ETHOSUXIMIDE

Ethosuximide (ESM) is a succinimide antiepileptic drug in clinical use since 1958 for a limited spectrum of seizure types, chiefly absence seizures, for which it remains the treatment of choice. Table 52.1 summarizes the facts on ethosuximide.

Chemistry

Ethosuximide (ESM) is 2-ethyl-2-methyl-succinimide, with two carbonyl groups separated by a ring nitrogen. Because of a chiral carbon at position two of the succinimide ring, it is a racemic mixture. ESM is a white crystalline powder with a molecular weight of 141.7. The conversion factor from milligrams (mg) to micromoles (μmol) is 7.08 (ie, 1 mg/L = 7.08 μmol/L).

Animal Pharmacology

Efficacy

In animal models, ESM is effective against clonic seizures induced by subcutaneous pentylenetetrazol (PTZ), and against spike–wave seizures induced by gamma-hydroxybutyrate (1). ESM also reduces the occurrence of spontaneous spike–wave discharges in WAG/Rij and GAERS genetic rat models of epilepsy (2,3). ESM is not effective against tonic extension seizures induced by maximal electroshock (MES), bicuculline, or N-methyl-d-aspartate (4). Thus, the anticonvulsant profile of ESM is consistent with its narrow clinical spectrum. It suppresses absence seizures but not generalized tonic–clonic seizures (even in the syndrome of childhood absence epilepsy) or focal onset seizures.

Toxicity

Acute studies. Estimates for TD₅₀, the dose eliciting evidence of minimal neurologic toxicity in 50% of experimental animals, are above 3,000 µmol/kg, far exceeding the ED₅₀ for PTZ-induced seizures (5).

Multiple dose studies. There are limited studies on the effects of chronic administration of ESM. The effects of long-term administration of ESM and valproic acid (VPA) have been evaluated in epileptic baboons performing incremental repeated acquisition and incremental fixed ratio tasks. ESM was reported to show more behavioral toxicity, with deficits lasting as long as 8 weeks after drug cessation (6).

Teratology studies. Teratogenicity of ESM has been studied in Swiss CD-1 mice, in which the teratogenic potency was estimated using the minimum teratogenic dose (tD₅₀), which was 5.2 mmol/kg/day (7). The fetal malformations in mice administered 18 times the therapeutic dose included cleft palate and enlarged cerebral ventricles, but the incidence of these findings was low compared to other antiepileptic drugs (8). The U.S. Food and Drug Administration (FDA) has categorized ESM as category C (some animal studies show adverse effects, but there is no available human data).

Mechanisms of Action

The main mechanism of action of ESM is widely thought to be the blockade of transient, low-threshold calcium currents produced by T-type calcium channels in thalamic neurons, thereby preventing the synchronized firing of corticothalamic neurons that produce the spike–wave discharges of absence seizures (9–11). This mechanism was first elucidated with electrophysiologic recordings from rat and guinea pig thalamocortical neurons in slice preparations (9), and later from cloned human T-type calcium channels tranfected into mammalian cells (12). Contradictory results from other groups raised doubts about this mechanism and led to observations of other potential mechanisms involving the reduction of noninactivating sodium current and calcium-activated potassium current in cortical and thalamic neurons (13–15). As with most antiepileptic drugs, it seems likely that ESM engages multiple mechanisms of action to block the generation of seizures.

More recently, a number of studies have demonstrated disease-modifying effects of ESM in animal models of genetic generalized epilepsy. In the WAG/Rij rat model of genetic generalized epilepsy (GGE), treatment with ESM prior to onset of seizures blocked change in the expression of sodium channels and hyperpolarization-activated cation channels that are seen in this model and suppressed spike–wave discharges, an effect that persisted for at least 3 months after the medication was stopped (16). Likewise, in the GAERS model of GGE, treatment with ESM effectively suppressed seizures not only during treatment, but also for 3 months after cessation of ESM. In addition, anxiety-like behavior in this model was mitigated in ESM treatment animals (17). Whether ESM has disease-modifying or comorbidity mitigating effects in children (in whom treatment is initiated after onset of symptoms) is not known, but these animal studies suggest an important new avenue of investigation.

Biotransformation, Pharmacokinetics, and Interactions

Absorption and Distribution

ESM is taken orally as a syrup or capsule, and is rapidly absorbed from the gastrointestinal tract. Its bioavailability is 95% to 100%, and is equivalent for capsule or syrup (18). Peak levels are reached 3 to 5 hours after intake. The apparent volume of distribution is 0.7 L/kg, in both children and adults. ESM is not bound to plasma proteins. Concentrations of ESM in cerebrospinal fluid, tears, and saliva are similar to its plasma concentration. ESM passes through the placenta and serum levels of ESM are essentially equivalent to maternal levels. Concentration of ESM in breast milk is around 85% of the maternal serum level, with serum concentrations in breast-fed infants about 30% to 50% of the maternal serum level (19).

Metabolism and Elimination

Liver metabolism accounts for 80% of ESM elimination, with the remaining 20% excreted unchanged by the kidneys during chronic intake. Hepatic metabolism primarily consists of hydroxylation followed by glucuronidation of the metabolites (20). The principal cytochrome P450 oxidase involved is CYP3A, with less contribution from CYP2E and CYP2C/B (11). No active metabolites have been identified.

The elimination half-life of ethosuximide is 40 to 60 hours in adults and 30 to 40 hours in children, with linear kinetics and no evidence of autoinduction (18,20). Accordingly, steady-state levels are reached after 7 to 10 days of daily intake of a stable dose. As with most antiepileptic drugs, the level-to-dose ratio may decrease during pregnancy (19).

Drug Interactions

Enzyme-inducing antiepileptic drugs such as phenytoin, phenobarbital, and carbamazepine increase ESM clearance, resulting in lower plasma levels (21). Valproic acid has unpredictable effects on ESM plasma levels, with reports of increased or decreased levels (22–25).

TABLE 52.1

Isoniazid can significantly raise the levels of ethosuximide, whereas rifampin may cause a significant decrease in ethosuximide levels (26,27). Ethosuximide is not highly protein bound and does not induce or inhibit liver metabolic enzymes, and it is not known to affect the clearance or levels of any other drug. In particular, there is no known interaction between ethosuximide and oral contraceptives.

Clinical Efficacy

Absence Seizures in Childhood Absence Epilepsy

ESM was introduced to clinical practice in 1958, and remains the medication of choice for absence seizures in the setting of childhood absence epilepsy (CAE). It may also be used to treat atypical absence seizures in other epilepsy syndromes, as well as myoclonic and atonic seizures, though perhaps less often now that the armamentarium for these seizure types has been strengthened by new drug development in the last 20 years.

Early studies observed a high degree of efficacy against absence seizures. In a 1975 case series by Dreifuss and colleagues, 50% of the 37 patients studied had a seizure reduction of at least 90%, and 95% of the patients had a reduction in seizure frequency by at least 50% (28). Prior to 2010, only six small randomized controlled trials of short duration evaluated the comparative efficacy of ESM, valproic acid (VPA), and lamotrigine (LTG) as initial monotherapy in children with absence epilepsy, but none met criteria for Class I or II studies (29).

In 2010, the results of a large, double-blind randomized controlled trial funded by the National Institutes of Health evaluating the effectiveness (efficacy and tolerability) of ESM, VPA, and LTG in childhood absence epilepsy were published (30). The study included 446 patients, aged 2.5 to 13 years, across 32 centers in the United States, and used parent reporting and electroencephalogram (EEG) to evaluate the primary outcome of freedom from failure (for efficacy or tolerability reasons) at 16 to 20 weeks. Freedom from failure rates were higher in subjects on ESM (53%) and VPA (58%) than on LTG (29%, P < .001), and subjects on ESM had less attentional dysfunction than subjects on VPA (33% vs. 49%, odds ratio 1.95, 95% CI 1.12–3.41, P = .03). The conclusion of these findings was that for children who have CAE with seizures limited to absence (that is, no generalized tonic–clonic seizures), ESM is the medication of choice for initial monotherapy. ESM failed in nearly half of subjects (47%), more often due to intolerable side effects (24%) than to persistent seizures (14%), with an additional 13% withdrawing from the study. The mean daily dose at the 16- to 20-week time point was 35.5 ± 15.3 mg/kg/day, and the mean steady-state trough concentration was 93 µg/mL (95% CI 0–185).

Long-term follow-up of the CAE cohort found consistent results at 12 months, with freedom from failure similar in the ESM and VPA groups (45% and 44% respectively), but less impaired attention in the ESM group compared to VPA (31).

Other Seizure Types and Epilepsy Syndromes

Evidence for efficacy of ESM in other seizure types and syndromes is limited chiefly to case series and expert opinion. Besides childhood absence epilepsy, ESM is only considered first-line therapy for one other syndrome: epilepsy with myoclonic absences (32,33). ESM has been used as adjunctive therapy to treat myoclonic seizures, atypical absence seizures, and drop attacks in Lennox–Gastaut syndrome, though perhaps less often now that there are a number of newer antiepileptic drugs available for this syndrome (34–37). ESM is also frequently used as adjunctive therapy in Doose syndrome (myoclonic astatic epilepsy) (38,39). Children with the epileptic encephalopathy known as electrical status epilepticus of sleep (ESES) or continuous spike and wave of slow wave sleep syndrome (CSWSS) are also not infrequently treated with ESM (40). Because ESM lacks efficacy against generalized tonic–clonic (GTC) seizures, it is not used as monotherapy in children with CAE who have had a GTC, or in children with juvenile absence epilepsy (JAE), who have a higher risk of GTCs than children with CAE.

Adverse Effects

Gastrointestinal Adverse Effects. Benign and fully reversible gastrointestinal side effects are by far the most common adverse reactions to ethosuximide (41,42). They include mostly abdominal discomfort, vomiting, diarrhea, and hiccups. Some of these effects can improve when the medication is taken at the end of a meal. Rarely are gastrointestinal side effects the sole reason for discontinuation of the medication (30).

Neurologic Adverse Effects. The neurologic side effects of ethosuximide can include headaches, sedation, drowsiness, fatigue, insomnia, and ataxia. Rarely, behavioral disturbances may occur, including nervousness, irritability, depression, hallucinations, and even psychosis (41). Occasionally, ethosuximide may also cause extrapyramidal reactions, such as dyskinesia (43,44).

Idiosyncratic Adverse Effects. Blood dyscrasias occur rarely with ESM treatment, and include thrombocytopenia, granulocytopenia, and pancytopenia (41). From its introduction in 1958 until 1994, eight cases of ESM-associated aplastic anemia were reported, occurring 6 weeks to 8 months after ESM initiation (45). Clinical alertness to possible signs and symptoms is likely to be more effective in recognizing such occurrences than routine monitoring of the blood count (46).

The risk of drug-induced lupus with ESM is well known but rare (47,48). Manifestations may include malar rash, arthritis, renal involvement, and cerebral involvement. Symptoms typically resolve with cessation of the drug, but recovery may be prolonged. Other idiosyncratic reations include allergic rashes, which typically resolve with withdrawal of the medication. Stevens–Johnson syndrome has been reported rarely (49).

Other. Based on pooled data from large clinical trials, all antiepileptic drugs now have an FDA warning about the increased risk of suicidal thoughts or behavior in patients taking them, which advises monitoring of patients for emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. However, there is no specific evidence of increased risk for suicidality with ESM.

Clinical Use

Indications

Ethosuximide is indicated as initial monotherapy in patients with childhood absence epilepsy, but only in those children with childhood absence epilepsy who have never experienced a GTC seizure, against which ESM has no protective effect. Because children with juvenile absence epilepsy are at higher risk for GTC seizures than those with CAE, a drug with a broader spectrum of action, such as VPA or LTG, should be used as monotherapy. ESM may be used as adjunctive treatment in other epilepsy syndromes, as discussed earlier.

Formulations

ESM is available in oral preparations, as syrup (250 mg/mL), and in capsule form (250 mg). The carbohydrate content of the syrup is 725 mg/mL (for concomitant use with the ketogenic diet, the capsule form is generally preferred).

Dosing

The initial target dose of ethosuximide is about 20 to 30 mg/kg/day. It is best to initiate treatment at one-third of this dose, preferably after meals, with two subsequent increases by the same amount at intervals of 5 to 7 days. If capsules are preferred, but the patient’s weight requires increments of 125 mg, the capsules can be frozen and then easily cut in half. The total daily dose can be divided into two daily doses, or also into three daily doses if this makes it easier for the child to take the medication or if it can be shown to improve gastrointestinal side effects. In absence epilepsy, parents or teachers may note a response within a few days, and provocation of seizures by forced hyperventilation also subsides. In addition, CAE is one of the rare epilepsies in which a dramatic EEG improvement accompanies clinical improvement. Because bursts of spike–wave discharges may persist even when seizures are no longer observed by parents, follow-up EEG recording is recommended after clinically apparent seizures have stopped. The goal of therapy should be normalization of the EEG, if possible. If there is doubt as to the whether the patient is free of seizures, a 24-hour ambulatory EEG may be helpful.

The suggested therapeutic range of ethosuximide plasma levels is 40 to 100 mg/L (300–700 pmol/L), but levels below 40 may be fully effective, and levels as high as 150 may be necessary and well tolerated. Once the patient is under good control, there is no need to monitor plasma levels routinely, unless there is a specific question that may be answered by a level. In patients who remain seizure free and have a normal EEG, ethosuximide can be gradually tapered over about 4 to 6 weeks. Because seizure recurrence may be subtle clinically, or significant subclinical spike and wave discharges may require reintroduction of therapy, it is good practice to repeat an EEG 1 to 3 months after ethosuximide has been discontinued.

Precautions

There are no clear guidelines regarding the need to monitor blood counts for the rare occurrence of bone marrow suppression, and clinical education and observation are likely to provide the best probability of early detection.

Contraindications

The only absolute contraindication is hypersensitivity to succinimides.

METHSUXIMIDE

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