This was a multicenter study of Japan Gabapentin Study Group no. 8J with financial research support by the sponsor, Pfizer Japan.
Treatment of partial seizures with gabapentin: Double-blind, placebo-controlled, parallel-group study*
Article first published online: 17 JUL 2006
Psychiatry and Clinical Neurosciences
Volume 60, Issue 4, pages 507–515, August 2006
How to Cite
YAMAUCHI, T., KANEKO, S., YAGI, K. and SASE, S. (2006), Treatment of partial seizures with gabapentin: Double-blind, placebo-controlled, parallel-group study. Psychiatry and Clinical Neurosciences, 60: 507–515. doi: 10.1111/j.1440-1819.2006.01553.x
- Issue published online: 17 JUL 2006
- Article first published online: 17 JUL 2006
- Received 16 February 2006; revised 10 April 2006; accepted 23 April 2006.
- adjunctive therapy;
- antiepileptic drug;
- partial seizures;
- refractory epilepsy
Abstract This double-blind study was conducted to evaluate the efficacy and safety of gabapentin 1200 mg/day and 1800 mg/day (t.i.d.) compared to placebo as an adjunctive therapy in patients with refractory epilepsy. Patients were included when they had partial seizures at least eight times during a 12-week baseline period despite treatment with one to two antiepileptic drugs. After baseline, eligible patients were randomized to gabapentin 1200 mg/day, 1800 mg/day, or placebo for 12-week treatment. The primary end-point, response ratio, was derived from seizure frequencies during treatment and baseline period based upon the seizure daily record by a patient. Of the 209 randomized patients, 86 received gabapentin 1200 mg/day, 41 received gabapentin 1800 mg/day, and 82 received placebo. A statistically significant difference was found between each of the two gabapentin groups and placebo for the primary efficacy end-point, response ratio (P < 0.005) with definite dose–response (P < 0.001). More gabapentin patients reported moderate to marked improvement in seizure frequency and intensity/duration of each seizure than placebo patients. Treatment-related adverse events were reported by approximately 65% of patients receiving gabapentin compared to approximately 46% of patients receiving placebo; somnolence and dizziness were the most common events. Gabapentin 1200 mg/day and 1800 mg/day significantly reduced the frequency of refractory seizures compared to placebo. Favorable tolerability of gabapentin was confirmed also in a Japanese population, consistent with previous global studies.
Partial seizures may occur at any age as a single episode or as a repeated, chronic disorder, accounting for almost 60% of all cases of epilepsy.1 The majority of partial seizures are complex (64%), with fewer than one-quarter presenting as simple partial seizures alone (24%) and the remaining 12% categorized as unknown.2 Among all seizure types, partial seizures have the highest incidence after the first year of life, with an age-adjusted incidence for those 1–65 years of age of approximately 20 per 100 000, a rate that is relatively constant throughout childhood and adulthood. After 65 years of age, there is an increase in the incidence of partial seizures with a rate of 98 per 100 000 in those over 75 years of age. Male subjects are affected more often than female subjects, but there is no racial or ethnic predisposition.1
Early seizure control is important for physiologic and social reasons; uncontrolled seizures may eventually lead to neuronal damage and cognitive impairment. The objective of drug therapy for epilepsy is freedom from seizures without bothersome adverse effects. However, this goal is not easily attained, especially with the old antiepileptic drugs (AED). Prior to the 1990s, there were limited numbers of major AED available for the treatment of all forms of epilepsy. These included phenobarbital, phenytoin, valproic acid, primidone, and carbamazepine. In 1985, Mattson et al. conducted a 2-year study in 622 adults with partial and secondarily generalized tonic–clonic seizures in which patients were randomly assigned to phenytoin, carbamazepine, primidone, and phenobarbital.3 Results indicated that only 39% of patients achieved total seizure control at 12 months with these old AED. Consequently, many patients have required treatment with two or more AED. Also in Japan, it is recognized that approximately 30% of patients do not achieve adequately controlled status with drug therapy utilizing the old AED. Thus, the need for new therapeutic options, especially for a new AED, is essential not only to improve medical care, but also to achieve better quality of life.
Over the past decade, a number of new AED have been approved in Europe and the USA for patients with seizure disorders, including gabapentin, lamotrigine, topiramate, tiagabine, oxcarbazepine, levetiracetam, zonisamide, and pregabalin. In contrast, no new AED have been available in Japan except for zonisamide, which was originally developed in Japan in the 1980s. Of the new AED listed here, gabapentin was first approved in the UK and the USA in 1993 as an adjunctive therapy for the treatment of partial seizures with and without secondary generalization in patients over 12 years of age, and in pediatric patients later.
Outside Japan, three pivotal double-blind, placebo-controlled studies have been conducted. Each has demonstrated a statistically significant decrease in seizure frequency for gabapentin patients compared to placebo patients.4–6 In addition, there was a 25% overall gabapentin responder rate, defined as the percentage of patients with ≥50% decrease in seizure frequency.7 A phase II Japanese trial for gabapentin demonstrated a responder rate of approximately 22–24% when used as an adjunctive therapy in patients with refractory epilepsy receiving no more than three existing AED. The present phase III study was performed in Japan to confirm the efficacy, safety, and tolerability of gabapentin 1200 mg/day and 1800 mg/day compared to placebo.
This double-blind, placebo-controlled study was carried out for patients with partial seizures inadequately controlled with existing AED in order to evaluate the efficacy and safety of the adjunctive therapy with gabapentin 1200 mg/day and 1800 mg/day. This study was conducted between March 2000 and October 2002 by the Japan Gabapentin Study Group no. 8J at 54 sites. The investigators of these sites are listed in Appendix I. The protocol was approved by the institutional review board at each site or an external review board. Prior to enrollment, each subject or legal guardian, if applicable, signed an informed consent.
Enrolled subjects were men and non-pregnant women who were at least 16 years of age with partial seizures as defined by criteria developed by the International League Against Epilepsy.8 Inpatients or outpatients weighing 40–110 kg were eligible if they were on a stable dose of no more than two AED. Patients were excluded from the study if they had evidence of unstable diseases, such as progressive lesions in the central nervous system, encephalopathy, or histological lesions as detected by magnetic resonance imaging or computed tomography scan conducted in the previous 2 years. Also excluded were nursing mothers, persons wishing to become pregnant, persons who had received an investigational drug in the previous 3 months, and persons with a history of alcohol or drug abuse in the previous 3 years. Finally, persons with certain predefined abnormal laboratory values (blood urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, total bilirubin ≥2-fold upper limit of normal; white blood cells <3000/mm3 or neutrophils <1500/mm3) were excluded from this study.
Patients who had at least eight partial seizures during the 12-week baseline period were eligible. They were randomized in a ratio of 2:1:2 to receive either gabapentin 1200 mg/day (t.i.d.), gabapentin 1800 mg/day (t.i.d.), or placebo, respectively (i.e. 80, 40, and 80 subjects in each group), for a 12-week treatment period. During an initial titration period, gabapentin-treated patients received 200 mg t.i.d. (600 mg/day) on day 1, 400 mg t.i.d. (1200 mg/day) on day 2, and for those receiving 1800 mg/day, a further increase to 600 mg t.i.d. was made on day 3. Patients continued to receive doses of 1200 mg/day or 1800 mg/day for the remainder of the 12-week treatment period. Placebo-treated patients received capsules identically matched to 200 mg capsule used for gabapentin. After 12 weeks treatment, a dose-reduction period lasting 8 days−4 weeks was instituted; this was followed by a 4-week post-dosing observation period. Patients were to be seen every 4 weeks throughout the study. The dosing regimen of AED used before the study was not to be modified throughout the trial. Concomitant medication to treat conditions other than seizures could be administered (i) without any later alteration of dose; or (ii) for temporary use, as for a cold.
Seizure frequency, that is, number of partial seizures per 28 days, was determined based on the seizure daily record that each patient kept on occurrence and type of seizures. The primary end-point was response ratio (RRatio). It was calculated according to the formula: RRatio = (T – B)/(T + B), where T and B are the seizure frequencies during treatment and during baseline, respectively. The RRatio can range from −1 to +1, with negative numbers indicating reduction in seizure frequency and zero indicating no change. Percent change from baseline in seizure frequency (PCH) was calculated according to the formula: PCH (%) = 100(T – B)/B; PCH is linked to RRatio by the formula: PCH (%) = 200 RRatio/(1–RRatio). Thus, the RRatio represents a robust transformation of PCH that permits use of parametric statistical methodology due to normalization of the data distribution.9 The responder rate, that is, the percentage of patients with an RRatio of ≤ −0.333, equivalent to a ≥50% reduction in seizures compared to the baseline, was also calculated.
Improvement in seizure frequency was categorized into six grades based on the PCH: completely resolved (−100%), markedly improved (−99.9 to −75.0%), moderately improved (−74.9 to −50%), slightly improved (−49.9 to −25%), no change (−24.9 to 0%), and aggravated (>+0.1%). Based on the subject’s report on seizure conditions, changes from baseline in seizure intensity/duration at 4, 8, and 12 weeks were rated by the investigator as better (1 point), no change (0 points), and worse (−1 point) compared to baseline. An overall change in seizure intensity/duration was categorized into three grades: better (1, 2 or 3 points derived from the summed scores from weeks 4, 8, and 12), no change (0 points), and worse (−1, −2, or −3 points).
The sample size for the study was determined from the RRatio obtained in the previous studies, where means of RRatio for placebo and gabapentin 1200 mg/day were −0.037 and −0.167, respectively. The primary efficacy analysis was the RRatio for the gabapentin 1200 mg/day group compared to the placebo group using an analysis of variance (anova), where the model includes the treatment. In a secondary analysis, the RRatio for the gabapentin 1800 mg/day group was compared with that for the placebo group. For evaluating dose–response relationship based on the RRatio and responder rate, the max t method10 was used, which tests the equality of means against the simple ordered alternative in a one-way anova model. A monotonic dose–response relationship can be concluded when the significance is observed. Finally, the responder rate in each group was evaluated by Fisher’s exact test. All efficacy analyses presented are for the cohort of the per-protocol set (PPS), defined as patients who met the inclusion criteria but none of the exclusion criteria. Reported P are two-tailed with a significance level of 0.05.
Safety was assessed based on evaluation of adverse events, clinical laboratory tests (chemistry, hematology, and urinalysis), and vital signs (blood pressure, heart rate, and weight). Furthermore, blood concentrations of concomitant AED were measured at −8, −4, 0, 4, 8, and 12 weeks to evaluate drug interaction as well as gabapentin at weeks 4, 8, and 12 under blind conditions. Safety analyses included all patients who entered the study and received at least one dose of study drug.
Two hundred and nine patients were randomized, including 86 patients in the gabapentin 1200 mg/day group, 41 in the gabapentin 1800 mg/day group, and 82 in the placebo group. Of the 209 patients, 194 (92.8%) completed the study; 15 patients withdrew prematurely due to aggravation of seizures (three in placebo), safety reasons (one placebo, four gabapentin 1200 mg/day, three gabapentin 1800 mg/day), and administrative reasons (two placebo, one gabapentin 1200 mg/day, one gabapentin 1800 mg/day). Demographics and disease state characteristics were balanced across treatment groups at baseline (Table 1).
|Gender, n (%)|
|Male||42 (51.2)||37 (43.0)||22 (53.7)|
|Female||40 (48.8)||49 (57.0)||19 (46.3)|
|Mean ± SD||31.8 ± 11.3||31.3 ± 10.6||32.7 ± 13.7|
|Bodyweight (kg) (mean ± SD)||59.3 ± 11.5||59.4 ± 11.1||62.1 ± 11.4|
|Type of seizure (n/%):|
|SP||44 (58.7)||44 (55.0)||18 (51.4)|
|CP||67 (89.3)||66 (82.5)||30 (85.7)|
|SG||25 (33.3)||21 (26.3)||13 (37.1)|
|Duration of epilepsy† (years)|
|Baseline seizure (per 28 days)|
|Concomitant AED, n (%)|
|One||16 (19.5)||12 (14.0)||2 (4.9)|
|Two||66 (80.5)||74 (86.0)||39 (95.1)|
Approximately half of the patients were female (51.7%), and the majority was between 18 and 44 years of age with a mean age across the three groups of 31–33 years. Most patients had complex partial seizures with a mean duration across the three groups of 20–21 years. Baseline median seizure frequency was comparable among the three treatment groups, ranging from 10 to 12 seizures per 28 days in the 12-week baseline period despite treatment with two AED by more than 85% of patients (179/209).
Under blinded review, data were excluded from the PPS cohort for 19 patients. The major reason for exclusion was treatment duration <56 days for 14 patients. The remaining five patients were excluded because of (i) administration compliance <90% (three patients); (ii) seizure frequency <8 during 12-week baseline (one patient); and (iii) addition of another AED during the treatment period (one patient).
The primary efficacy, RRatio between each of the two gabapentin groups and placebo, was statistically significantly different at end-point (P < 0.005; Fig. 1). In addition, responder rates were 20.0% in the gabapentin 1800 mg/day group, compared to 6.7% in placebo group (Table 2). Median seizure frequency decreased during treatment with gabapentin but not with placebo (Fig. 2). Dose–response was also demonstrated based upon results for the RRatio (P = 0.0008) and responder rate (P = 0.0418). Gabapentin patients demonstrated greater improvement in seizure frequency than placebo patients, as well as in seizure intensity/duration (gabapentin 1200 mg/day, 45.0%; gabapentin 1800 mg/day, 45.7%; placebo, 33.3%). Subpopulation analyses on the RRatio demonstrated no special effects of sex, age, bodyweight, duration of epilepsy, seizure frequency in baseline, seizure type, and number of concomitantly used AED on the efficacy of gabapentin.
|Efficacy parameters||Placebo (n = 75)||Gabapentin|
|1200 mg/day (n = 80)||1800 mg/day (n = 35)|
|% change in partial seizures†|
|Responder rate‡, n (%)||5 (6.7)||13 (16.3)||7 (20.0)|
|Improvement in seizure frequency§, n (%)|
|Markedly improved||0||2 (2.5)||1 (2.9)|
|Moderately improved||5 (6.7)||11 (13.8)||6 (17.1)|
|Slightly improved||17 (22.7)||22 (27.5)||13 (37.1)|
|No change||23 (30.7)||29 (36.3)||7 (20.0)|
|Worse||30 (40.0)||16 (20.0)||8 (22.9)|
|Improvement in seizure intensity/duration¶, n (%)|
|Better||25 (33.3)||36 (45.0)||16 (45.7)|
|No change||40 (53.3)||39 (48.8)||17 (48.6)|
|Worse||7 (9.3)||5 (6.3)||2 (5.7)|
Treatment-related adverse events were reported by more than half of all patients, including 46.3% of placebo patients, 64.0% of gabapentin 1200 mg/day patients, and 65.9% of gabapentin 1800 mg/day patients (Table 3). Consistent with the safety profile of gabapentin shown in the previous study,4–6 the most common adverse events were somnolence (44–51%) and dizziness (19–20%). Of note, placebo patients receiving other AED, also reported somnolence (20.7%) and dizziness (4.9%).
|Placebo n (%)||Gabapentin (mg/day)|
|1200 n (%)||1800 n (%)|
|No. patients with events (%)||38 (46.3)||55 (64.0)||27 (65.9)|
|Somnolence||17 (20.7)||44 (51.2)||18 (43.9)|
|Dizziness||4 (4.9)||16 (18.6)||8 (19.5)|
|Headache||4 (4.9)||5 (5.8)||3 (7.3)|
|Diplopia||3 (3.7)||4 (4.7)||2 (4.9)|
|Nausea||1 (1.2)||3 (3.5)||1 (2.4)|
|Malaise||3 (3.7)||1 (1.2)||0|
|Epilepsy aggravated||3 (3.7)||0||0|
Serious treatment-related adverse events were reported for two gabapentin patients: ataxic gait, nystagmus, dizziness, ataxia and leg pains appeared in one patient receiving gabapentin 1200 mg/day, and seizures and dizziness appeared in another patient receiving gabapentin 1800 mg/day. The former was admitted to the hospital longer than originally expected due to the cerebellar ataxia, which disappeared with reduction of the phenytoin dose. The latter was admitted to the hospital due to dizziness and complex partial seizures associated with dyslalia, which disappeared with reduction of the phenytoin dose.
Mean serum levels of carbamazepine, phenytoin, and valproate, major AED concomitantly used in the present study, were kept nearly constant during the treatment period and consistent with baseline (Fig. 3). No statistical significance was detected over the time for each treatment group with each AED, using repeated measures analysis of variance with the general linear model procedure in sas version 8.02 (SAS Institute, Cary, NC, USA). Furthermore, plasma concentrations of gabapentin were also kept almost constant without any statistical significance by the same method with measurements at 4, 8 and 12 weeks (data not shown). There were no clinically meaningful differences among the treatment groups with regard to laboratory abnormalities. Discontinuation rates due to adverse events or laboratory test abnormalities were 5.5% for gabapentin-treated patients (7/127) compared to 1.2% for placebo-treated patients (1/82).
The study demonstrated that 1200 mg/day and 1800 mg/day gabapentin significantly reduced the frequency of refractory partial seizures compared to placebo and that there was a definite dose–response relationship for this effect. Gabapentin was the third added AED for major subjects, indicating that the study population was characterized with refractory epilepsy. In this dose range, tolerability of gabapentin was acceptable.
From the viewpoint of mode of action, affinity of gabapentin for the α2δ subunit of the voltage-dependent Ca2+ channel suggests that modulation of the Ca2+ channels may be important to the antiepileptic action of gabapentin.11 Gabapentin does not have a direct effect on voltage-dependent sodium channels, γ-aminobutyric acid (GABA)A-, GABAB-, N-methyl-d-aspartate-, glutamate-, and glycine-receptors.7 Gabapentin increases the concentration and probably the rate of synthesis of GABA.12 Adjunctive therapy of gabapentin could be partly justified by this novel profile of pharmacology.
The efficacy data from this study are consistent with those reported elsewhere for gabapentin when it was used as an adjunctive therapy in patients with refractory partial seizure disorder.4–6 In the previous studies, the RRatios were comparable to results observed in the current study (1200 mg/day: −0.192 to −0.118 for previous studies, −0.144 for the present study; 1800 mg/day: −0.233 for the previous study, −0.160 for the present study; placebo: −0.025 to −0.060 for previous studies, −0.037 for the present study).4–7 In addition, results from the present study demonstrated that gabapentin is not only effective in reducing seizure frequency, but it is also safe and well-tolerated. These findings are particularly significant given the relatively short 1–2-day titration period and low rate of discontinuation.
There are several factors a physician needs to take into account when selecting an AED for a patient. As noted previously, the choice of AED was limited prior to the 1990s. The old AED have the advantage of familiarity, known efficacy, and long-term experience but they also are associated with significant side-effects. Perhaps one of the most significant differences between the old and new AED is the more favorable pharmacokinetic profile of the newer ones. Old products share many of the same complex pharmacokinetic characteristics.13 For example, phenytoin, carbamazepine, and valproate are highly protein bound; phenytoin, carbamazepine, phenobarbital, and primidone are hepatic enzyme inducers, which may also cause a profound effect in terms of drug–drug interactions.13 In contrast, gabapentin is (i) not protein-bound (<5%); (ii) neither an inducer nor an inhibitor of hepatic enzymes (CYP 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, 3A4); (iii) not metabolized by hepatic enzymes; and (iv) excreted unchanged in urine with plasma clearance linearly related to creatinine clearance. This profile may make gabapentin a recommended treatment as an adjunctive therapy.14 In fact, less potential of gabapentin for drug–drug interaction was shown in the present study (Fig. 3). An investigation on medical practice for epilepsy showed that gabapentin is positioned as a second-line therapy for simple partial seizures.15 In another review, gabapentin is recommended as an adjunctive therapy in refractory epilepsy as well as lamotrigine, tiagabine, topiramate, oxcarbazepine, levetiracetam, zonisamide, and pregabalin.16
For a comparison of the safety and tolerability of new AED, 1222 patients who were receiving more than 1200 AED regimens were reviewed for the incidence of rash.17 The incidence was highest for patients receiving phenytoin (9.4%), carbamazepine (6.6%), oxcarbazepine (6.1%), and lamotrigine (5.6%); rates were lowest for patients receiving gabapentin (0.2%) and topiramate (0%). Data from 1286 patients were also reviewed for the incidence of psychiatric side-effects.18 These effects were reported most commonly in patients receiving levetiracetam (16%) and resulted in dosage or medication change in many (11.1%). In order of frequency, topiramate (7.9%), oxcarbazepine (5.7%), felbamate (4.6%), and lamotrigine (3.9%) were also associated with psychiatric effects; gabapentin had the lowest incidence (2%). Thus, historical data in Western markets as well as data from the present study in a Japanese population confirm that gabapentin is both safe and effective when used as an adjuvant therapy in patients with refractory partial seizures.
The discontinuation rate due to safety reasons among gabapentin patients (5.5%) seen in the present study can be recognized as low. The current study attests to gabapentin’s efficacy, tolerability, and low incidence of side-effects. Moreover, gabapentin has an advantageous pharmacokinetic profile that limits its potential for drug–drug interactions when compared to traditional AED.7 Gabapentin is a drug of choice for adjunctive therapy for partial seizures.
- 10Isotonic inference. In : ArmitageP, ColtonT (eds). Encyclopedia of Biostatistics, Vol. 3. John Wiley & Sons, New York, 1998; 2107–2115..
- 13Efficacy and tolerability of the new antiepileptic drugs I: treatment of new onset epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004; 62: 1252–1260., , et al.
- 16Efficacy and tolerability of the new antiepileptic drugs II: treatment of refractory epilepsy: Report of the Therapeutics and Technology Assessment Subcommittee and Quality Standards Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 2004; 62: 1261–1273., , et al.
- 172004., , et al. Comparative incidence of rash related to twelve antiepileptic drugs: results from the Columbia antiepileptic drug database. Program and Abstracts of the American Academy of Neurology 56th Annual Meeting, San Francisco, California, Abstract S41.003,
- 182004., , et al. Psychiatric side effects of the newer antiepileptic drugs: results from the Columbia antiepileptic drug database. Program and Abstracts of the American Academy of Neurology 56th Annual Meeting, San Francisco, California, Abstract P04.085,
Members of the Japan Gabapentin Study Group 8J included the following investigators. For each site, the principal investigator is listed first, followed by subinvestigators. Y. Takeda, F. Nakamura, J. Shiraki, J. Honma (Hokkaido University School of Medicine, Sapporo); M. Mizobuchi (Nakamura Memorial Hospital, Sapporo); K. Hashizume, A. Sawamura, K. Yoshida (Asahikawa Medical College School of Medicine, Asahikawa); H. Fujita, H. Muranaka (Hirosaki University School of Medicine, Hirosaki); T. Kondo, K. Wada (Hirosaki University School of Medicine, Hirosaki); N. Koide (Iwaki National Hospital, Namioka, Aomori); H. Yokoyama (Tohoku University School of Medicine, Sendai); N. Nakasato (Kohnan Hospital, Sendai); T. Soga (Bethel Hospital, Iwanuma, Miyagi); S. Niwa, R. Kan, Y. Miyamoto, M. Uejima, M. Watabe (Fukushima Medical University School of Medicine, Fukushima); T. Akada (Gunma University School of Medicine, Maebashi); K. Nishijima, K. Takano (Jichi Medical School Hospital, Minamikawachi, Tochigi); T. Nakano (Dokkyo University School of Medicine); S. Mine (Chiba University School of Medicine, Chiba); T. Sassa, K. Hara, Y. Okubo, H. Takahashi, I. Ito (Asai Hospital, Togane, Chiba); H. Watanabe, Y. Nagahori (Tokyo Metropolitan Police Hospital, Tokyo); T. Hori, F. Yamane, K. Hirasawa (Tokyo Women’s Medical University, Tokyo); M. Osawa, H. Oguni (Tokyo Women’s Medical University, Tokyo); I. Suzuki (Japanese Red Cross Medical Center, Tokyo); A. Haba, A. Kawana (Toho University Omori Medical Center, Tokyo); S. Hara (Keio University School of Medicine) H. Shimizu (Tokyo Metropolitan Fuchu Hospital, Fuchu); M. Kato, M. Okazaki, T. Onuma (Musashi Hospital, National Center of Neurology and Psychiatry, Kodaira); Y. Koga (Kyorin University School of Medicine); M. Saito, M. Inami (Kitasato University East Hospital, Sagamihara); H. Miura, W. Sunaoshi (Kitasato University Hospital, Sagamihara); T. Tottori, Y. Inoue, K. Fukushima, T. Kudo, M. Kageyama (Shizuoka Institute of Epilepsy and Neurological Disorders, Shizuoka); M. Sasagawa, M. Wachi, O. Kanazawa, K. Tanaka (Nishi-Niigata Chuo National Hospital, Niigata); M. Murata, Y. Hasegawa (Toyama Medical and Pharmaceutical University Hospital, Toyama); I. Jibiki (Kanazawa Medical University); G. Hirose (Kanazawa Medical University); T. Fukuchi (Fukuchi Clinic, Nagoya); J. Kawasaki (Utano National Hospital, Kyoto); T. Isotani (Kansai Medical University Hospital, Moriguchi); S. Ukai, K. Yamashita (Osaka University School of Medicine, Suita); K. Imai, K. Shimono (Osaka University School of Medicine, Suita); T. Hoshida (Nara Medical University, Kashihara); K. Murata (Nara Medical University, Kashihara); E. Oka, N. Murakami, Y. Otsuka (Okayama University Medical School, Okayama); K. Kurisu, R. Hanaya (Hiroshima University School of Medicine, Hiroshima); S. Kondo (Tottori University School of Medicine, Yonago); K. Moritake, H. Nagai (Shimane University School of Medicine, Izumo); T. Akimura (Yamaguchi University School of Medicine, Ube); K. Kamikaseda, T. Araki, Y. Taniwaki (Kaizuka Hospital, Fukuoka); J. Kira, H. Kikuchi (Kyushu University School of Medicine, Fukuoka); T. Morioka (Kyushu University School of Medicine, Fukuoka); Y. Mori (Kyushu University School of Medicine, Fukuoka); A. Mitsudome, A. Ogawa, M. Ohfu (Fukuoka University School of Medicine, Fukuoka); N. Akamatsu (University of Occupational and Environmental Health School of Medicine, Kitakyushu); S. Ishida (Kurume University School of Medicine, Kurume); M. Matsushima (Saga University School of Medicine, Saga); Y. Kuroda, H. Takashima, M. Yukitake (Saga University School of Medicine, Saga); H. Baba (National Hospital Organization Nagasaki Medical Center, Ohmura); T. Ishitsu (Kumamoto Saisyunsou Hospital, Nishigoushi).