To investigate the efficacy of topiramate monotherapy in West syndrome prospectively.
The study population included 28 patients (15 male and 13 female children aged 2 to 18 months) diagnosed with West syndrome. After a 2-week baseline period for documentation of the frequency of spasms, topiramate was initiated at 2 mg/kg/day. The dose was increased by 2 mg/kg every week to a maximum of 12 mg/kg/day. Clinical assessment was based on the parents' report and a neurological examination every 2 weeks for the first 2 months of treatment. The baseline electroencephalograms (EEGs) were compared with the post-treatment EEGs at 2 weeks and 1 month.
West syndrome was considered to be cryptogenic in 7 of the 28 patients and symptomatic in 21 patients. After treatment, 11 patients (39%) became spasm-free, 6 (21%) had more than 50% spasmsreduction, 3 (11%) showed less than 50% reduction, and 8 (29%) did not respond. The effective daily dose for achieving more than 50% reduction in spasm frequency, including becoming spasm-free, was found to be 5.8±1.1 mg/kg/day. Nine patients (32%) showed complete disappearance of spasms and hypsarrhythmia, and 11 (39%) showed improved EEG results. Despite adverse events (4 instances of irritability, 3 of drowsiness, and 1 of decreased feeding), no patients discontinued the medication.
Topiramate monotherapy seems to be effective and well tolerated as a first line therapy for West syndrome and is not associated with serious adverse effects.
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 structures
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 anhydrase
For the management of West syndrome, TPM has been used as an add-on therapy to first-line drugs in most studies
A total of 28 patients with newly diagnosed West syndrome who had agreed to get TPM monotherapy between March 2007 and February 2009 were included. Subjects were required to exhibit an average of more than one cluster of spasms per day over a 2-week baseline period before TPM therapy. The following criteria were used to establish the diagnosis of West syndrome: 1) clinical seizures consistent with infantile spasms, and 2) EEG findings demonstrating hypsarrhythmia, modified hypsarrhythmia, and suppression-burst. To ensure that we obtained informed consents from the patients' parents, we provided them with detailed information about the standard treatment options for West syndrome, and the efficacy and potential side effects of TPM. Additionally, we educated them about keeping daily diaries of the occurrences of the spasms.
After a 2-week baseline period for documentation of frequency of spasms, TPM was started at a dose of 2 mg/kg/day. The dosage was increased by 2 mg/kg increments every week until spasms disappeared or a maximal dose of 12 mg/kg/day was achieved.
At 2 months after the initiation of TPM monotherapy, we analyzed all patients to measure the effectiveness and tolerability of TPM. The primary efficacy measure was a comparison of frequencies of spasms between the 2 weeks of the baseline period and the first 2 months of treatment with TPM. We also compared baseline EEGs with posttreatment EEGs done at 2 weeks and 1 month after initiation of treatment. We monitored clinical progress every 2 weeks for the first 2 months of treatment. At each visit, frequency of spasms was recorded, and complete physical and neurologic examinations were performed. We also obtained routine laboratory data, including blood cell counts, electrolyte analysis, urinalysis, and liver and renal function tests. After the first 2 months of treatment, a routine follow up schedule for each patient was offered. At each visit, adverse effects were also monitored with patients' statement and results of examination.
The statistical tool we used was the SPSS ver. 17.0 (SPSS Inc., Chicago, IL, USA). The Mann-Whitney
This study included 15 male and 13 female subjects between 2 and 18 months of age. The median age for spasm onset was 8.4 months. Flexor spasms were the most common type of spasm. Regarding etiologic factors, 7 of 28 patients (25%) had cryptogenic epilepsy and the other 21 (75%) had symptomatic causes including hypoxicischemic encephalopathy, tuberous sclerosis, pachygyria, hemorrhagic infarction and meningitis (
Overall, 11 of 28 patients (39%) had cessation of spasms at TPM doses ranging from 5 to 8 mg/kg/day. A total of 17 patients (61%), including 11 spasms-free patients, achieved ≥50% reduction in frequency of spasms compared to baseline. Regarding the etiologies of West syndrome, 4 of 7 cryptogenic patients (57%) and 7 of 21 symptomatic patients (33%) became free of spasms with TPM monotherapies (
Eight of 28 patients (29%) exhibited adverse effects during titration, stabilization or both. The most common side effect was irritability. Other adverse effects included excessive drowsiness and decreased feeding. None of the patients discontinued from TPM because of side effects.
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-Bauloye
TPM is a newer antiepileptic drug that has been widely used for control of partial and generalized tonic-clonic seizures in adults
In most studies on TPM in West syndrome, however, they used TPM as concurrent therapy with other epileptic drugs. Although Kwon et al.
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 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 stones
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.
Demographic and Clinical Characteristics of the Subjects (n=28)
HIE, hypoxic-ischemic encephalopathy; TS, tuberous sclerosis.
Seizure Outcomes after 2-Month Topiramate Monotherapy in West Syndrome
HIE, hypoxic-ischemic encephalopathy; TS, tuberous sclerosis.
Electroencephalographic Findings after Topiramate Monotherapy with Outcomes in Terms of Seizure Frequencies
TPM, topiramate; EEG, electroencephalogram.