Adjunctive levetiracetam in the treatment of Chinese and Japanese adults with generalized tonic-clonic seizures: A double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To assess the efficacy, safety, and tolerability of adjunctive levetiracetam (LEV) in Chinese and Japanese adults with generalized tonic-clonic (GTC) seizures (N01159; NCT01228747). METHODS: This double-blind, randomized, placebo-controlled, multicenter phase III trial comprised: 4-week retrospective and 4-week prospective baseline, 12-week dose-adjustment, and 16-week evaluation periods. Chinese and Japanese patients ≥16 years old with idiopathic generalized, symptomatic generalized, or undetermined epilepsy with GTC seizures received a single-blind placebo during the prospective baseline, and then were randomized 1:1 to placebo or LEV 1,000 mg/day administered twice daily. Patients reporting GTC seizures up to week 8 had the LEV dosage increased to 3,000 mg/day. The primary efficacy variable was percent reduction from combined baseline in GTC seizures/week during the 28-week treatment period. RESULTS: Overall, 251 patients were randomized (208 from China; 43 from Japan); 141 (56.2%) completed the 28-week treatment period. Least-squares mean percent reduction from combined baseline in GTC seizures/week (treatment period) was placebo 12.6% versus LEV 68.8% (95% confidence interval, 44.0-68.2; p < 0.0001). GTC seizure frequency reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. The 50% responder rate (treatment period) was placebo 28.4% versus LEV 77.8%. Freedom from GTC seizures (evaluation period) was placebo 3.1% versus LEV 29.6%. Incidence of treatment-emergent adverse events (TEAEs; treatment period) was placebo 52.0% versus LEV 57.1%; most frequently nasopharyngitis, protein in urine, decreased platelet count, and pyrexia. Incidence of TEAEs leading to discontinuation was 4.8% versus 3.2%; incidence of serious TEAEs was 3.2% versus 0.8% for placebo and LEV, respectively; 3 patients taking placebo died versus none taking LEV. SIGNIFICANCE: In this trial, adjunctive LEV 1,000-3,000 mg/day was effective in reducing GTC seizure frequency in Chinese and Japanese patients ≥16 years old with GTC seizures. Seizure reduction occurred in both patients with idiopathic and symptomatic generalized epilepsy. LEV was well tolerated in this population.

Efficacy and tolerability of levetiracetam as adjunctive therapy in Japanese patients with uncontrolled partial-onset seizures.

AIMS: The aim of this study was to confirm the efficacy and safety of adjunctive levetiracetam in adult Japanese patients with uncontrolled partial-onset seizures. METHODS: In a double-blind, placebo-controlled, confirmatory trial, eligible patients were randomized to receive levetiracetam 500, 1000, 2000, or 3000 mg/day or placebo for 16 weeks. The primary end-point was percentage reduction from baseline in seizure frequency/week over a 12-week evaluation period. Tolerability assessments were also conducted. Findings of this and a previous randomized, double-blind trial were compared. RESULTS: Of 401 patients screened, 352 were randomized and 316 completed the study. Median percentage reduction in seizure frequency/week from baseline was 12.92%, 18.00%, 11.11% and 31.67% in the levetiracetam 500, 1000, 2000 and 3000-mg groups, respectively, compared with 12.50% in the placebo group. Unlike the previous trial, the primary efficacy analysis between the levetiracetam 1000 and 3000-mg and placebo groups did not reach statistical significance (P = 0.067). Exploratory analyses demonstrated that the difference in seizure reduction versus placebo was 14.93% (95% confidence interval, 1.98-27.64; P = 0.025) for the levetiracetam 3000-mg group. All levetiracetam doses were well tolerated. The main difference between the two trials was a high placebo response in the present trial. CONCLUSIONS: The primary efficacy analysis did not reach statistical significance, a finding that could be attributed to an unexpectedly high placebo response. Nonetheless, exploratory analysis suggests that levetiracetam at 3000 mg/day may, at least marginally, be beneficial for patients with uncontrolled partial-onset seizures.

KCC2 was downregulated in small neurons localized in epileptogenic human focal cortical dysplasia.

Focal cortical dysplasia (FCD), which is characterized histologically by disorganized cortical lamination and large abnormal cells, is one of the major causes of intractable epilepsies. γ-aminobutyric acid (GABA)(A) receptor-mediated synchronous depolarizing potentials have been observed in FCD tissue. Since alterations in Cl(-) homeostasis might underlie these depolarizing actions of GABA, cation-Cl(-) cotransporters could play critical roles in the generation of these abnormal actions. We examined the expression patterns of NKCC1 and KCC2 by in situ hybridization histochemistry and immunohistochemistry in FCD tissue obtained by surgery from patients with intractable epilepsy. KCC2 mRNA and protein were expressed not only in non-dysplastic neurons in histologically normal portions located in the periphery of the excised cortex, but also in dysplastic cells in FCD tissue. The levels of KCC2 mRNA and protein were significantly decreased in the neurons around large abnormal neurons (giant neurons), but not in giant neurons, compared with non-dysplastic neurons. The neurons localized only around giant neurons significantly smaller than non-dysplastic neurons. However NKCC1 expression did not differ among these cell types. These results suggest that the intracellular Cl(-) concentration ([Cl(-)](i)) of small neurons might increase, so that depolarizing GABA actions could occur in the FCD tissue of epileptic foci.

Magnetoencephalographic correlates of different types of aura in temporal lobe epilepsy.

PURPOSE: To estimate magnetoencephalography (MEG) correlates of different types of aura in temporal lobe epilepsy (TLE). METHODS: MEG study was performed on 57 patients (26 male and 31 female) with TLE, whose ages ranged from 14-46 years (mean 27 years). Interictal magnetoencephalograms showing discharges were analyzed, and spike-dipole clusters were categorized into left and right inferotemporal-horizontal (IH) and superotemporal-vertical (SV) types. Auras were classified into autonomic, auditory, and psychic seizures. The correlation between the four types of interictal spike-dipole and three types of aura was analyzed using Fisher's exact probability test. RESULTS: IH type correlated with autonomic seizures (p = 0.0004), whereas SV type correlated with both auditory (p = 0.0002) and psychic seizures (p = 0.042). When subdivided into left and right, left IH type correlated with autonomic seizures (p = 0.046), but right IH type did not. Right SV type correlated with both auditory (p = 0.014) and psychic seizures (p = 0.002), but left SV did not correlate with either. Both types did not correlate with "no aura." CONCLUSIONS: Using our proposed classification of spike-dipoles, MEG distinguishes auras of mesial temporal origin from those of lateral temporal region. Furthermore, by adopting our classification, laterality of spike-dipoles is clearly demonstrated in auditory and psychic seizures.

Magnetoencephalographic characteristics of psychosis in temporal lobe epilepsy.

To test the hypothesis that some particular magnetoencephalographic findings characterize psychosis manifesting in temporal lobe epilepsy (TLE) patients, the authors performed statistical analyses on the correlation between a history of psychosis and four magnetoencephalographic spike-dipole patterns, namely, left and right inferotemporal-horizontal (IH) and superotemporal-vertical (SV) types. Fifty-seven patients with TLE were studied, 16 of whom had a history of psychosis. Of the four types of spike-dipoles, only left SV type showed a strong correlation with psychosis, suggesting that dysfunction of the left temporal neocortex specifically contributes to the manifestation of psychotic symptoms in TLE patients.

Treatment of partial seizures with gabapentin: double-blind, placebo-controlled, parallel-group study.

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.

Postictal mania versus postictal psychosis: differences in clinical features, epileptogenic zone, and brain functional changes during postictal period.

PURPOSE: To clarify the differences between postictal mania (PIM) and postictal psychosis (PIP). METHODS: Five patients with PIM were compared to 17 patients with PIP, with respect to clinical, epileptological, electrophysiological, and neuroimaging features. PIM was distinguished from PIP by the symptoms observed in the postictal period based on the ICD-10 criteria. RESULTS: Postictal manic episodes lasted for a longer period than postictal psychotic episodes. Patients with PIM had more recurrent postictal episodes than patients with PIP. The age at onset of epilepsy in patients with PIM was older than that in patients with PIP. PIM was associated with frontal lobe and temporal lobe epilepsies, whereas PIP was associated with temporal lobe epilepsy. The estimated epileptogenic zone was on the language dominant side in PIM, whereas there was no predominant hemispheric laterality in PIP. Electroencephalography (EEG) performed during the early period of postictal manic and psychotic episodes showed decreased frequency of interictal epileptiform discharges in both PIM and PIP. Single-photon emission computed tomography (SPECT) during postictal manic and psychotic episodes showed increased perfusion in the temporal and/or frontal lobes in both PIM and PIP. Three patients with PIM showed increased perfusion during postictal episodes on bilateral or the language nondominant side, which were contralateral to the estimated epileptogenic zone, whereas three patients with PIP showed increased perfusion on the areas, which were ipsilateral to the estimated epileptogenic zone. CONCLUSIONS: PIM has a distinct position among the mental disorders observed in the postictal period.

Development of an epilepsy comprehensive care center: a Japanese model.

PURPOSE: To review the requirements of a comprehensive care center for people with epilepsy. METHODS: Twenty-seven years have passed since the foundation of the Japanese Epilepsy Center in Shizuoka. The development of this center is presented as a model of an epilepsy comprehensive care center. RESULTS: Between 1926 and 1947, the Shizuoka Higashi Hospital (the former name of SMIND) served as a tuberculosis hospital. In 1975, a proposal for a special center for the care of people with epilepsy was submitted to the Japanese government. An epilepsy center (the Center) was soon built, and the tuberculosis sanatorium ended its 50-year history. The facilities of the Center include an outpatient clinic, four inpatient wards with 200 beds, a day-care center for medical rehabilitation, and classrooms for elementary and junior high school children. The Center has modern diagnostic tools such as electroencephalography (EEG), closed-circuit TV-EEG (CCTVEEG), computed tomography (CT) scan, magnetic resonance imaging (MRI), single-photon emission CT (SPECT), and magnetoencephalography (MEG). Neurosurgery for intractable seizures has been conducted at the Center since 1983. Approximately 25,000 patients with epilepsy from all over Japan have been registered since 1975. Annually, approximately 5,000 outpatients and 600 inpatients attend the Center. As of March 2002, 500 patients had received resective surgery for epilepsy. Other activities in the Center include research and specialized training of professionals, including foreign nationals, in the treatment of epilepsy. CONCLUSIONS: The experience in Shizuoka suggests that management of epilepsy should be oriented toward psychological well-being, social rehabilitation, and seizure control.

Postictal mania associated with frontal lobe epilepsy.

A 38-year-old man, possibly with frontal lobe epilepsy, developed postictal mania. The changes in psychiatric symptoms and laboratory examinations over time were investigated in two episodes of postictal mania, using long-term electroencephalography with closed circuit television (EEG/CCTV) monitoring, magnetoencephalography (MEG), and single-photon emission computed tomography (SPECT) to elucidate the underlying mechanism of postictal mania. According to the clinical symptoms, the postictal manic episodes of this case had four phases: a lucid interval, manic phase, hypomanic phase, and recovery phase. EEG showed forced normalization during the florid manic phase. The serial findings of EEG, MEG, and SPECT during the postictal manic episodes suggest that functional changes in bilateral frontal lobes, especially the right frontal lobe, right temporal lobe, and right paralimbic area, are crucial in the development of postictal mania, and that these functional changes are dynamic.

Discontinuation and duration of antiepileptic drug therapy: a retrospective study of factors for specific epileptic syndromes.

PURPOSE: To study factors associated with discontinuation of antiepileptic drugs (AEDs) in idiopathic generalized epilepsy (IGE) and symptomatic/cryptogenic localization-related epilepsy (S/CLRE) METHODS: For the IGE study, 71 patients who were able to discontinue their AED (discontinued-IGE group) were compared to 71 patients who continued AED therapy (continued-IGE group) and 20 patients with seizure relapse after discontinuing AED (relapsed-IGE group). For S/CLRE, 90 patients who were able to discontinue AED (discontinued-S/CLRE group) were compared to 90 patients who continued AED (continued-S/CLRE group) and 76 patients with benign childhood epilepsy with centrotemporal spikes who were able to discontinue AED (discontinued-BECTS group). RESULTS: Compared to the continued-IGE group, the discontinued-IGE group showed a weaker seizure propensity, better response to AEDs, more frequent epileptiform discharge suppression, and lower frequency of generalized tonic-clonic seizures (GTCs). Compared to the relapse-IGE group, the discontinued-IGE group had more frequent epileptiform discharge suppression. The discontinued-S/CLRE group showed a weaker seizure propensity, better response to AEDs, more frequent epileptiform discharge suppression, and less frequent symptomatic signs compared to the continued-S/C LRE group. Notably, the age at epilepsy onset was not a critical factor for discontinuing AEDs in both IGE and S/CLRE. Although the discontinued-S/CLRE group had more frequent symptomatic signs, older age at epilepsy onset and less frequent epileptiform discharge suppression than the discontinued-BECTS group, no difference was found in seizure propensity and response to AEDs between the two groups. CONCLUSIONS: Seizure propensity, epileptiform discharge, and response to AEDs should be considered to predict the possibility of terminating AED therapy in IGE or S/CLRE. In addition, attention should be paid to seizure pattern in IGE and symptomatic signs in LRE.

Overview of Japanese experience-controlled and uncontrolled trials.

Zonisamide is a new type of benzisoxazole derivative, first marketed in Japan in 1989. This study analyzed: (1) the drug's efficacy by seizure and epilepsy type in a total of 1008 patients treated during the development of zonisamide in Japan; (2) the effectiveness of zonisamide for 726 newly-diagnosed patients treated with zonisamide postmarketing; and (3) 50 patients with generalized epilepsies and epileptic syndromes (idiopathic generalized epilepsies, symptomatic generalized epilepsies, Lennox-Gastaut syndrome, Doose syndrome, and West syndrome), and 19 patients with undetermined epilepsies and specific syndromes (refractory grand mal in childhood, severe myoclonic epilepsy in infancy, other undetermined epilepsy, familial essential myoclonic epilepsy, and mitochondrial encephalomyopathy with ragged-red fibers). Analysis of study results showed that among all patients treated, zonisamide was highly effective for the treatment of idiopathic generalized epilepsy, temporal lobe epilepsy, and other partial epilepsies. The compound was also effective for other symptomatic generalized epilepsies. In 50 patients with generalized epilepsies, and 19 with undetermined epilepsies and specific syndromes, seizure frequency was reduced by >50% with monotherapy or two-drug therapy with zonisamide. Zonisamide was effective not only for partial epilepsies and generalized epilepsies but also for undetermined epilepsies and specific syndromes such as myoclonus epilepsy.

Role of lateral non-primary motor cortex in humans as revealed by epicortical recording of Bereitschaftspotentials.

In order to clarify the role of the lateral non-primary motor area in the control of voluntary movements, we studied movement-related cortical potentials (MRCPs) by direct epicortical recording from the lateral frontal lobe in nine patients with intractable partial epilepsy as a part of presurgical evaluation. We adopted movement tasks involving different body sites: eye closing, lip pursing, shoulder abduction, middle finger extension, thumb abduction, and foot dorsiflexion. We found that one or two small areas on the caudal lateral convexity of the frontal lobe generated pre-movement potential shifts regardless of the sites of movement (omni-Bereitschaftspotential; "omni-BP"). Such regions were located at or just rostral to the primary motor face area in six subjects, and at or rostral to the primary motor upper extremity area in three. Moreover, half of those areas were identified just adjacent (either rostral or caudal) to the primary negative motor area (PNMA), a cortical area of the lateral frontal lobe where negative motor responses were elicited by electric cortical stimulation. In conclusion, it is suggested that the lateral non-primary motor area plays a significant role, and has a close and direct relationship with other cortical areas in the frontal lobe, just like its counterpart on the mesial frontal cortex (supplementary negative motor area, SNMA).

Long-term seizure outcome following resective surgery at National Epilepsy Center in Shizuoka, Japan.

We analyzed the seizure outcome of 357 patients who were followed for at least 2 years after resective surgeries; 282 underwent temporal lobe resection and 75 had extratemporal lobe resection. This study confirmed that resective surgery provides sustained, positive benefits with a high seizure-free rate of nearly 80% for most medically refractory patients. In patients with no MRI-detectable lesion who underwent extratemporal lobe resection, however, Engel's class I-II (seizure-free or rare seizures) was achieved in less than 50% of patients. High-resolution MRI should be performed at the early stage of disease in all patients with partial epilepsies. The findings would certainly urge clinicians to actively select surgical intervention.

Mutations of sodium channel alpha subunit type 1 (SCN1A) in intractable childhood epilepsies with frequent generalized tonic-clonic seizures.

A group of infant onset epilepsies manifest very frequent generalized tonic-clonic seizures (GTC) intractable to medical therapy, which may or may not be accompanied by minor seizures such as myoclonic seizures, absences and partial seizures. They include severe myoclonic epilepsy in infancy (SMEI) and intractable childhood epilepsy with GTC (ICEGTC). They are commonly associated with fever-sensitivity, family history of seizure disorders and developmental decline after seizure onset. Mutations of the neuronal voltage-gated sodium channel alpha subunit type 1 gene (SCN1A) were recently reported in SMEI patients. To clarify the genotypic differences in this group of epilepsies, we searched for SCN1A abnormalities in 25 patients with SMEI and 10 with ICEGTC, together with the family members of 15 patients. Frameshift mutations in SCN1A were observed in four patients, nonsense mutations in five patients, missense mutations in 21 patients, other mutations in two patients and no mutation in five patients. SMEI patients showed nonsense mutations, frameshifts, or missense mutations, while ICEGTC patients showed only missense mutations. Study of both parents of 11 patients revealed that the mutations in these patients were de novo. However, two mothers had the same missense mutations as their ICEGTC children, and they had generalized epilepsy with febrile seizures plus. Here we suggest that SMEI and ICEGTC represent a continuum with minor phenotypic and genotypic differences.

Quantitative analysis of benzodiazepine receptor in temporal lobe epilepsy: [(125)I]iomazenil autoradiographic study of surgically resected specimens.

PURPOSE: To evaluate the changes of the inhibitory neurotransmitter receptor system related to epileptogenesis by measuring central benzodiazepine receptors (BZDRs) in surgically resected specimens of temporal lobe epilepsy by using [(125)I]iomazenil autoradiography. METHODS: Surgically resected specimens were obtained from 66 temporal lobe epilepsy patients [51 with mesial temporal lobe epilepsy (MTLE) and 15 with non-MTLE] receiving no BZDs and seven MTLE patients receiving BZDs. BZDR densities in brain sections were measured by using [(125)I]iomazenil autoradiography. Cell densities were measured from cresyl violet-stained sections. RESULTS: Compared with non-MTLE patients, non-BZD-treated MTLE patients showed remarkable reduction of BZDR density in the pyramidal cell region of cornu ammonis (CA) 1, CA3, and CA4, and a smaller but significant reduction in CA2 and the molecular and granule cell layers of dentate gyrus (mDG). In the MTLE group, the BZDR density in the mDG correlated with that in lateral cortex. Significant correlations between BZDR density and cell density were found in all hippocampal regions. A significant difference in BZDR density/cell-density ratio was observed in CA1 region between MTLE and non-MTLE. BZD-treated patients tended to have lower BZDR densities than did non-BZD-treated patients, although the differences did not reach significance. In all MTLE cases, [(123)I]iomazenil singlephoton emission computed tomography (SPECT) showed decreased BZDR binding in MTL. CONCLUSIONS: In MTLE, BZDR densities decreased parallel to reduction in cell density in most hippocampal subfields, but BZDR density appeared to decrease in excess of neuron loss in CA1. [(125)I]iomazenil SPECT might be useful for detecting in vivo changes of BZDR density.