Continuing Education Activity

Ethosuximide is a medication used in the management and treatment of absence epilepsy. This activity outlines the indications, actions, and contraindications for ethosuximide as a valuable agent for absence epilepsy. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent for the interprofessional team members in treating patients with absence seizures.

Objectives:

• Describe the mechanism of action of ethosuximide.
• Identify the indications for ethosuximide.
• Identify the most common adverse events associated with ethosuximide therapy.
• Outline the importance of collaboration and coordination among the interprofessional team can enhance patient care for patients receiving ethosuximide with absence epilepsy.

Indications

Ethosuximide is FDA approved for the management of absence seizures in patients over three years of age.[1] Currently, there are no off-label uses for ethosuximide; however, there is some evidence it may have some analgesic effects. Specifically, several studies have suggested value in the management of neuropathic pain.[2][3]

Ethosuximide has level A evidence for childhood absence seizures and has been an effective medication in the management of absence seizures in humans since the 1960s and 1970s.[4][5] A landmark trial in 2010 showed that ethosuximide and valproic acid were more effective than lamotrigine for managing childhood absence seizures.[6] Seizure freedom rates for ethosuximide and valproic acid were 53% and 58%, respectively. These patients were then followed for 12 months to evaluate their long-term outcomes. This data was published in 2013, showing that ethosuximide had better tolerability than valproic acid.[7] Similar data has been found in adolescents.[8] Due to its effectiveness and relatively limited side effect profile as outlined above, ethosuximide is considered the first-line therapy for absence epilepsy. If a patient continues to be refractory to ethosuximide monotherapy, valproic acid can to added to increase the likelihood of seizure control. 

While ethosuximide is effective for absence seizures, it otherwise has a very narrow therapeutic profile. It has no benefit in symptomatic epilepsies or other generalized epilepsies. If a patient has concurrent generalized tonic-clonic (GTC) seizures, valproic acid is recommended over ethosuximide as initial monotherapy since ethosuximide does not control GTC seizures and can potentially exacerbate them. 

Mechanism of Action

Ethosuximide (3-ethyl-3-methyl pyrrolidine-2,5-dione) is one of three succinimides known to have anticonvulsant properties. The other two succinimides, phensuximide and methsuximide, have worse side effect profiles and are less effective than ethosuximide.[9] Studies of this class of organic compounds first took place in the 1950s in mouse models. 

Thalamocortical neurons are hypothesized to be generators of the classic 3 Hz spike-and-wave discharges seen with absence seizures and rely heavily on low threshold T-type calcium channels to do so. Ethosuximide can lower the threshold of T-type calcium currents and disrupt the oscillatory activity of thalamocortical circuitry by blocking T-type calcium channels.[10]

Administration

Ethosuximide administration is via 250 mg capsules or a 250mg/5 mL oral suspension. The oral suspension has a faster absorption rate than the capsules. 

Dosing should start at 125 mg twice daily for children between ages 3 and 6. Children above the age of 6 and adults can begin with 250 mg twice daily. Dosing can then be increased by 250 mg every 4 to 7 days to 20 mg/kg/day divided twice daily. Serum concentrations of ethosuximide follow linear kinetics with increasing doses. The maximum dose is 1500 mg/day. Patients on hemodialysis may require additional doses before or after their treatments to maintain therapeutic levels. When being discontinued, it should be tapered slowly as abrupt withdrawal may precipitate absence status epilepticus.

Ethosuximide has excellent bioavailability (over 90%). It has negligible protein binding once it enters the bloodstream and readily crosses the blood-brain barrier.[11] It is hepatically metabolized (80%) primarily by CYP3A4 into inactive metabolites. About 10 to 20% may be excreted unchanged in the urine. If the patient's creatinine clearance falls below 10, the dose should be decreased by 25%. Hepatic dose adjustments are undefined, but caution is advised in cases of hepatic impairment. It has a relatively long half-life; 30 hours in children and 50 to 60 hours in adults. Because of its long half-life, ethosuximide can take several days (7 to 10) to reach a steady state. 

Adverse Effects

The overall rate of adverse side effects with ethosuximide use is less than most other AEDs (26 to 46%). Gastrointestinal side effects (nausea, vomiting, diarrhea, and anorexia) are a common initial side effect that often diminishes after 1 to 2 weeks. Other common side effects include drowsiness, lethargy, insomnia, and hiccups. Headache can occur in 14% of children on ethosuximide. 

Reports exist of rare idiosyncratic reactions Stevens-Johnson syndrome, agranulocytosis, aplastic anemia, and systemic lupus erythematosus.[12][13] Discontinuation of ethosuximide is necessary if any idiosyncratic reactions occur. Recovery may take time but usually occurs with discontinuation. 

Contraindications

Patients with hypersensitivity to succinimides should avoid taking ethosuximide. Its use requires caution in patients with hepatic and renal disease, although, as previously stated above, hepatic dosing adjustments are undefined.

Monitoring

There are no guidelines for therapeutic drug monitoring of ethosuximide. Dosing can be adjusted purely on the patient's clinical response to a particular dose and electroencephalogram (EEG). Ethosuximide level checking is done as a trough. The therapeutic range for ethosuximide is between 40 to 100 mcg/ml. Higher levels than 100 mcg/ml are usually tolerable without toxicity. Patients in absence status epilepticus may need serum concentrations higher than 120 mcg/ml to achieve seizure control.[11] Complete blood counts (CBC) and liver function tests (LFT) can also be checked intermittently to monitor for severe but rare hematologic dyscrasias (pancytopenia, agranulocytosis, leukopenia) despite no evidence that this is sufficient to alert physicians about this potential serious idiosyncratic reaction.

Enzyme-inducing antiepileptic drugs (AEDs) such as phenytoin, carbamazepine, and phenobarbital can reduce serum concentrations of ethosuximide by accelerating its elimination.[14] The effect of valproic acid on ethosuximide concentrations can be variable.[15][16][17][18] Ethosuximide may increase phenytoin levels, but it has no enzyme-inducing properties. 

Isoniazid may reduce ethosuximide metabolism, while rifampicin can increase ethosuximide clearance.[19][20]

Toxicity

Mouse models suggest symptoms of ethosuximide toxicity begin with incoordination and can progress to dyspnea, respiratory failure, and death.[21] Comparably, overdose in humans can lead to coma and respiratory depression. Recommendations are that patients with an acute overdose of ethosuximide should be observed in an emergency room or inpatient setting, with supportive care if needed.[22] Hemodialysis can be a safe and effective way to rapidly clear ethosuximide from the body.[23]

Ethosuximide is a category C drug (possibly unsafe in pregnancy) known to cross the placenta; Serum concentrations of ethosuximide in neonates are comparable to that of the mothers.[24] Recommendations are that ethosuximide should be used as monotherapy with the lowest effective dose when possible during pregnancy. Levels could be checked pre-pregnancy and then monitored intermittently during pregnancy. Ethosuximide can be excreted in breastmilk at concentrations comparable to maternal serum. Because of this, breastfeeding while on ethosuximide is considered potentially hazardous.

Enhancing Healthcare Team Outcomes

Primary care clinicians are commonly the first medical care providers to be informed about staring episodes or poor school performance, suggesting absence seizures, prompting a referral to neurology. After diagnosing absence epilepsy and initiating ethosuximide, both primary care physicians and neurologists should monitor for clinical benefit from ethosuximide therapy. If a patient remains seizure-free for over two years while on ethosuximide, and if the patient's EEG has normalized, one could consider slowly tapering the medication off over weeks to see if the patient developed terminal remission. 

Ethosuximide therapy requires the efforts of an interprofessional healthcare team, including clinicians as outlined above, but also nursing staff, pharmacists, and mental health professionals. Nursing can counsel on medications and the disease state and serve as a liaison between other disciplines. Pharmacists will verify appropriate dosing, check for potential drug-drug interactions, and offer the patient further counsel on proper medication administration. SPecialists will also weigh in with their opinion and work with the prescriber(s) to ensure the patient is receiving the appropriate therapeutic interventions. This interprofessional approach will optimize the therapeutic success of ethosuximide while minimizing adverse events. [Level 5]