kg per day for children. Clonazepam intranasal spray is designated as an orphan drug for recurrent acute repetitive seizures.

While diazepam is an effective agent for treatment of status epilepticus, its short duration of action is a disadvantage, leading to the more frequent use of lorazepam. Although diazepam is not useful as an oral agent for the treatment of seizure disorders, clorazepate is effective in combination with certain other drugs in the treatment of partial seizures. The maximal initial dose of clorazepate is 22.5 mg per day in three portions for adults and children > 12 years and 15 mg per day in two divided doses in children 9-12 years of age. Clorazepate is not recommended for children under the age of 9.

Pharmacological Effects and Mechanisms of Action. Gabapentin inhibits tonic hind limb extension in the electroshock seizure model. Interestingly, gabapentin also inhibits clonic seizures induced by pentylenetetrazol. Its efficacy in both these tests parallels that of valproic acid and distinguishes it from phenytoin and carbamazepine. Despite their design as GABA agonists, neither gabapentin nor pregabalin mimics GABA when iontophoretically applied to neurons in primary culture. These compounds bind with high affinity to a protein in cortical membranes with an amino acid sequence identical to that of the Ca²⁺ channel subunit α2δ-1 (Gee et al., 1996). It has been speculated that the anticonvulsant effects of gabapentin are mediated by α2δ-1 protein, but whether and how the binding of gabapentin to the α2δ-1 regulates neuronal excitability remains unclear. Pregabalin binding is reduced but not eliminated in mice carrying a mutation in the α2δ-1 protein (Field et al., 2006). Analgesic efficacy of pregabalin is eliminated in these mice; whether the anticonvulsant effects of pregabalin are also eliminated was not reported. It is unclear whether the anticonvulsant and analgesic effects of gabapentin and pregabalin are mediated by affecting Ca²⁺ currents and, if so, how.

Pharmacokinetics. Gabapentin and pregabalin are absorbed after oral administration and are not metabolized in humans. These compounds are not bound to plasma proteins and are excreted unchanged, mainly in the urine. Their half-lives, when used as monotherapy, approximate 6 hours. These compounds have no known interactions with other anti-seizure drugs.

Therapeutic Uses. Gabapentin and pregabalin are effective for partial seizures, with and without secondary generalization, when used in addition to other anti-seizure drugs.

Double-blind placebo-controlled trials of adults with refractory partial seizures demonstrated that addition of gabapentin or pregabalin to other anti-seizure drugs is superior to placebo (Sivenius et al., 1991; French et al., 2003). A double-blind study of gabapentin (900 or 1800 mg/day) monotherapy disclosed that gabapentin was equivalent to carbamazepine (600 mg/day) for newly diagnosed partial or generalized epilepsy (Chadwick et al., 1998). Gabapentin also is being used for the treatment of migraine, chronic pain, and bipolar disorder.

Gabapentin usually is effective in doses of 900-1800 mg daily in three doses, although 3600 mg may be required in some patients to achieve reasonable seizure control. Therapy usually is begun with a low dose (300 mg once on the first day), which is increased in daily increments of 300 mg until an effective dose is reached.

Pharmacological Effects and Mechanisms of Action. Lamotrigine suppresses tonic hind limb extension in the maximal electroshock model and partial and secondarily generalized seizures in the kindling model, but does not inhibit clonic motor seizures induced by pentylenetetrazol. Lamotrigine blocks sustained repetitive firing of mouse spinal cord neurons and delays the recovery from inactivation of recombinant Na⁺ channels, mechanisms similar to those of phenytoin and carbamazepine (Xie et al., 1995). This may well explain lamotrigine's actions on partial and secondarily generalized seizures. However, as mentioned in the subsequent "Therapeutic Use" section, lamotrigine is effective against a broader spectrum of seizures than phenytoin and carbamazepine, suggesting that lamotrigine may have actions in addition to regulating recovery from inactivation of Na⁺ channels. The mechanisms underlying its broad spectrum of actions are incompletely understood. One possibility involves lamotrigine's inhibition of glutamate release in rat cortical slices treated with veratridine, a Na⁺ channel activator, raising the possibility that lamotrigine inhibits synaptic release of glutamate by acting at Na⁺ channels themselves.

Pharmacokinetics. Lamotrigine is completely absorbed from the gastrointestinal tract and is metabolized primarily by glucuronidation. The plasma t_1/2 of a single dose is 24-30 hours. Administration of phenytoin, carbamazepine, or phenobarbital reduces the t_1/2 and plasma concentrations of lamotrigine. Conversely, addition of valproate markedly increases plasma concentrations of lamotrigine, likely by inhibiting glucuronidation. Addition of lamotrigine to valproic acid produces a reduction of valproate concentrations by ~25% over a few weeks. Concurrent use of lamotrigine and carbamazepine is associated with increases of the 10,11-epoxide of carbamazepine and clinical toxicity in some patients.

Therapeutic Use. Lamotrigine is useful for monotherapy and add-on therapy of partial and secondarily generalized tonic-clonic seizures in adults and Lennox-Gastaut syndrome in both children and adults. Lennox-Gastaut syndrome is a disorder of childhood characterized by multiple seizure types, mental retardation, and refractoriness to anti-seizure medication.

Lamotrigine monotherapy in newly diagnosed partial or generalized tonic-clonic seizures is equivalent to carbamazepine or phenytoin, monotherapy (Brodie et al., 1995; Steiner et al., 1999). A double-blind, placebo-controlled trial of addition of lamotrigine to existing anti-seizure drugs further demonstrated effectiveness of lamotrigine against tonic-clonic seizures and drop attacks in children with the Lennox-Gastaut syndrome (Motte et al., 1997). Lamotrigine was also found to be superior to placebo in a double-blind study of children with newly diagnosed absence epilepsy (Frank et al., 1999).

Patients who are already taking a hepatic enzyme–inducing anti-seizure drug (such as carbamazepine, phenytoin, phenobarbital, or primidone, but not valproate) should be given lamotrigine initially at 50 mg/day for 2 weeks. The dose is increased to 50 mg twice per day for 2 weeks and then increased in increments of 100 mg/day each week up to a maintenance dose of 300-500 mg/day divided into two doses. For patients taking valproate in addition to an enzyme-inducing anti-seizure drug, the initial dose should be 25 mg every other day for 2 weeks, followed by an increase to 25 mg/day for 2 weeks; the dose then can be increased by 25-50 mg/day every 1-2 weeks up to a maintenance dose of 100-150 mg/day divided into two doses.

Toxicity. The most common adverse effects are dizziness, ataxia, blurred or double vision, nausea, vomiting, and rash when lamotrigine was added to another anti-seizure drug. A few cases of Stevens-Johnson syndrome and disseminated intravascular coagulation have been reported. The incidence of serious rash in pediatric patients (~0.8%) is higher than in the adult population (0.3%).

Pharmacological Effects and Mechanism of Action. Levetiracetam exhibits a novel pharmacological profile insofar as it inhibits partial and secondarily generalized tonic-clonic seizures in the kindling model, yet is ineffective against maximum electroshock- and pentylenetetrazol-induced seizures, findings consistent with clinical effectiveness against partial and secondarily generalized tonic-clonic seizures. The mechanism by which levetiracetam exerts these anti-seizure effects is unknown. No evidence for an action on voltage-gated Na⁺ channels or either GABA- or glutamate-mediated synaptic transmission has emerged. The correlation between binding affinity of levetiracetam analogs and their potency toward audiogenic seizures suggests that a synaptic vesicle protein, SV2A, mediates the anticonvulsant effects of levetiracetam (Rogawski and Bazil, 2008). Uncertainty as to the function of SV2A limits insights into how binding of levetiracetam to SV2A might affect cellular function or neuronal excitability.

Pharmacokinetics. Levetiracetam is rapidly and almost completely absorbed after oral administration and is not bound to plasma proteins. Ninety-five percent of the drug and its inactive metabolite are excreted in the urine, 65% of which is unchanged drug; 24% of the drug is metabolized by hydrolysis of the acetamide group. It neither induces nor is a high-affinity substrate for CYP isoforms or glucuronidation enzymes and thus is devoid of known interactions with other anti-seizure drugs, oral contraceptives, or anticoagulants.

Therapeutic Use. Double-blind, placebo-controlled trials of adults with either refractory partial seizures or uncontrolled generalized tonic-clonic seizures associated with idiopathic generalized epilepsy revealed that addition of levetiracetam to other anti-seizure medications was superior to placebo. Levetiracetam also has efficacy as adjunctive therapy for refractory generalized myoclonic seizures (Andermann et al., 2005). Insufficient evidence is available about its use as monotherapy for partial or generalized epilepsy.

Toxicity. Levetiracetam is well tolerated. The most frequently reported adverse effects are somnolence, asthenia, and dizziness.

Pharmacological Effects and Mechanism of Action. Tiagabine inhibits the GABA transporter, GAT-1, and thereby reduces GABA uptake into neurons and glia. In CA1 neurons of the hippocampus, tiagabine increases the duration of inhibitory synaptic currents, findings consistent with prolonging the effect of GABA at inhibitory synapses through reducing its reuptake by GAT-1. Tiagabine inhibits maximum electroshock seizures and both limbic and secondarily generalized tonic-clonic seizures in the kindling model, results suggestive of clinical efficacy against partial and tonic-clonic seizures. Paradoxically, tiagabine has been associated with the occurrence of seizures in patients without epilepsy and off-label use of the drug is discouraged.

Pharmacokinetics. Tiagabine is rapidly absorbed after oral administration, extensively bound to serum or plasma proteins, and metabolized mainly in the liver, predominantly by CYP3A. Its t_1/2 of ~8 hours is shortened by 2-3 hours when co-administered with hepatic enzyme–inducing drugs such as phenobarbital, phenytoin, or carbamazepine.

Therapeutic Use. Double-blind, placebo-controlled trials have established tiagabine's efficacy as add-on therapy of refractory partial seizures with or without secondary generalization. Its efficacy as monotherapy for newly diagnosed or refractory partial and generalized epilepsy has not been established.

Toxicity. The principal adverse effects include dizziness, somnolence, and tremor; they appear to be mild to moderate in severity and appear shortly after initiation of therapy. Tiagabine and other drugs that enhance effects of synaptically released GABA can facilitate spike-and-wave discharges in animal models of absence seizures. Case reports suggest that tiagabine treatment of patients with a history of spike-and-wave discharges causes exacerbations of their EEG abnormalities. Thus, tiagabine may be contraindicated in patients with generalized absence epilepsy.

Pharmacological Effects and Mechanisms of Action. Topiramate reduces voltage-gated Na⁺ currents in cerebellar granule cells and may act on the inactivated state of the channel similar to phenytoin. In addition, topiramate activates a hyperpolarizing K⁺ current, enhances postsynaptic GABA_A-receptor currents, and limits activation of the AMPA-kainate-subtype(s) of glutamate receptor. Topiramate is a weak carbonic anhydrase inhibitor. Topiramate inhibits maximal electroshock and pentylenetetrazol-induced seizures as well as partial and secondarily generalized tonic-clonic seizures in the kindling model, findings predictive of a broad spectrum of anti-seizure actions clinically.

Pharmacokinetics. Topiramate is rapidly absorbed after oral administration, exhibits little (10-20%) binding to plasma proteins, and is mainly excreted unchanged in the urine. The remainder undergoes metabolism by hydroxylation, hydrolysis, and glucuronidation with no single metabolite accounting for > 5% of an oral dose. Its t_1/2 is ~1 day. Reduced estradiol plasma concentrations occur with concurrent topiramate, suggesting the need for higher doses of oral contraceptives when coadministered with topiramate.

Therapeutic Use. A double-blind study revealed topiramate to be equivalent to valproate and carbamazepine in children and adults with newly diagnosed partial and primary generalized epilepsy (Privitera et al., 2003). Additional studies disclosed topiramate to be effective as monotherapy for refractory partial epilepsy (Sachdeo et al., 1997) and refractory generalized tonic-clonic seizures (Biton et al., 1999). Topiramate also was found to be significantly more effective than placebo against both drop attacks and tonic-clonic seizures in patients with Lennox-Gastaut syndrome (Sachdeo et al., 1999).

Toxicity. Topiramate is well tolerated. The most common adverse effects are somnolence, fatigue, weight loss, and nervousness. It can precipitate renal calculi, which is most likely due to inhibition of carbonic anhydrase. Topiramate has been associated with cognitive impairment and patients may complain about a change in the taste of carbonated beverages.

Pharmacological Effects and Mechanisms of Action. Felbamate is effective in both the maximal electroshock and pentylenetetrazol seizure models. Clinically relevant concentrations of felbamate inhibit NMDA-evoked responses and potentiate GABA-evoked responses in whole-cell, voltage-clamp recordings of cultured rat hippocampal neurons (Rho et al., 1994). This dual action on excitatory and inhibitory transmitter responses may contribute to the wide spectrum of action of the drug in seizure models.

Therapeutic Use. An active control, randomized, double-blind protocol demonstrated the efficacy of felbamate in patients with poorly controlled partial and secondarily generalized seizures (Sachdeo et al., 1992). Felbamate also reduced seizures in patients with Lennox-Gastaut syndrome (Felbamate Study Group in Lennox-Gastaut Syndrome, 1993). The clinical efficacy of this compound, which inhibits responses to NMDA and potentiates those to GABA, underscores the potential value of additional anti-seizure agents with similar mechanisms of action.

Pharmacological Effects and Mechanism of Action. Zonisamide inhibits the T-type Ca²⁺ currents. In addition, zonisamide inhibits the sustained, repetitive firing of spinal cord neurons, presumably by prolonging the inactivated state of voltage-gated Na⁺ channels in a manner similar to actions of phenytoin and carbamazepine.

Zonisamide inhibits tonic hind limb extension evoked by maximal electroshock and inhibits both partial and secondarily generalized seizures in the kindling model, results predictive of clinical effectiveness against partial and secondarily generalized tonic-clonic seizures. Zonisamide does not inhibit minimal clonic seizures induced by pentylenetetrazol, suggesting that the drug will not be effective clinically against myoclonic seizures.

Pharmacokinetics. Zonisamide is almost completely absorbed after oral administration, has a long t_1/2 (~63 hours), and is ~40% bound to plasma protein. Approximately 85% of an oral dose is excreted in the urine, principally as unmetabolized zonisamide and a glucuronide of sulfamoylacetyl phenol, which is a product of metabolism by CYP3A4. Phenobarbital, phenytoin, and carbamazepine decrease the plasma concentration/dose ratio of zonisamide, whereas lamotrigine increases this ratio. Conversely, zonisamide has little effect on the plasma concentrations of other anti-seizure drugs.

Therapeutic Use. Double-blind, placebo-controlled studies of patients with refractory partial seizures demonstrated that addition of zonisamide to other drugs was superior to placebo. There is insufficient evidence for its efficacy as monotherapy for newly diagnosed or refractory epilepsy.

Toxicity. Overall, zonisamide is well tolerated. The most common adverse effects include somnolence, ataxia, anorexia, nervousness, and fatigue. Approximately 1% of individuals develop renal calculi during treatment with zonisamide, which may relate to its ability to inhibit carbonic anhydrase. Post-marketing experience indicates that zonisamide can cause metabolic acidosis in some patients. Patients with predisposing conditions (e.g., renal disease, severe respiratory disorders, diarrhea, surgery, ketogenic diet) may be at greater risk. The risk of zonisamide-induced metabolic acidosis also appears to be more frequent and severe in younger patients. Measurement of serum bicarbonate prior to initiating therapy and periodically thereafter, even in the absence of symptoms, is recommended.

Pharmacological Effects and Mechanism of Action. Lacosamide enhances slow inactivation of voltage-gated Na⁺ channels and limits sustained repetitive firing, the neuronal firing pattern characteristic of partial seizures. Lacosamide also binds collapsin response mediator protein 2 (crmp-2), a phosphoprotein involved in neuronal differentiation and axon outgrowth. Its anti-seizure mechanism of action is more likely mediated by its enhancing slow inactivation of Na⁺ channels.

Therapeutic Use. Double-blind, placebo-controlled studies of adults with refractory partial seizures demonstrated that addition of lacosamide to other drugs was superior to placebo.

Pharmacological Effects and Mechanism of Action. Rufinamide enhances slow inactivation of voltage gated Na⁺ channels and limits sustained repetitive firing, the firing pattern characteristic of partial seizures. Whether this is the mechanism by which rufinamide suppresses seizures is presently unclear.

Therapeutic Use. A double-blind, placebo-controlled study of children with Lennox-Gastaut syndrome demonstrated that rufinamide reduced tonic-atonic seizure frequency to a greater extent than placebo.

Pharmacological Effects and Mechanism of Action. Vigabatrin is a structural analog of GABA that irreversibly inhibits the major degradative enzyme for GABA, GABA-transaminase, thereby leading to increased concentrations of GABA in the brain. Its mechanism of action is thought to involve enhancement of GABA-mediated inhibition.

Therapeutic Use. A 2-week, randomized, single masked clinical trial of vigabatrin for infantile spasms in children < 2 years old revealed time- and dose-dependent increases in responders, evident as freedom from spasms for 7 consecutive days. The subset of children in whom infantile spasms were caused by tuberous sclerosis was particularly responsive to vigabatrin.

Acetazolamide

Acetazolamide, the prototype for the carbonic anhydrase inhibitors, is discussed in Chapter 25. Its anti-seizure actions have been discussed in previous editions of this textbook. Although it is sometimes effective against absence seizures, its usefulness is limited by the rapid development of tolerance. Adverse effects are minimal when it is used in moderate dosage for limited periods.

Measurement of plasma drug concentration at appropriate intervals greatly facilitates the initial adjustment of dosage to minimize dose-related adverse effects without sacrificing seizure control. Periodic monitoring during maintenance therapy can also detect noncompliance. Knowledge of plasma drug concentrations can be especially helpful during multiple-drug therapy. If toxicity occurs, monitoring helps to identify the particular drug(s) responsible and can guide adjustment of dosage.

Factors associated with high risk for recurrent seizures following discontinuation of therapy include EEG abnormalities, known structural lesions, abnormalities on neurological exam, and history of frequent seizures or medically refractory seizures prior to control. Conversely, factors associated with low risk for recurrent seizures include idiopathic epilepsy, normal EEG, onset in childhood, and seizures easily controlled with a single drug. The risk of recurrent seizures ranges from 12-66% (French and Pedley, 2008). Typically 80% of recurrences will occur within 4 months of discontinuing therapy. The clinician and patient must weigh the risk of recurrent seizure and the associated potential deleterious consequences (e.g., loss of driving privileges) against the various implications of continuing medication including cost, unwanted effects, implications of diagnosis of epilepsy, etc. Medications should be tapered slowly over a period of several months.

Simple and Complex Partial and Secondarily Generalized Tonic-Clonic Seizures

The efficacy and toxicity of carbamazepine, phenobarbital, and phenytoin for treatment of partial and secondarily generalized tonic-clonic seizures in adults have been examined in a double-blind prospective study (Mattson et al., 1985). Carbamazepine and phenytoin were the most effective agents. The choice between carbamazepine and phenytoin required assessment of toxic effects of each drug. Decreased libido and impotence were associated with all three drugs (carbamazepine 13%, phenobarbital 16%, and phenytoin 11%). In direct comparison with valproate, carbamazepine provided superior control of complex partial seizures (Mattson et al., 1992). With respect to adverse effects, carbamazepine was more commonly associated with skin rash, but valproate was more commonly associated with tremor and weight gain. Overall, the data demonstrated that carbamazepine and phenytoin are preferable for treatment of partial seizures, but phenobarbital and valproic acid are also efficacious.

Control of secondarily generalized tonic-clonic seizures did not differ significantly with carbamazepine, phenobarbital, or phenytoin (Mattson et al., 1985). Valproate was as effective as carbamazepine for control of secondarily generalized tonic-clonic seizures (Mattson et al., 1992). Since secondarily generalized tonic-clonic seizures usually coexist with partial seizures, these data indicate that among drugs introduced before 1990, carbamazepine and phenytoin are the first-line drugs for these conditions.

One key issue confronting the treating physician is choosing the optimal drug for initiating treatment in new onset epilepsy. At first glance, this issue may appear unimportant because ~50% of newly diagnosed patients become seizure free with the first drug, whether old or new drugs are used (Kwan and Brodie, 2000). However, responsive patients typically receive the initial drug for several years, underscoring the importance of proper drug selection. Among the drugs available before 1990, phenytoin, carbamazepine, and phenobarbital induce hepatic CYPs, thereby complicating use of multiple anti-seizure drugs as well as impacting metabolism of oral contraceptives, warfarin, and many other drugs. These drugs also enhance metabolism of endogenous compounds including gonadal steroids and vitamin D, potentially impacting reproductive function and bone density. By contrast, most of the newer drugs have little if any effect on the CYPs. Factors arguing against use of recently introduced drugs include higher costs and less clinical experience with the compounds.

Ideally, a prospective study would systematically compare newly introduced anti-seizure drugs with drugs available before 1990 in a study design adjusting dose as needed and observing responses for extended periods of time (e.g., 2 years or more), in much the same manner as that used when comparing the older anti-seizure drugs with one another as described earlier (Mattson et al., 1985).

Unfortunately, such a study has not been performed. Many of the studies referenced in description of newer drugs did compare a new with an older anti-seizure drug, but study design did not permit declaring a clearly superior drug; moreover, differences in study design and patient populations preclude comparing a new drug with multiple older drugs or with other new drugs. The use of recently introduced anti-seizure drugs for newly diagnosed epilepsy was analyzed by subcommittees of the American Academy of Neurology and the American Epilepsy Society (French et al., 2004a; French et al., 2004b); the authors concluded that available evidence supported the use of gabapentin, lamotrigine, and topiramate for newly diagnosed partial or mixed seizure disorders. None of these drugs, however, has been approved by the FDA for either of these indications. Insufficient evidence was available on the remaining newly introduced drugs to permit meaningful assessment of their effectiveness for this indication.

Absence Seizures

Ethosuximide and valproate are considered equally effective in the treatment of absence seizures (Mikati and Browne, 1988). Between 50% and 75% of newly diagnosed patients are free of seizures following therapy with either drug. If tonic-clonic seizures are present or emerge during therapy, valproate is the agent of first choice. French and others concluded that available evidence indicates that lamotrigine is also effective for newly diagnosed absence epilepsy despite the fact that lamotrigine is not approved for this indication by the FDA.

Myoclonic Seizures

Valproic acid is the drug of choice for myoclonic seizures in the syndrome of juvenile myoclonic epilepsy, in which myoclonic seizures often coexist with tonic-clonic and absence seizures. Levetiracetam also has demonstrated efficacy as adjunctive therapy for refractory generalized myoclonic seizures.

Febrile Convulsions

Two to four percent of children experience a convulsion associated with a febrile illness. From 25-33% of these children will have another febrile convulsion. Only 2-3% become epileptic in later years, a 6-fold increase in risk compared with the general population. Several factors are associated with an increased risk of developing epilepsy: preexisting neurological disorder or developmental delay, a family history of epilepsy, or a complicated febrile seizure (i.e., the febrile seizure lasted > 15 minutes, was one-sided, or was followed by a second seizure in the same day). If all of these risk factors are present, the risk of developing epilepsy is ~10%.

The increased risk of developing epilepsy or other neurological sequelae led many physicians to prescribe anti-seizure drugs prophylactically after a febrile seizure. Uncertainties regarding the efficacy of prophylaxis for reducing epilepsy combined with substantial side effects of phenobarbital prophylaxis (Farwell et al., 1990) argue against the use of chronic therapy for prophylactic purposes (Freeman, 1992). For children at high risk of developing recurrent febrile seizures and epilepsy, rectally administered diazepam at the time of fever may prevent recurrent seizures and avoid side effects of chronic therapy.

Seizures in Infants and Young Children

Infantile spasms with hypsarrhythmia (abnormal inter-ictal high amplitude slow waves and multifocal asynchronous spikes on EEG) are refractory to the usual anti-seizure agents. Corticotropin or the glucocorticoids are commonly used and repository corticotropin (h.p. acthar gel) was designated as an orphan drug for this purpose in 2003. A randomized study found vigabatrin (γ-vinyl GABA; sabril) to be efficacious in comparison to placebo (Appleton et al., 1999). Constriction of visual fields has been reported in a high percentage of patients treated with vigabatrin (Miller et al., 1999). The potential for progressive and permanent vision loss has resulted in vigabatrin being labeled with a black-box warning and marketed under a restrictive distribution program. The drug received orphan drug status for the treatment of infantile spasms in the U.S. in 2000 (and was FDA-approved in 2009 as adjunctive therapy for adults with refractory complex partial seizures). Ganaxolone also has been designated as an orphan drug since 1994 for the treatment of infantile spasms and completed a phase II clinical trial for uncontrolled partial-onset seizures in adults in 2009.

The Lennox-Gastaut syndrome is a severe form of epilepsy which usually begins in childhood and is characterized by cognitive impairments and multiple types of seizures including tonic-clonic, tonic, atonic, myoclonic, and atypical absence seizures. Addition of lamotrigine to other anti-seizure drugs resulted in improved seizure control in comparison to placebo in a double-blind trial (Motte et al., 1997), demonstrating lamotrigine to be an effective and well-tolerated drug for this treatment-resistant form of epilepsy. Felbamate also was found to be effective for seizures in this syndrome, but the occasional occurrence of aplastic anemia and hepatic failure have limited its use (French et al., 1999). Topiramate has also been demonstrated to be effective for Lennox-Gastaut syndrome (Sachdeo et al., 1999).

Status Epilepticus and Other Convulsive Emergencies

Status epilepticus is a neurological emergency. Mortality for adults approximates 20% (Lowenstein and Alldredge, 1998). The goal of treatment is rapid termination of behavioral and electrical seizure activity; the longer the episode of status epilepticus is untreated, the more difficult it is to control and the greater the risk of permanent brain damage. Critical to the management is a clear plan, prompt treatment with effective drugs in adequate doses, and attention to hypoventilation and hypotension. Since hypoventilation may result from high doses of drugs used for treatment, it may be necessary to assist respiration temporarily. Drugs should be administered by the intravenous route only. Because of slow and unreliable absorption, the intramuscular route has no place in treatment of status epilepticus. To assess the optimal initial drug regimen, a double-blind, multicenter trial compared four intravenous treatments: diazepam followed by phenytoin; lorazepam; phenobarbital; and phenytoin alone (Treiman et al., 1998). The treatments had similar efficacies, with success rates ranging from 44-65%. Lorazepam alone was significantly better than phenytoin alone. No significant differences were found with respect to recurrences or adverse reactions.

The effectiveness of oral contraceptives appears to be reduced by concomitant use of anti-seizure drugs. The failure rate of oral contraceptives is 3.1/100 years in women receiving anti-seizure drugs compared to a rate of 0.7/100 years in non-epileptic women. One attractive explanation of the increased failure rate is the increased rate of oral contraceptive metabolism caused by anti-seizure drugs that induce hepatic enzymes (Table 21–2); particular caution is needed with anti-seizure drugs that induce CYP3A4.

Teratogenicity. Epidemiological evidence suggests that anti-seizure drugs have teratogenic effects (Pack, 2006). These teratogenic effects add to the deleterious consequences of oral contraceptive failure. Infants of epileptic mothers are at 2-fold greater risk of major congenital malformations than offspring of non-epileptic mothers (4-8% compared to 2-4%). These malformations include congenital heart defects, neural tube defects, cleft lip, cleft palate, and others. Inferring causality from the associations found in large epidemiological studies with many uncontrolled variables can be hazardous, but a causal role for anti-seizure drugs is suggested by association of congenital defects with higher concentrations of a drug or with polytherapy compared to monotherapy. Phenytoin, carbamazepine, valproate, lamotrigine, and phenobarbital all have been associated with teratogenic effects. Newer anti-seizure drugs have teratogenic effects in animals but whether such effects occur in humans is yet uncertain. One consideration for a woman with epilepsy who wishes to become pregnant is a trial free of anti-seizure drug; monotherapy with careful attention to drug levels is another alternative. Polytherapy with toxic levels should be avoided. Folate supplementation (0.4 mg/day) has been recommended by the U.S. Public Health Service for all women of childbearing age to reduce the likelihood of neural tube defects, and this is appropriate for epileptic women as well.

Anti-seizure drugs that induce CYPs have been associated with vitamin K deficiency in the newborn, which can result in a coagulopathy and intracerebral hemorrhage. Treatment with vitamin K₁, 10 mg/day during the last month of gestation, has been recommended for prophylaxis.