Methsuximide in Intractable Epilepsies in Childhood

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Seizure 2001; 10: 120–124 doi:10.1053/seiz.2000.0467, available online at http://www.idealibrary.com on

Effective and safe but forgotten: methsuximide in intractable epilepsies in childhood

† ‡ § † MATTHIAS SIGLER , HANS MICHAEL STRASSBURG & HANS ERICH BOENIGK ∗

† Pediatric Hospital Kidron, Bethel Epilepsy Centre, Germany; ‡Department of Pediatric Cardiology, Aachen University of Technology, Germany; §Department of Pediatrics, University of Wuerzburg, Germany

Correspondence to: Matthias Sigler MD, Department of Pediatric Cardiology, Aachen University of Technology, D-52057 Aachen, Germany. E-mail: [email protected]

The efficacy and safety of methsuximide (MSM) was evaluated in children with intractable epilepsies in a prospective uncontrolled study. MSM was added to the therapeutic regimen of 112 children with intractable epilepsy under inpatient conditions, all of whom were therapeutically refractory to various first-line antiepileptic drugs (AED) or combinations of other AED. Titration of MSM was performed following a uniform protocol. Administration of MSM resulted in a 50% or greater reduction in seizure frequency in 40 patients after a short-term obser- vation period (mean 9.1 weeks). After a mean of 3.7 years, the rate of seizures and side effects were re-evaluated in 39 patients who were still receiving MSM as part of their antiepileptic regimen. Twenty two of these patients derived long-term benefit from MSM. In patients with good seizure control, fasting plasma levels of N-desmethylmethsuximide, the principal active 1 1 metabolite of MSM, were 25.3–44.7 mg l− (mean 36.0 mg l− ). Thus effective plasma levels of N-desmethylmethsuximide in children were found to be higher than previously described. Forty one of 112 patients (28.9%) developed side effects during MSM treatment. No serious or irreversible side effects were seen. Our study demonstrates the value of MSM as an ‘add-on’ drug in intractable epilepsies. c 2001 BEA Trading Ltd

Key words: methsuximide; Lennox–Gastaut syndrome; symptomatic focal epilepsy; intractable childhood epilepsy; metabolism of methsuximide; N-desmethylmethsuximide.

INTRODUCTION of patients taking MSM at levels 700 times greater than those of the parent drug5. The mechanisms of In 1951 methsuximide (Celontinr, Petinutinr) was action of MSM are not known and are possibly mul- found to be an antiepileptic agent when Chen1 and tiple6. In combination therapy MSM raises the lev- Miller2, 3 tested several succinimides for their seizure els of phenobarbital, phenytoin and primidone signif- inhibiting properties. After its introduction in the icantly and lowers levels of carbamazepine and val- United States in 1957 it became a widely used drug, proic acid7, 8. mainly (but not only) for the control of absence seizures4. However, its use declined after ethosux- Clinical studies show efficacy of MSM against ab- imide was shown to be even more effective and less sence seizures, juvenile myoclonic epilepsy, mixed toxic in absences. Currently the use of MSM is re- epilepsies, Lennox–Gastaut syndrome and various stricted to epilepsy centres, where it is used in com- other types of epilepsy9–12 (see Table 1). There is no bination with other established antiepileptic drugs prospective controlled study which shows efficacy of (AED) for intractable epilepsies. MSM in defined epileptic syndromes. Side effects de- N-Desmethylmethsuximide is the active metabolite scribed in patients under treatment with MSM are se- of methsuximide (MSM) and is found in the serum dation, gastrointestinal disturbances, hiccups, ataxia,

∗Dr Hans Erich Boenigk died on November 2nd, 2000.

1059–1311/01/020120 + 05 $35.00/0 c 2001 BEA Trading Ltd

Methsuximide in children 121 leukopenia and allergic rash8. Patients with MSM in- Sixty-eight patients were male, 44 female. The mean toxication develop coma and respiratory depression13. age at onset of MSM therapy was 8.9 years (range No fatal outcome has been published yet. 15 months to 20 years). The mean duration of epilepsy prior to consideration of MSM treatment was 6.4 years Table 1: Clinical reports on MSM. (range 12 months to 16 years). A mean of 5.3 other AED (SD 1.9) had been used in various combina- Source, year No. of Decrease in Side-effect tions without satisfactory result. Prior to starting the patients seizure rated (%) frequencyb (%) MSM therapy, previous AED treatments and their re- lated plasma levels had been reviewed. In cases of in- 20 c Zimmerman , 1954 90 32 20% sufficient dosage, the drugs were re-administered until 10 Cordoba , 1956 50 46 61% sufficient seizure control was achieved or side effects Zimmerman21, 1956 66 38c 14% Carter22, 1957 16 80 30% occurred without therapeutic success before adminis- Livingston9, 1957a 136 — 15% tration of MSM was considered. Dow23, 1958 54 22c 46% Forty of the 112 patients were classified as hav- French24, 1958 106 — 38% ing a symptomatic focal epilepsy. Thirty-eight patients Scholl25, 1959 53 33 57% were diagnosed with Lennox–Gastaut syndrome con- Trolle26, 1959 66 71 29% 16 27 c sistent with the definition of Gastaut et al. 1966 . Rabe , 1960 102 76 15% Other diagnoses included juvenile myoclonic epilepsy Dreyer19, 1969 24 43 46% 11 a (n 4), generalized cryptogenic (n 4) or symp- Stenzel , 1977 80 46 41% = = 28 c tomatic epilepsy (n 4), and West syndrome (n 3). Browne , 1980 19 56 — = = Wilder18, 1981 21 71c 58% The period during which the AED regimen was not Browne8, 1983 26 31 100% altered before introduction of MSM (for a minimum Tennison14, 1991a 25 60 36% of 2 weeks; average 3.7 weeks) was considered the 12 Hurst , 1996 5 100 20% baseline phase. At the beginning of the titration phase a These studies focused on the use of MSM in children. (mean duration 5.2 weeks) MSM was started with b Reported rate of patients with more than 50% (c75%) reduction 1 a single daily dose of about 5 mg kg− . The MSM in seizure frequency. dose was raised by increments of 3.2–5.5 mg kg 1 d Reported rate of patients who developed side effects during MSM − treatment. per week until sufficient seizure control was achieved Of the 17 studies of MSM listed in Table 1, only or side effects were observed. During titration and three studies focused on the use of MSM in chil- treatment phases, serum concentrations of NDM and dren9, 11, 14. Most of the studies are difficult to interpret all co-administered AED were determined weekly by means of high performance liquid chromatography because of ill-defined and unspecified patient popula- 17 tions, seizure classifications and methods used for de- (HPLC) . The ratio of N-desmethylmethsuximide termining therapeutic success and plasma levels of N- serum concentrations and daily MSM doses were de- desmethylmethsuximide. Stenzel et al.11 and Tennison termined in order to evaluate the individual MSM me- et al.14 reported good efficacy of MSM in epilepsies tabolization rate. which were refractory to modern AED treatment. For obtaining data on long-term outcome, parents, At the Pediatric Hospital of the Bethel Epilepsy current caregivers, pediatricians and pediatric neurol- Centre, MSM is still used as a drug of further choice ogists responsible for the antiepileptic treatment were in epilepsies which are not controlled by treatment interviewed by questionnaire and (if necessary) by with standard AED. Since several new antiepileptic telephone. compounds have been introduced during the last two For determining the therapeutic effect of MSM we decades15 it seemed interesting to analyse data of compared seizure frequency during the baseline phase children on treatment with the ‘old’ drug MSM. We and during the treatment phase (short-term) or with in- wanted to determine if MSM should still be consid- formation on seizure frequency from the questionnaire ered in the treatment of epilepsies. (long-term). Accordingly, patients were classified into the following groups: (I) greater than 50% decrease in seizure frequency, MATERIALS AND METHODS (II) no appreciable change (<50% decrease and Data were collected prospectively from 116 consec- <100% increase in seizure frequency), and utive children in whom MSM treatment was started. (III) deterioration. Four patients were excluded from the study because neurometabolic or neurodegenerative disease All patients with intolerable side effects were classi- was found to be the underlying cause for the seizures. fied in group III without regard to possible reduction Thus data of 112 patients were analysed. of seizure frequency. 122 M. Sigler et al.

RESULTS Table 2: Side effects during MSM treatment.

A 50% or greater reduction in seizure frequency Side effect No. of Rate (%) Mean serum (group I) during short-term phase (mean 9.1 weeks) patients concentration of MSM at occurrence of was obtained in 40 of the 112 patients (35.7%). Ten side effect (mg l 1) of these patients became seizure free (8.9%). Forty- − a seven patients did not show significant changes in their Hiccups 17 ( 0) 5.2 26.5 Nausea/vomiting 16 (a3) 4.3 27.4 seizure frequency (group II) and 25 patients became Drowsiness 12 (a2) 0.7 28.8 worse (group III). Included in group III were those Allergic rash 6 (a3) 5.4 28.0 patients in whom side effects prompted a discontin- Aggressive behaviour 5 (a3) 4.5 32.0 Ataxia 4 (a1) 3.6 54.0 uation of MSM administration (n 12). Leukopenia 2 (a0) 1.8 48.7 Twenty-seven point 5 percent of= the patients with a symptomatic focal epilepsy (n 11) showed a 50% The number of patients in whom this particular side effect prompted a discontinuation of MSM treatment. or greater decrease in seizure frequency= (group I— short-term) compared to 39.5% of patients with Ataxia and leukopenia were only documented with Lennox–Gastaut syndrome (n 15). Ten of the corresponding N-desmethylmethsuximide plasma lev- = 1 40 patients with symptomatic focal epilepsy became els higher than 45 mg l− . No serious idiosyncratic, worse when MSM was administered, whereas only hepatic, or renal toxicity occurred. five of the Lennox–Gastaut patients had to be classi- Metabolism of MSM appeared to be correlated with fied in group III (deterioration). age in a nonlinear fashion (Figure 1). Thus younger Variance analysis of reduction of seizure frequency children need higher doses of MSM compared to in relation to sex, age, epilepsy diagnosis, types of older children to reach the same plasma levels of N- seizures, prior drug treatment and co-medication re- desmethylmethsuximide. This effect was found to be vealed no significant influence of any of these factors independent of sex, epilepsy diagnosis, therapeutic ef- on therapeutic efficacy of MSM in our patient popula- fect of MSM and of the occurrence and type of side tion. effects. At the time of discharge from the epilepsy Centre, 71 patients continued to take MSM as part of their DISCUSSION medication. Fourteen patients were lost to follow up; thus follow up data were obtained in 57 patients. After several years of unsatisfactory trials to control When we re-evaluated the 57 patients after an aver- seizures with various combinations of different sub- age of 3.7 years (range 18 months to 7.1 years) we stances an additional AED is not very likely to cause dramatic improvement in the outcome of a child with found 39 still receiving MSM, of whom 22 (19.6% the types of epilepsy we saw in our patient population. of all 112 patients) continued to benefit from the drug Every possible effort must still be made to control or (greater than 50% decrease in seizure frequency com- at least to reduce the frequency of seizures in these pared with baseline and absence of intolerable side ef- patients. fects). Six of 38 patients with Lennox–Gastaut syn- Compared with AED which have shown similar ef- drome and 7 of 40 patients with symptomatic fo- ficacy and safety, little has been published on MSM cal epilepsies were classified in group I on reviewing and consequently little may be known about its use long-term outcome of patients on MSM. especially in children. On analysing data of the ‘in- The mean effective NDM plasma concentration of tractable’ patients who were treated with MSM at the 1 patients in group I was 36.0 mg l− (SD 6.2). No Bethel Centre we found MSM not only to be effec- seizure inhibiting effect of MSM was documented tive, reducing seizure frequencies in an uncontrolled in children with N-desmethylmethsuximide plasma prospective study, but also safe; no serious or irre- 1 levels below 25 mg l− . Plasma levels of all co- versible toxicity occurred. administered AED were within normal range during In contrast to reports on adult patients, in treatment phase. whom plasma levels of the active metabolite N- 8 15 Side effects occurred in 41 of the 112 patients desmethylmethsuximide of 10–30 or 10–40 mg l− (28.9%) while taking MSM (Table 2). In 12 of these were reported to be effective, we found in children the children MSM administration had to be discontinued therapeutic range of the metabolite to be as high as 25– 1 due to side effects. All side effects were completely 45 mg l− . No therapeutic effect of MSM was seen in reversible after removal of MSM from the therapeutic children with N-desmethylmethsuximide serum con- 1 regimen or by temporary lowering of the daily dose centrations below 25 mg l− whereas no signs of toxi- of MSM. There was no association of a particular side city occurred with corresponding plasma levels of less 1 effect with one of the co-administered AED. than 45 mg l− . Methsuximide in children 123

95. percentile

50. percentile

5. percentile

n = 91 Quotient of NDM blood level per daily dose of MSM Quotient of NDM blood level

Age (years)

Fig. 1: Metabolization of MSM in relation to age.

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