Antiepileptic Drugs, 5th Edition

Succinimides

68

Clinical Efficacy and Use in Epilepsy

Allan L. Sherwin MD, FRCP (C)

Professor of Neurology, Department of Neurology and Neurosurgery, McGill University; and Emeritus Neurologist, Montreal Neurological Hospital and Institute, Montreal, Quebec, Canada

SPECTRUM OF EFFICACY

Ethosuximide, a succinimide derivative, was initially used for the treatment of generalized absence seizures, but it also proved effective in certain other seizure types including atypical absence attacks and myoclonic seizures (1). This agent has also been reported to prevent epileptic negative myoclonus (2,3), which is a seizure type observed in certain childhood epileptic syndromes.

Typical Absence Seizures

Absence seizures are an age-related manifestation of generalized epilepsy with onset between 4 and 8 years of age (4). Absence seizures are accompanied by very characteristic bilateral spike-and-wave discharges in the electroencephalogram (EEG), as shown in Figure 68.1. This disorder is rare, with an annual incidence of newly diagnosed cases of 1 in 100,000 (5). It occurs in 8% of children with epilepsy between the ages of 5 and 14 years (6), and it is more common in girls (60% to 70%) than in boys. Epidemiologic studies indicate that a family history of epilepsy is present in 15% to 44% of cases.

Despite their brevity, frequent absence seizures require treatment because of their disruptive effect on the child's normal activities (7). Often they lead to embarrassment at school or interference with work, and the possibility of accidental injury is always present. There is also evidence that the generalized 3-Hz spike-and-wave epileptic discharge (Figure 68.1), the hallmark of this seizure pattern, causes impairment in sustained attention (8,9).

Browne et al. (10) and Penry et al. (9) were the first to carry out a prospective study of the efficacy of ethosuximide in controlling absence attacks. These investigators reported that 18 of 37 patients (49%) had a ≥90% reduction, and 35 (95%) had a ≥50% reduction in seizures. My colleagues and I carried out a prospective study of 70 patients with absence seizures treated with ethosuximide. The group comprised 38 female and 32 male patients ranging in age from 4 to 28 years (median, 12 years). Absence attacks were the sole manifestation of epilepsy in 38 of the patients (54%). Tonic-clonic seizures were also present in 21 patients (30%), and additional 11 patients (16%) had a history of one or more other generalized seizures before they entered the study. The dosage of ethosuximide employed

P.653


ranged from 0.5 to 1.75 g/day (9.4 to 73.5 mg/kg). Medications administered to prevent tonic-clonic seizures were phenytoin (30 patients) and phenobarbital (six patients). In the group of 33 patients who had completely seizures, only 9% were found to have serum ethosuximide levels <40 µg/mL, with none <30 µg/mL. Thus, efforts were directed toward achieving levels >40 µg/mL in patients with uncontrolled seizures. A significant improvement in the clinical control of absence seizures was observed within the first 2½ years (Figure 68.2).

 

FIGURE 68.1. Electroencephalogram recorded from a 7-year-old boy before and during an absence seizure that lasted approximately 9 seconds. The generalized and bilaterally synchronous spike-and-wave activity at 2.5 to 3 Hz emerges abruptly from normal background activity. Complete seizure control was achieved with ethosuximide monotherapy (30 mg/kg, plasma concentration 85 µg/mL). Epilepsy remitted at 13 years; the child had no history of tonic-clonic seizures.

Patients with absence seizures tend to cease having attacks with advancing age (11), although some studies have reported a more guarded prognosis (12). Janz (13) observed that the rate of spontaneous remission of absence seizures over 2-year periods was 3%. This gradual rate of improvement could not account for the observed increase in the number of patients with controlled seizures in the study conducted by my colleagues and I (1); however, patients who continued to have tonic-clonic seizures were less likely to have attained control of absence seizures. There is no clear evidence that ethosuximide influences the remission rate of absence seizures (14).

Controlled trials in which ethosuximide and valproate were compared indicate that both drugs are equally effective in controlling absence seizures (15,16). In clinical practice, individual patients may respond to one or the other drug in monotherapy. Rowan et al. (17) carefully studied five patients with absence seizures refractory to treatment with either ethosuximide or valproate monotherapy whose seizures became controlled when the two agents were combined.

If absence attacks are the sole seizure pattern, ethosuximide provides a relatively safe and effective form of monotherapy. If tonic-clonic seizures are also present, ethosuximide can be readily combined with another antiepileptic agent, because clinically significant drug interactions are rare. Alternatively, monotherapy with valproate, lamotrigine, zonisamide, or another antiepileptic drug that protects against both absence and tonic-clonic seizures is a more direct approach (7,18,19). Children ≥7 years old with generalized childhood absence epilepsy have a high incidence (~40%) of new-onset tonic-clonic seizures.

 

FIGURE 68.2. Control of absence attacks in a study performed when ethosuximide was the only safe antiepileptic drug available for this seizure type. Approximately two-thirds of the patients received ethosuximide monotherapy.

Atypical Absence Seizures

Patients with atypical absence seizures, in whom the attacks usually have a more gradual onset and cessation, more pronounced alteration of tone, and more heterogeneous EEG findings, also respond to ethosuximide. These patients often exhibit other types of seizures including myoclonus, tonic-clonic seizures, and drop attacks.

Absence Status

Absence status, an almost continuous state of abnormal behavior and responses ranging from mild confusion to stupor (20,21), can often be prevented or controlled by ethosuximide, especially when plasma ethosuximide levels are >120 µg/mL.

Epileptic Negative Myoclonus

Ethosuximide is also very efficacious in epileptic negative myoclonus, a rare form of partial seizures seen in various epileptic syndromes of childhood. This seizure type has been defined as a brief and involuntary loss of postural tone, which is time related to spike-and-wave complexes in the contralateral cerebral hemisphere. Negative myoclonus is caused by muscular inhibition with a brief loss of postural tone, in contrast to the more frequently observed brisk jerks of positive myoclonus. Epileptic negative myoclonus in a lower limb may result in an unexpected fall, but the attacks are usually more subtle and must be documented by simultaneous EEG and electromyography (EMG) recordings (Figure 68.3).

The localization and morphology of paroxysmal abnormalities, such as high-amplitude spikes followed by large slow waves over the contralateral motor area, suggest this disorder. Ethosuximide may prevent this negative motor seizure phenomenon by selectively blocking T-type calcium channels in the thalamus (22). Oguni et al. (2) reported that ethosuximide achieved complete control of epileptic negative myoclonus in six patients, in contrast to their findings with carbamazepine, which was ineffective in eight patients. Capovilla et al. (3) carried out a detailed prospective study of epileptic myoclonus in nine patients with partial epilepsy of varying causes including benign epilepsy with centrotemporal spikes, cryptogenic partial epilepsy, cortical dysplasia, and tuberous sclerosis. Epileptic negative myoclonus appeared as brief interruptions of the tonic EMG activity related to a contralateral focal or diffuse spike-and-wave complex. Back averaging of EEG activity revealed that the onset of the slow wave followed the onset

P.654


of the EMG silent period. Ethosuximide was added to preexisting antiepileptic medications, which were maintained unchanged for the next 6 months. Epileptic negative myoclonus disappeared in all patients when an effective therapeutic dose was attained, usually within 15 to 30 days. Plasma ethosuximide levels in patients with controlled seizures ranged from 55 to 89 µg/mL.

 

FIGURE 68.3. A: Waking electroencephalogram (EEG) before ethosuximide introduction showing triphasic vertex spikes diffusing mainly to left parasagittal regions associated with epileptic negative myoclonus in both right tibialis anterior and triceps surae. B: Waking EEG after ethosuximide monotherapy showing complete disappearance of paroxysms. C: Confirmation of this finding by means of a sleep EEG. (From Capovilla G, Beccaria F, Veggiotti P, et al. Ethosuximide is effective in the treatment of epileptic negative myoclonus in childhood partial epilepsy. J Child Neurol 1999;14:395-400, with permission.)

The EEG and EMG findings in a child studied before and after the start of ethosuximide monotherapy are shown in Figure 68.3. The clinical responses observed in these patients did not appear to be influenced by the nature of the preexisting treatment, and various more modern antiepileptic drugs had been ineffective. Shirasaka et al. (23) also reported a patient with epileptic negative myoclonus in whom active unilateral interictal focal epileptic discharges were recorded from the centrotemporal region. Carbamazepine, zonisamide, and valproate exacerbated the negative myoclonus, but complete control of this seizure type was achieved after the addition of ethosuximide to the preexisting medication.

Myoclonic and Miscellaneous Seizure Types

Ethosuximide is also useful as an adjunctive agent in patients with myoclonic epilepsy in infancy, juvenile myoclonic epilepsy (18,19), and Lennox-Gastaut syndrome (24). Likely because of its inhibitory effects on thalamic oscillatory discharges, ethosuximide has been helpful in epilepsy with continuous spikes and waves during slow-wave sleep. Anecdotal reports indicate that ethosuximide is efficacious in some patients with photosensitive seizures (25).

MODE OF USE

Guidelines for ethosuximide therapy are summarized in Table 68.1. Treatment should be started with a small dose to minimize side effects, but care should be taken to prescribe an adequate final dose based on the weight of the patient.

P.655


Daily administration of 20 mg/kg ethosuximide in children ≤11 years of age will result in mean plasma levels of 50 µg/mL, whereas in older patients, the administration of approximately 15 mg/kg will result in similar levels (Figure 68.4). The generally accepted maximum daily dosage is 30 mg/kg for adults and 40 mg/kg for children. The daily dose may be increased every 4 to 7 days until seizure control is achieved.

TABLE 68.1. GUIDELINES FOR ETHOSUXIMIDE THERAPY

Indications: Absence seizures, both typical and atypical; adjunctive therapy of myoclonic epilepsy and epileptic negative myoclonus

Maintenance dosage: 15-40 mg/kg/day, once daily or with meals

Peak levels: Children, 3-7 h; adults, 2-4 h

Dose-related effects: Gastric distress, nausea, vomiting, anorexia, fatigue, lethargy, headache, dizziness, hiccups, and behavioral changes

Plasma concentrations: Effective levels 40-100 µg/mL (300-700 µmol/L); but levels of up to 150 µg/mL (1,000 µmol/L) may be required and well tolerated

Time to reach steady state: Children, 6 days; adults, 12 days

Interactions: Minimal with other antieileptic drugs; negligible binding by plasma proteins; levels increased by valproate alone or in combination

Indications for plasma level monitoring: Poor response, poor compliance, suspected toxicity, maintenance of optimal concentrations following addition or withdrawal of potentially interacting drugs

 

FIGURE 68.4. Relation of plasma ethosuximide concentration to dosage at steady state. The slope of the regression line for patients ranging in age from 2 to 10 years (n = 23) is significantly less than that for patients ≥11 years of age (n = 49) (p < .01). The regression lines are useful as guidelines for selecting the appropriate dosage. Significant differences between boys and girls were not observed.

Although ethosuximide therapy can usually be individualized empirically based on clinical and EEG monitoring of drug response, measurement of plasma ethosuximide levels can be helpful when good seizure control is not easily achieved, such as because of to noncompliance, but frequent measurements are not necessary as long as the dosage is adjusted to account for weight gain (Figure 68.4). Plasma ethosuximide levels ranging from 40 to 100 µg/mL have been associated with practical seizure control in 80% of patients, with 60% becoming seizure free (Figure 68.2). Overall, concentrations ranging from 40 to 100 µg/mL are considered optimal for effective seizure control, but concentrations ≤150 µg/mL may be required and tolerated if achieved by slow titration (1).

Plasma ethosuximide levels remain extremely stable on successive examination of patients when the medication is taken regularly. Although trough levels are theoretically more accurate, it appears that the time of day that the blood sample is obtained is not likely to change the therapeutic implications of the plasma level significantly. Saliva and plasma ethosuximide levels are very similar, and salivary levels can be used to monitor therapy (26).

P.656

 

USE DURING PREGNANCY AND BREAST-FEEDING

Fortunately, typical absence seizures have often ceased to be a major problem by the time many patients reach childbearing age. If so, it may be possible to discontinue therapy before conception, although therapy with other agents must be maintained if tonic-clonic seizures are also present (27). Preliminary findings suggest that plasma ethosuximide levels tend to decrease somewhat during pregnancy, with modest increases in maternal levels reported after delivery (28). The mean fetal:maternal plasma concentration ratio was 0.97 at birth, a finding indicating that the fetus is exposed to similar drug concentrations as the mother. There are insufficient data on ethosuximide monotherapy in pregnancy to predict the precise risk of fetal malformations. Congenital malformations have been described in some patients taking ethosuximide therapy during pregnancy, but these patients were also taking at the same time other anticonvulsants known to be teratogenic (29). Dansky et al. (30) monitored ethosuximide in five patients, one of whom had a malformed child. Her mean dosage (17 mg/kg) and mean plasma level (42 µg/mL), although within the therapeutic range, were about twice the corresponding mean values for the four mothers with normally formed children (10 mg/kg, 27 µg/mL). Because uncontrolled absence seizures, unlike tonic-clonic seizures, are unlikely to cause any harm to the fetus, it would seem prudent to minimize fetal exposure to ethosuximide by keeping plasma drug levels as low as possible during the first trimester of pregnancy and in women who are planning to become pregnant.

Breast milk ethosuximide concentrations are approximately 90% of the mother's steady-state plasma levels. Kuhnz et al. (31) reported hyperexcitability during the first 2 weeks in a newborn who had been breast-fed for 10 days, during which time the mother received ethosuximide monotherapy. In a group of five infants exposed to ethosuximide through breast milk, plasma levels ranged between 15 and 40 µg/mL, whereas the corresponding maternal plasma concentrations ranged between 28 and 84 µg/mL. Based on the high ethosuximide plasma levels found in suckling infants and the reports of behavioral effects, infants breast-fed by mothers taking ethosuximide should be carefully monitored for potential adverse effects (32).

CONCLUSION

Ethosuximide is particularly effective as monotherapy in patients with absence seizures as the sole seizure type when both the intelligence quotient and the EEG background activity are within the normal range. However, ethosuximide is also highly effective in atypical absence seizures, and it can be valuable in patients with myoclonic seizures and epileptic negative myoclonus. If seizure control is not attained with ethosuximide, the patient should be gradually switched to monotherapy with another medication. If seizures remain uncontrolled, then combination therapy, particularly with ethosuximide and valproate, is frequently successful, especially in patients with myoclonic absences (19) or partial seizures with epileptic negative myoclonus (2,3,23). In patients with a history of tonic-clonic seizures, ethosuximide should also be associated with another antiepileptic drug.

When absence seizures have been controlled for 2 years, consideration may be given to discontinuing therapy, particularly if the EEG examination, including 3 minutes of forceful hyperventilation, fails to reveal evidence of 3-Hz spike-and-wave discharges. Ethosuximide therapy can be discontinued, but the patient should be reexamined 1 month later, and the EEG with hyperventilation should be repeated (33). Ambulatory EEG monitoring has been demonstrated to be an effective technique to identify those patients in whom ethosuximide therapy can be discontinued (34). A similar approach applies when ethosuximide is administered for the control of epileptic negative myoclonus. If behavioral seizures or epileptogenic discharges are recorded, continuation of drug therapy for an additional period should be considered.

REFERENCES

  1. Sherwin AL, Robb JP, Lechter M. Improved control of epilepsy by monitoring plasma ethosuximide. Arch Neurol1973;28: 178-181.
  2. Oguni H, Uehara T, Tanaka T, et al. Dramatic effect of ethosuximide on epileptic negative myoclonus: implications for the neurophysiological mechanism. Neuropediatrics1998;29:29-34.
  3. Capovilla G, Beccaria F, Veggiotti P, et al. Ethosuximide is effective in the treatment of epileptic negative myoclonus in childhood partial epilepsy. J Child Neurol1999;14:395-400.
  4. Berkovic SF, Andermann F, Andermann E, et al. Concepts of absence epilepsies: discrete syndromes or biological continuum. Neurology1987;37:993-1000.
  5. Loiseau J, Loiseau P, Guyot M, et al. A survey of epileptic disorders in Southwest France: seizures in elderly patients. Ann Neurol1990;27:232-237.
  6. Cavazzuti GB. Epidemiology of different types of epilepsy in school age children of Modena, Italy. Epilepsia1980;22:57-62.
  7. Pellock JM. Treatment of epilepsy in the new millenium. Pharmacotherapy2000;20[Suppl S]:129S -138S.
  8. Browne TR, Penry JK, Porter RJ, et al. Responsiveness before, during and after spike-wave paroxysms. Neurology1974;24: 659-665.
  9. Penry JK, Porter RJ, Dreifuss FE. Simultaneous recording of absence seizures with video tape and electroencephalography: a study of 374 seizures in 48 patients. Brain1975;98;427-440.
  10. Browne TR, Dreifuss FE, Dyken PR, et al. Ethosuximide in the treatment of absence (petit mal) seizures. Neurology1975;25: 515-524.
  11. Dalby MA. Epilepsy and 3 per second spike-and-wave rhythms. Acta Neurol Scand1969;45[Suppl 40]: 1-83.
  12. Rodin EA. The prognosis of patients with epilepsy.Springfield, IL: Charles C Thomas, 1968.

P.657

 

  1. Janz D. Die Epilepsien-Spezielle Pathologie und Therapie.Stuttgart: Georg Thieme, 1969:94.
  2. Okuma T, Kumashiro H. Natural history and prognosis of epilepsy: report of a multi-institutional study in Japan. Epilepsia1981;22:35-53.
  3. Sato S, White BG, Penry JK. Valproic acid versus ethosuximide in the treatment of absence seizures. Neurology1982;32: 157-163.
  4. Callaghan N, O'Hare J, O'Driscoll D, et al. Comparative study of ethosuximide and sodium valproate in the treatment of typical absence seizures (petit mal). Dev Med Child Neurol1982;24: 830-836.
  5. Rowan AJ, Meijer JW, de Beer-Pawlikowski N, et al. Valproate-ethosuximide combination therapy for refractory absence seizures. Arch Neurol1983;40:797-802.
  6. Brodie MJ, Dichter MA. Established antiepileptic drugs. Seizure1997;6:159-174.
  7. Wallace SJ. Myoclonus and epilepsy in childhood: a review of treatment with valproate, ethosuximide, lamotrigine and zonisamide. Epilepsy Res1998;29:147-154.
  8. Andermann F, Robb JP. Absence status: a reappraisal following a review of 38 patients. Epilepsia1972;13:177-187.
  9. Porter RJ, Penry JK. Petit mal status. Adv Neurol1983;34:61—67.
  10. Huguenard JR. Neuronal circuitry of thalamortical epilepsy and mechanisms of antiabsence drug action. Adv Neurol1999;79: 991-999.
  11. Shirasaka Y, Mitsuyshi I. A case of epileptic negative myoclonus: therapeutic considerations. Brain Dev1999;21:209-212.
  12. Schmidt D, Bourgeois B. A risk-benefit assessment of therapies for Lennox-Gastaut syndrome. Drug Saf2000,22:467-477.
  13. Zifkin B, Andermann F. Epilepsy with reflex seizures. In: Wyllie E, ed. The treatment of epilepsy: principles and practices,3rd ed. Philadelphia: Lea & Febiger, 1993;614-623.
  14. Liu H, Delgado MR. Therapeutic drug concentration monitoring using saliva samples. Clin Pharmacokinet1999;36:453-470.
  15. Schmidt D, Beck-Mannagetta G, Janz D, et al. The effect of pregnancy on the course of epilepsy: a prospective study. In: Janz D, Dan M, Pickens A, et al., eds. Epilepsy, pregnancy and the child.New York: Raven Press; 1982:39-49.
  16. Koup JR, Rose JQ, Cohen ME. Ethosuximide pharmacokinetics in a pregnant patient and her newborn. Epilepsia1978;19: 535-539.
  17. Samren EB, van Duijn CM, Koch S, et al. Maternal use of antiepileptic drugs and the risk of major congenital malformations: a joint European prospective study of human tetragenesis associated with maternal epilepsy. Epilepsia1997;38:981-990.
  18. Dansky L, Andermann E, Sherwin AL. Maternal epilepsy and birth defects: a prospective study with monitoring of plasma anticonvulsant levels during pregnancy. In: Dam M, Gram L, Penry JK, eds. Advances in epileptology: XIIth Epilepsy International Symposium.New York: Raven Press, 1981:607-612.
  19. Kuhnz W, Koch S, Jakob S, et al. Ethosuximide in epileptic women during pregnancy and lactation period: placental transfer, serum concentrations in nursed infants and clinical status. Br J Clin Pharmacol1984;18:671-677.
  20. Häag S, Spigset O. Anticonvulsant use during lactation. Drug Saf2000;6:425-440.
  21. Dreifuss FE. Treatment of the nonconvulsive epilepsies. Epilepsia1983;24[Suppl 1]:S45-S54.
  22. Amit R, Vitale S, Maytal J. How long to treat childhood onset absence epilepsy. Clin Electroencephalogr1995;26:163-165.