West syndrome is an age-related epilepsy syndrome that includes the triad of infantile spasms, an inter-ictal electroencephalographic (EEG) pattern called hypsarrhythmia, and mental retardation. West syndrome is believed to reflect abnormal interactions between the cortex and brainstem structures1,2). The frequent onset of West syndrome in infancy suggests that an immature central nervous system may have an important role in its pathogenesis. The brain-adrenal axis also may be involved3). One theory holds that the effect of different stressors in the immature brain produces an abnormal excessive secretion of corticotrophin-releasing hormone, causing spasms4). The clinical response to adrenocorticotropic hormone (ACTH) and glucocorticoids can be explained by suppression of corticotrophin-releasing hormone production. For this reason, ACTH and glucocorticoids were widely used for the management of West syndrome as the first-line therapy for many decades5). The efficacy of ACTH for resolution of West syndrome has varied from as low as 33% to as high as 100%6,7). These patients may have, however, significant and potentially fatal adverse effects; electrolyte imbalance, hypertension, hypertrophic cardiomyopathy and secondary infection8-10). Some previous controlled studies support vigabatrin as a first line therapy, but visual field defect which is a possible adverse effect of this drug may limit its use11,12).

Recently, many researches are reported in order to treat West syndrome effectively with avoiding harmful adverse effects of existing drugs. Topiramate (TPM) is the one of new antiepileptic drugs which has been studied for this purpose. TPM has multiple mechanisms of action, including state-dependent inhibition of sodium channels, potentiation of r-aminobutyric acid-induced chloride influx, blockade of glutamate related excitatory neurotransmission, and inhibition of carbonic anhydrase13). Thus, TPM exerts beneficial effects on several seizure types, including those that are resistant to older antiepileptic drugs.

For the management of West syndrome, TPM has been used as an add-on therapy to first-line drugs in most studies14-16). Other studies have treated patients with multiple antiepileptic drugs concurrently with TPM17). But only a few studies suggested that TPM can be a first-line drug and can be used as monotherapy18,19). The aim of our study was to evaluate the efficacy and tolerability of TPM monotherapy in patients with newly diagnosed West syndrome.

West syndrome is one of the catastrophic epileptic syndromes of infancy and is commonly associated with poor long-term outcomes, development of other seizure types, and impaired cognitive and psychosocial functioning. Despite the clinical significance of West syndrome, complete remission of spasms is difficult to achieve and the optimal treatment remains uncertain. To date, many drugs have been tried to control seizures and were proposed as first-line therapy for West syndrome. Since Sorel and Dusaucy-Bauloye20) reported the efficacy of ACTH treatment for West syndrome, ACTH has been used as the drug of choice for many decades21). In several randomized controlled trials, ACTH was effective for the short-term treatment of West syndrome and in the resolution of hypsarrhythmia. The cessation or reduction of spasms was reported in 42 to 87% of patients who had ACTH therapy and the relapse rate varied from 15 to 36% of responders5). However ACTH therapy also has problems which include the inconvenience of administration, daily intramuscular injection and increased risk of severe adverse events such as electrolyte imbalance, hypertension, hypertrophic cardiomyopathy and secondary infection8-10).

TPM is a newer antiepileptic drug that has been widely used for control of partial and generalized tonic-clonic seizures in adults22,23). In children, TPM is used as adjunctive treatment for partial-onset seizures24) and for Lennox-Gastaut syndrome. Sachdeo et al.25) reported that TPM as adjunctive therapy for the management of Lennox-Gastaut syndrome reduced seizure rates by 33%. Recently, a few trials for TPM as a first-line drug for West syndrome have been reported. Glauser et al.14) conducted a pilot study to test the effects of TPM in patients with West syndrome who were refractory to conventional drugs. With high doses (up to 24 mg/kg/day, with a mean dose of 15.0±5.7 mg/kg/day) and rapid titration rates (raising doses every 2 to 3 days), 9 of 11 subjects, including 5 spasms-free patients, achieved a ≥50% reduction of spasms. Using the modified method of Glauser et al.14), Hsieh et al.26) conducted a study of the efficacy of TPM with lower starting doses and a slower titration rate. With a mean dose of 7.4±4.9 mg/kg/day, 11 of 13 subjects, including 5 spasms-free patients, achieved a ≥50% reduction of spasms. These studies suggested that TPM had the similar effects in the treatment of West syndrome compared to other first-line drugs.

In most studies on TPM in West syndrome, however, they used TPM as concurrent therapy with other epileptic drugs. Although Kwon et al.18) reported that 14 of 20 patients (70%) were improved (≥50% reduction of spasms after using TPM monotherapy), data on TPM monotherapy in West syndrome are still scarce. We enrolled 28 patients with newly diagnosed West syndrome and evaluated the efficacy of TPM monotherapy. A total 17 patients (61%) including 11 spasms-free patients (39%) achieved a ≥50% reduction of spasms. This result was similar to outcomes of other studies in which TPM had been used as add-on therapy14,26-28) as well as a study of TPM monotherapy18). Although there were diversities in maximal dosages of TPM among each patients who could achieve the optimal outcomes, the lower maximal dose and slower dose titration of TPM were respected to allow the assessment of the patients' responses and increased patient tolerability to the drug29). In our study, TPM was initiated at 2 mg/kg/day and titrated up to a maximal dose of 12 mg/kg/day by 2 mg/kg increments every week. The mean doses of TPM were 5.8±1.1 mg/kg/day in the group having ≥50% reduction of spasms including those who were spasms-free. The mean dosage of TPM applied in our study was relatively low compared with other reports conducted with the low dosages18,26,27) as well as high14). There was a study, however, which concluded that the mean dosage during stabilization was 5.2 mg/kg/day similar to that of our study17). In the other study30), a wide range of TPM dosage (ranges from 1.3 to 35 mg/kg/day) was reported and some patients who responded in 1 month or less did so at very low doses, 1.3 and 3.4 mg/kg/day. These results showed that the optimal dosage of TPM was not determined yet and further studies are required. Hence, we concluded that a low maximal dose and slower titration during TPM monotherapy might be effective as a first-line therapy for West syndrome.

It seems that the response rate of TPM in patients with different seizure etiologies is controversial. Although several reports showed that the patients who had cryptogenic etiology responded better to TPM than did the symptomatic patients18,31,32), different results were also reported28,33). In our study, 4 of 7 cryptogenic patients had complete disappearance of spasms and hypsarrhythmia, and 6 of 7 cryptogenic patients (85%) achieved a ≥50% reduction in seizure frequencies. In symptomatic patients, 11 of 21 patients (52%) including 7 spasms-free patients responded. There was no statistical difference between cryptogenic and symptomatic groups (P=0.208). It is presumed that the different results among studies are due to the small number of patients.

The reported adverse effects of TPM include central nervous system problems, behavioral and cognitive problems, gastrointestinal effects, weight loss, acute angle-closure glaucoma, oligohydrosis, and kidney stones34-39). These adverse effects can cause a failure or prolongation of treatment in spite of milder problems in severity than those of ACTH. Although 8 of 28 patients in our study exhibited several kinds of adverse effects (e.g., irritability, drowsiness), side effects were not severe to discontinue or reduce the dose of TPM and resolved spontaneously.

In conclusion, our results suggest that TPM is both effective and well tolerated as a first-line monotherapy for newly diagnosed West syndrome. We recommend that a low maximal dose of TPM and a slow dose titration are considered to avoid adverse effects. However, our study has limitations such as a small number of subjects and a short follow up period. Further studies will be required to determine long term outcomes of TPM monotherapy including evaluation of relapse rates and delayed side effects.