Significance of High-frequency Electrical Brain Activity.

　Electroencephalogram (EEG) data include broadband electrical brain activity ranging from infra-slow bands (< 0.1 Hz) to traditional frequency bands (e.g., the approx. 10 Hz alpha rhythm) to high-frequency bands of up to 500 Hz. High-frequency oscillations (HFOs) including ripple and fast ripple oscillations (80-200 Hz and>200 / 250 Hz, respectively) are particularly of note due to their very close relationship to epileptogenicity, with the possibility that they could function as a surrogate biomarker of epileptogenicity. In contrast, physiological high-frequency activity plays an important role in higher brain functions, and the differentiation between pathological / epileptic and physiological HFOs is a critical issue, especially in epilepsy surgery. HFOs were initially recorded with intracranial electrodes in patients with intractable epilepsy as part of a long-term invasive seizure monitoring study. However, fast oscillations (FOs) in the ripple and gamma bands (40-80 Hz) are now noninvasively detected by scalp EEG and magnetoencephalography, and thus the scope of studies on HFOs /FOs is rapidly expanding.

Importance of the multisystem follow-up in patients with tuberous sclerosis complex.

Objective: Tuberous sclerosis complex (TSC) is a multisystem disorder characterized by the formation of hamartoma in multiple organ systems of the body. However, without a well-established cooperative system involving related departments, some organ lesions might be overlooked until symptoms appear or even until the disorder progresses. Therefore, the purpose of this study is to investigate the current status of follow-ups in the TSC patients in the Department of Child Neurology at Okayama University Medical Hospital. Methods: We performed a retrospective chart review of 38 patients with TSC who visited our hospital at least twice between January 2005 and December 2014. Patients were between 3 years and 48 years of age at their latest visit. We divided the patients into a child group and an adult group, and investigated the patients' follow-up data while focusing on the various multiorgan systems. Results: The follow-ups were well conducted in the child group in terms of every organ. In the adult group, neuroimaging tests were unsatisfactorily performed. The kidney has not been examined in seven patients more than five years even though these patients all had kidney lesions. The lung was not been examined in 7 out of 14 female patients over 18 years of age who are most at risk for lymphangioleiomyomatosis (LAM). In 12 out of 18 child patients, echocardiograms were performed every few years, while electrocardiograms to assess underlying conduction defects were rarely performed in either age group. Conclusions: In Europe, guidelines for the management of TSC have been well established. However, in our hospital, the multiorgan system follow-up is not satisfactorily performed especially in adult patients. We decided the establishment of a TSC board in our hospital for the management of this multiorgan disorder.

A storm of fast (40-150Hz) oscillations during hypsarrhythmia in West syndrome.

OBJECTIVE: Fast oscillations (FOs) were first explored from scalp electroencephalographic (EEG) data from hypsarrhythmia in West syndrome (infantile spasms) to investigate the meaning of FOs in this epileptic encephalopathy. METHODS: In 17 infants with West syndrome, we conservatively detected fast frequency peaks that stood out from the time-frequency spectral background with square root power > 1µV (spectral criterion) and corresponded to clear FOs with at least 4 oscillations in the filtered EEG traces (waveform criterion) in sleep EEGs. RESULTS: We found a total of 1,519 interictal FOs that fulfilled both the spectral and waveform criteria. The FOs with a median frequency of 56.6Hz (range = 41.0-140.6Hz) were dense, with a median rate of 66 (range = 24-171) per minute before adrenocorticotropic hormone (ACTH) treatment, which was significantly higher than that in control infants without seizures (median = 1, p < 0.001). The FOs were reduced by treatment. The mean gamma and ripple oscillation rates that were detected using the waveform criterion alone were 40.62/min and 15.75/min, respectively, per channel; these results were 112.8 and 98.4 times higher, respectively, than the previously reported corresponding rates in adult epilepsy patients. INTERPRETATION: The observed FOs corresponded to epileptogenicity because of their close relation to the severity of hypsarrhythmia during the course of ACTH treatment. The very high epileptic FO rates in hypsarrhythmia are thought to affect the process of neurodevelopment by interfering with physiological functions in West syndrome, taking into account that high frequencies are also important in physiological higher brain functions.

Questionnaire-based assessment of behavioral problems in Japanese children with epilepsy.

Behavioral problems in Japanese children with epilepsy were investigated by means of a questionnaire for parents consisting of three checklists: the Child Behavior Checklist (CBCL)/4-18 Japanese Edition, the High-Functioning Autism Spectrum Screening Questionnaire (ASSQ), and the Attention-Deficit/Hyperactivity Disorder (ADHD) Rating Scale-IV (ADHD-RS) for parents. The participants were the parents of 108 children aged 6-18 years with apparently normal intelligence. The CBCL indicated abnormal behavior in 10.5 to 35.6% of the children, and T scores on both the internalizing and externalizing scales had a significant positive relation with scores on the ASSQ and ADHD-RS. It was revealed through multivariate logistic regression analysis that the persistence of seizures was significantly related with abnormality on the externalizing scale of the CBCL (p=0.010, odds ratio: 3.48, 95% confidence interval: 1.34-9.02). Future studies are needed to determine whether seizure freedom improves behavior in children with epilepsy.

[Peculiar involuntary movements in premature babies with specific cerebellar injuries].

We observed characteristic involuntary movements in premature babies during early infancy. These movements consisted of asymmetrical irregular banging of the extremities, similar to chorea, ballisms, or jitteriness. We investigated the clinical characteristics and neuroimaging findings of the patients with these peculiar involuntary movements to clarify their pathophysiological mechanisms and to find a treatment. In our sequential follow-up study on 90 premature infants with various pre-and perinatal brain insults, we found various types of cerebellar injuries in 28 patients. In 19 of these, the prominent injuries were observed in the inferior cerebellar hemispheres. These cerebellar injuries were often observed in patients born before the gestational age of 27 weeks. Fourteen of the 28 patients with cerebellar injuries displayed the above-mentioned characteristic involuntary movements. Twelve of these 14 patients with both cerebellar injury and involuntary movements were born before the gestational age of 27 weeks. On the contrary, 10 patients with cerebellar injury born after the gestational age of 27 weeks did not display these peculiar involuntary movements. It is noteworthy that cerebral injuries were not associated with the occurrence of these involuntary movements. Two patients with asymmetrical cerebellar deformity caused by compression due to a cystic lesion did not show these involuntary movements. The movements appeared around the corrected age of 3 months, and they disturbed the patients' acquisition of sitting ability. Nine patients with these involuntary movements developed severe athetotic cerebral palsy. These movements showed drug resistance, however, benzodiazepines had a partial effect in some patients. Recently, cerebellar injury in premature infants has received a lot of attention. We believe that the peculiar involuntary movements we observed in the present patient group may be caused by a particular type of cerebellar damage specific to premature infants born before 27 weeks of gestational age.

[Lamotrigine add-on therapy for childhood-onset refractory epilepsy: comparison of the efficacy between 3 months and 6 months after initiation].

We investigated the effect of lamotrigine (LTG) add-on therapy in 50 patients with childhood-onset refractory epilepsy (25 males and 25 females): 15 with localization-related epilepsy, 33 with generalized epilepsy, and 2 with undetermined epilepsy. Twenty-four patients had experienced a period of West syndrome during their clinical course. Age at the start of LTG therapy ranged from 2 years 6 months to 41 years 2 months: <16 years in 43 and > or = 16 years in 7. Seizure frequency was > or = 1 per day in 36 patients (72%) and > or = 1 per week in 14 (28%). We increased the LTG dosage every two weeks in accordance with usage recommendations. We evaluated efficacy at two points: 3 and 6 months after the start of LTG. At the 6-month point, seizure freedom was achieved in 2 patients (4%), > or = 50% seizure reduction in 14 (28%), 25 to 50% seizure reduction in 20 (40%), no effect in 6 (12%), and aggravation in 4 (8%). Only 4 patients (8%) stopped LTG therapy within 6 months due to LTG-related mild skin rash in 2 and suspicion of seizure aggravation in the other 2. In terms of seizure types, seizure freedom or > or = 50% seizure reduction was achieved in 29% for epileptic spasms, 32% for tonic seizures, and 29% for partial seizures. A comparison between the 3- and 6-month points revealed that the efficacy level was increased or maintained in 77% of the patients and decreased in 23%. In most cases, the highest level of efficacy appeared within 3 months with doses that were smaller than maintenance doses. Observed CNS-related adverse effects included somnolence in 16 patients, irritability in 14, and sleep disturbance in 11. Positive psychotropic effects in daily activities were seen in 28 patients (56%). These effects appeared regardless of the change in seizure frequency with doses that were smaller than maintenance doses.

[Treatment of adult patients with childhood-onset epilepsy by child neurologists].

A significant number of patients with childhood-onset epilepsy continue to be treated by child neurologists after reaching adulthood. In this article, the issue of these so-called carry-over cases is discussed based on the results of two studies: our previous study on carry-over patients at the Department of Child Neurology, Okayama University Hospital, and a questionnaire survey on carry-over cases by the Japan Epilepsy Society. These two studies revealed that child neurologists currently treat many carry-over epilepsy patients in Japan, and that these patients, even those who have low seizure frequencies or are in remission, suffer from many problems such as comorbidities and socioeconomic difficulties. To ameliorate these problems, a comprehensive care system should be established, based on cooperation between various kinds of doctors and comedical staff members.

Action of antiepileptic drugs on neurons.

The recent development of various new antiepileptic drugs (AEDs) has provided a wide range of therapeutic strategies for epilepsy. Information regarding the mechanisms of the action of AEDs is valuable when selecting drugs for individual epilepsy patients. AEDs can be categorized as those acting at the excitatory synapse, at the inhibitory synapse, on the extrasynaptic neuronal membrane, or with multiple or miscellaneous mechanisms of action. We herein briefly summarize and illustrate the action of AEDs on neurons and related findings that are pertinent to the clinical aspect of epileptology.

Longitudinal correspondence of epilepsy and scalp EEG fast (40-200 Hz) oscillations in pediatric patients with tuberous sclerosis complex.

INTRODUCTION: Epilepsy associated with tuberous sclerosis complex (TSC) has very complex clinical characteristics. Scalp electroencephalogram (EEG) fast (40-200 Hz) oscillations (FOs) were recently suggested to indicate epilepsy severity. Epileptic FOs may undergo age-dependent longitudinal change in individual patients, however, and the typical pattern of such change is not yet fully clarified. We therefore investigated the age-related correspondence between clinical courses and FOs in pediatric patients with TSC-associated epilepsy. SUBJECTS AND METHODS: FOs were semi-automatically detected from scalp sleep EEG data recorded from 23 children (15 boys, 8 girls; initial data obtained at <10 years of age) with TSC-associated epilepsy. RESULTS: The number of FOs per patient that were associated with spikes was significantly greater than that of FOs unassociated with spikes (median 145 and 5, respectively; p = 0.0001 by the Wilcoxon signed-rank test). In the eight patients who had West syndrome (WS) in infancy, FOs associated with spikes were abundant during the WS period prior to adrenocorticotropic hormone therapy, with significantly greater numbers of FOs compared to the post-WS period (median 242 and 0, respectively; p = 0.0078). As there was no such time-dependent difference regarding FOs unassociated with spikes, FOs associated with spikes were identified as epileptic. The detected FOs included both gamma and ripple oscillations with no consistent age-dependent shifts in dominant frequency. There were no apparent age-related changes in FO duration. CONCLUSIONS: Epileptic scalp FOs are confirmed to correspond to severity of epileptic encephalopathy, particularly in WS, even during the long-term evolutional courses of TSC-associated epilepsy.

Detection of fast (40-150 Hz) oscillations from the ictal scalp EEG data of myoclonic seizures in pediatric patients.

OBJECTIVE: We explored fast (40-150 Hz) oscillations (FOs) from the ictal scalp electroencephalogram (EEG) data of myoclonic seizures in pediatric patients to obtain insight into the pathophysiological mechanisms involved in the generation of myoclonic seizures. SUBJECTS AND METHODS: The participants were 21 children (11 boys, 10 girls; age ranging from 5 months to 17 years 2 months) with myoclonic seizures associated with generalized (poly)spike-wave bursts in the ictal EEG data. The patients had heterogeneous etiologies and epilepsy diagnoses. In the ictal data, we detected FOs that clearly showed oscillatory morphology in filtered EEG traces and an outstanding spectral blob in time-frequency analysis. RESULTS: We identified FOs in 61 (88.4%) of all 69 myoclonic seizures. Every patient had at least one myoclonic seizure-associated FO. The observed FOs were embedded in the spike component of (poly)spike-wave discharges, and they had a focal distribution with frontal predominance. They ranged in frequency from 41.0 to 123.0 Hz and involved both the gamma and ripple bands, and their spectral peak frequencies were higher in the group of patients with a genetic background free of apparent fundamental brain pathology than in the group of other patients (p = 0.019). CONCLUSION: FOs were found to represent at least part of the cortical pathophysiological process in the generation of myoclonic seizures that should involve the thalamocortical network system.

Electroencephalographic changes before the onset of symptomatic West syndrome.

To clarify the characteristics of the mode of appearance and morphology of epileptiform discharges before the onset of West syndrome (WS). The subjects were 25 infants whose electroencephalograms (EEGs) were recorded before the onset of WS and whose first EEG was recorded before 6 months of corrected age (CA). We extensively analyzed the chronological and topographical changes of the epileptiform discharges before the onset of WS. The location of the initial epileptiform discharges was in the posterior areas in 14 (Group O), the multiple areas in 7 (Group M), and areas other than occipital in 4 (Group non-O). Twelve of the 14 patients in Group O were premature infants, and all but one had PVL. Most patients in Group M were full-term infants or near full-term infants who had hypoxic damage. The ages at the appearance of the initial epileptiform discharges in Group O were significantly later than those in Group M: 3.0-5.9 months of CA in Group O vs. -0.1 to 2.0 months of CA in Group M. These facts suggest that the difference of brain damage is related to both the topographical characteristics and the age at the appearance of initial epileptiform discharges, and around 3 months of CA is a critical period for the appearance of occipital hyperexcitability. Hypsarrhythmia and tonic spasms appeared almost simultaneously from 4 to 6 months of CA in most patients. To predict the occurrence of WS in high-risk infants, EEG follow-ups from early infancy are very useful.

Complex observation of scalp fast (40-150 Hz) oscillations in West syndrome and related disorders with structural brain pathology.

We investigated the relationship between the scalp distribution of fast (40-150 Hz) oscillations (FOs) and epileptogenic lesions in West syndrome (WS) and related disorders. Subjects were 9 pediatric patients with surgically confirmed structural epileptogenic pathology (age at initial electroencephalogram [EEG] recording: mean 7.1 months, range 1-22 months). The diagnosis was WS in 7 patients, Ohtahara syndrome in 1, and a transitional state from Ohtahara syndrome to WS in the other. In the scalp EEG data of these patients, we conservatively detected FOs, and then examined the distribution of FOs. In five patients, the scalp distribution of FOs was consistent and concordant with the lateralization of cerebral pathology. In another patient, FOs were consistently dominant over the healthy cerebral hemisphere, and the EEG was relatively low in amplitude over the pathological atrophic hemisphere. In the remaining 3 patients, the dominance of FOs was inconsistent and, in 2 of these patients, the epileptogenic hemisphere was reduced in volume, which may result from atrophy or hypoplasia. The correspondence between the scalp distribution of FOs and the epileptogenic lesion should be studied, taking the type of lesion into account. The factors affecting scalp FOs remain to be elucidated.

EEG and seizure exacerbation induced by carbamazepine in Panayiotopoulos syndrome.

We report on a 4-year 8-month-old boy with Panayiotopoulos syndrome who showed atypical evolution with newly developed absence seizures and EEG exacerbation induced by carbamazepine. Soon after the introduction of carbamazepine, EEGs began to worsen, and finally absence seizures and myoclonic seizures appeared. Immediately after we discontinued carbamazepine, the seizures disappeared and the EEG improved. Carbamazepine may induce unusual electroclinical features, electrophysiologically explained by bilateral synchrony. This case provides more evidence of the close links between Panayiotopoulos syndrome and benign childhood epilepsy with centrotemporal spikes.

Fast (40-150Hz) oscillations are associated with positive slow waves in the ictal EEGs of epileptic spasms in West syndrome.

OBJECTIVE: To elucidate the generative mechanisms of epileptic spasms (ESs) in West syndrome, we investigated the temporal relationship between scalp fast (40-150Hz) oscillations (FOs) and slow waves in the ictal electroencephalograms (EEGs) of ESs. METHODS: In 11 infants with WS, ictal FOs were detected in a bipolar montage based on spectral and waveform criteria. Their temporal distribution was analyzed in terms of the positive peaks (trough point, TT) of identical EEG data in a referential montage. Among six EEG data sections defined according to TT, the number of FOs, peak power values, and peak frequencies were compared. RESULTS: We identified a total of 1014 FOs (946 gamma and 68 ripple oscillations), which clustered closely at TT. The number of gamma oscillations in the 1s epoch including TT was significantly higher than those in the prior and subsequent phases. Peak power values and frequencies tended to be higher in these positive phase sections. CONCLUSIONS: The temporal association of FO clustering and positive slow waves in the ictal EEGs of ES indicated that active neuronal firing related to FOs underlies the generation of ESs and their ictal slow waves.

Predictive factors for relapse of epileptic spasms after adrenocorticotropic hormone therapy in West syndrome.

PURPOSE: To investigate whether serial electroencephalographic (EEG) findings can predict relapse of epileptic spasms after synthetic adrenocorticotropic hormone (ACTH) therapy in patients with West syndrome (WS). SUBJECTS AND METHODS: Thirty-nine WS patients (8 cryptogenic and 31 symptomatic) were included in this study. These patients received ACTH therapy for the first time and were regularly followed up for more than three years at our hospital. Sixteen patients (41.0%) showed seizure relapse (relapse group) and 23 patients (59.0%) did not show relapse (non-relapse group). We used survival analysis to investigate the influence of etiology and presence of epileptic discharges after the ACTH therapy on seizure outcome. RESULTS: Immediately after the ACTH therapy, etiology was associated with seizure outcome (p=0.003). In the early stage (1 month after the ACTH therapy), only the presence of epileptic discharges (p=0.001) had a significant association with seizure outcome, regardless of etiology. Because all relapsed patients were in the symptomatic group, we performed the same statistical analysis on symptomatic WS patient data only. We found that the group with no epileptic discharges on EEG showed a significantly higher seizure-free rate than those with epileptic discharges in the early stage (p=0.0091). CONCLUSION: This study demonstrated that serial EEG findings after ACTH therapy are significantly related to relapse of epileptic spasms.

Occurrence of bilaterally independent epileptic spasms after a corpus callosotomy in West syndrome.

We report a patient with intractable West syndrome whose epileptic spasms (ESs) were initially bilaterally synchronous, as is typical; after a complete corpus callosotomy, however, bilaterally independent ESs originated in either hemisphere. Activity of probable cortical origin associated with ESs was detected by observing ictal gamma oscillations. Brain MRI revealed no structural abnormality before surgery. This case suggests that ESs with a hemispheric origin may appear generalized because of synchronizing effects in the corpus callosum in some patients.

A Japanese adult case of guanidinoacetate methyltransferase deficiency.

Guanidinoacetate methyltransferase (GAMT) deficiency is a rare disorder of creatine synthesis resulting in cerebral creatine depletion. We present a 38-year-old patient, the first Japanese case of GAMT deficiency. Developmental delay started after a few months of age with a marked delay in language, which resulted in severe intellectual deficit. She showed hyperactivity and trichotillomania from childhood. Epileptic seizures appeared at 18 months and she had multiple types of seizures including epileptic spasms, brief tonic seizures, atypical absences, complex partial seizures with secondary generalization, and "drop" seizures. They have been refractory to multiple antiepileptic drugs. Although there have been no involuntary movements, magnetic resonance imaging revealed T2 hyperintense lesions in bilateral globus pallidi. Motor regression started around 30 years of age and the patient is now able to walk for only short periods. Very low serum creatinine levels measured by enzymatic method raised a suspicion of GAMT deficiency, which was confirmed by proton magnetic resonance spectroscopy and urinary guanidinoacetate assay. GAMT gene analysis revealed that the patient is a compound heterozygote of c.578A>G, p.Gln193Arg and splice site mutation, c.391G>C, p.Gly131Arg, neither of which have been reported in the literature. We also identified two aberrant splice products from the patient's cDNA analysis. The patient was recently started on supplementation of high-dose creatine and ornithine, the effects of which are currently under evaluation. Although rare, patients with developmental delay, epilepsy, behavioral problems, and movement disorders should be vigorously screened for GAMT deficiency, as it is a treatable disorder.

Cortical contribution to scalp EEG gamma rhythms associated with epileptic spasms.

The cortical contribution for the generation of gamma rhythms detected from scalp ictal EEG was studied in unique cases of epileptic spasms and a review of the related literature was conducted. Ictal scalp gamma rhythms were investigated through time-frequency analysis in two cases with a combination of focal seizures and spasms and another case with spasms associated with cortical dysplasia. In the two patients with combined seizures, the scalp distribution of ictal gamma rhythms was related to that of focal seizure activity. In the third patient, an asymmetric distribution of the ictal scalp gamma rhythms was transiently revealed in correspondence to the dysplasic cortex during hormonal treatment. Therefore, the dominant region of scalp gamma rhythms may correspond to the epileptogenic cortical area. The current findings have reinforced the possibility of the cortical generation of ictal scalp gamma rhythms associated with spasms. The detection of high frequencies through scalp EEG is a technical challenge, however, and the clinical significance of scalp gamma rhythms may not be the same as that of invasively recorded high frequencies. Further studies on the pathophysiological mechanisms related to the generation of spasms involving high frequencies are necessary in the future, and the development of animal models of spasms will play an important role in this regard.

Clinical implications of preceding positive spikes in patients with benign partial epilepsy and febrile seizures.

PURPOSE: To clarify the clinical implications of the preceding positive spikes (PPSs) observed primarily in rolandic spikes, we analyzed PPSs in the rolandic and occipital spikes observed in the electroencephalograms (EEGs) of patients with two types of benign partial epilepsies (benign childhood epilepsy with centro-temporal spikes [BECT] and Panayiotopoulos syndrome [PS]) and febrile seizures (FS). SUBJECTS AND METHODS: We identified patients from our outpatient EEG database that were seen between 2006 and 2008 that had BECT, PS, and FS with rolandic or occipital spikes. We generated an averaged spike for each patient from the rolandic and occipital spikes that were detected using an automatic spike detection and clustering system. We compared the presence rate of the averaged spikes with the PPS among the three groups (BECT vs. PS vs. FS) using sequential mapping. RESULTS: We identified 25 BECT, 18 PS, and 15 FS patients with rolandic spikes. Fifteen BECT and nine PS patients exhibited a PPS in their averaged rolandic spikes, whereas only four FS patients did. Three of these four FS patients later developed afebrile seizures, and one of them was diagnosed as having PS. We analyzed eight PS and six FS patients with occipital spikes. Five PS patients exhibited a PPS in their averaged occipital spikes, whereas only one FS patient did. This FS patient later developed prolonged autonomic febrile seizures. CONCLUSION: PPSs are observed not only in rolandic spikes associated with BECT that is related strictly to sylvian seizures, but also in rolandic and occipital spikes associated with PS. Although PPSs are rare in such spikes observed in FS, patients with FS and PPSs may have an increased risk of developing afebrile seizures or prolonged autonomic febrile seizures. Further studies are warranted to determine the diagnostic utility of PPSs as a marker of the future development of epilepsy when they are observed in FS patients.

Efficacy of topiramate for intractable childhood generalized epilepsy with epileptic spasms: with special reference to electroencephalographic changes.

PURPOSE: Epileptic spasms (ES) beyond infancy are a highly refractory type of seizures that require the development of an effective treatment. We therefore studied the efficacy and safety of topiramate (TPM), which is a drug that is indicated to be effective for intractable childhood epilepsy, for ES. METHODS: Out of 58 children with ES, we enrolled 33 patients treated with TPM at ≤ 12 years of age. The administration of TPM was limited to cases of epilepsies that were resistant to any other potent treatment. We retrospectively investigated the efficacy of TPM for seizures and changes in electroencephalogram (EEG) findings. RESULTS: The median age at the start of TPM treatment was 5 years, 8 months. All patients had ES and 28 also had tonic seizures. As for the efficacy of TPM for all seizures, five patients became seizure-free and two had a ≥ 50% reduction in seizures. Seizure aggravation was observed in six patients. Of 29 patients whose EEG findings were compared before and during TPM treatment, nine showed EEG improvement with reduced epileptic discharges. Adverse effects were observed in 13 patients and included somnolence, anorexia, and irritability. In general, TPM was well tolerated. CONCLUSIONS: TPM can be effective at suppressing very intractable ES in a proportion of patients who do not respond to any other treatment. The efficacy of TPM may be predictable based on EEG changes observed early in the course of treatment. TPM is promising for the treatment of extremely intractable childhood epilepsy and it has largely tolerable adverse effects.