Efficacy and safety of perampanel monotherapy in patients with focal-onset seizures with newly diagnosed epilepsy or recurrence of epilepsy after a period of remission: The open-label Study 342 (FREEDOM Study).

OBJECTIVE: Our study assessed perampanel monotherapy in patients (aged ≥12 years) with focal-onset seizures (FOS) with or without focal to bilateral tonic-clonic seizures (FBTCS) in Japan and South Korea. METHODS: Study 342 (NCT03201900; FREEDOM) is a single-arm, open-label, Phase III study. Patients initially received perampanel in a 32-week 4-mg/d Treatment Phase (6-week Titration; 26-week Maintenance Periods). If they experienced a seizure during the 4-mg/d Maintenance Period, they could be up-titrated to 8 mg/d across an additional 30-week Treatment Phase (4-week Titration; 26-week Maintenance Periods). Primary endpoint was the seizure-freedom rate during the Maintenance Period (4 mg/d and last evaluated dose [4 or 8 mg/d]). Secondary endpoints included time to first seizure onset and to withdrawal during Maintenance. Treatment-emergent adverse events (TEAEs) were monitored. RESULTS: At data cutoff (February 28, 2019), 89 patients with FOS (84 [94.4%] with newly diagnosed epilepsy and 5 [5.6%] with recurrence of epilepsy after a period of remission) had received ≥1 perampanel dose; 16 patients discontinued during the 4-mg/d Titration Period, meaning 73 patients entered the 4-mg/d Maintenance Period and were included in the primary analysis set for efficacy. Seizure-freedom rate in the 26-week Maintenance Period was 46/73 (63.0%; 95% confidence interval [CI]: 50.9-74.0) at 4 mg/d and 54/73 (74.0%; 95% CI: 62.4-83.5) at 4 or 8 mg/d. Cumulative probability of seizure-onset and withdrawal rates during Maintenance was 30.8% (95% CI: 21.5-43.0) and 23.7% (95% CI: 15.4-35.3) at 4 mg/d, and 18.2% (95% CI: 11.0-29.3) and 23.3% (95% CI: 15.2-34.8) at 4 or 8 mg/d. Perampanel was generally well tolerated, and the most common TEAE was dizziness. SIGNIFICANCE: Perampanel monotherapy (4 to 8 mg/d) was efficacious and consistent with the known safety profile up to 26 weeks in patients (≥12 years) with primarily newly diagnosed FOS with or without FBTCS.

[Cases of three patients undergoing chemotherapy for gastric cancer who developed Trousseau's syndrome].

Trousseau's syndrome involves unexplained thrombotic events along with malignancy. We report the cases of 3 patients undergoing chemotherapy for gastric cancer in whom Trousseau's syndrome occurred. Case 1 involved a 43-year-old woman undergoing S-1/cisplatin( CDDP) combination therapy as first-line chemotherapy for type 4 remnant gastric cancer( cT4bN2M1P1/stage IV) who experienced left hemiplegia. Cerebral hemorrhage of the right parietal lobe was diagnosed by computed tomography( CT), and thrombosis from the upper sagittal sinus to the right sinus sigmoideus was diagnosed by magnetic resonance venography( MRV). Case 2 involved a 59-year-old man undergoing S-1/irinotecan (CPT-11) combination therapy as second-line chemotherapy for type 3 gastric cancer( cT3N1M0H1/stage IV) who experienced ataxic, stuttering, and left membrum inferius paralysis. Multiple cerebral infarction of the right parietal lobe was diagnosed by magnetic resonance imaging (MRI). Case 3 involved a 67-year-old woman undergoing S-1/CDDP combination therapy as preoperative chemotherapy for type 3 gastric cancer( cT4aN1M0/stage IIIA) who experienced right cerebellum incontinentia, nystagmus, and right facioplegia. Multiple cerebral infarction of the right cerebellum and pedunculus cerebellaris medius was diagnosed by MRI. An anticoagulant was administered orally for stroke, and chemotherapy for gastric cancer was resumed after activities of daily living( ADL) improved in all 3 patients. Recurrent stroke was not diagnosed in any of the 3 patients. Patients with malignancy often exhibit hypercoagulability associated with cancer. Accordingly, periodic blood tests for coagulation should be performed and dehydration should be prevented to prevent strokes in cancer patients.

Determination of language dominance with synthetic aperture magnetometry: comparison with the Wada test.

Cerebral dominance for language function was investigated with synthetic aperture magnetometry (SAM). The results were compared with those of the Wada test. SAM is a spatial filtering technique that enables demonstration of the spatiotemporal distribution of oscillatory changes (synchronization and desynchronization) in magnetoencephalography (MEG) signals elicited by specific brain activation. MEG was conducted during a silent reading task in 20 consecutive preoperative neurosurgical patients who also underwent a Wada test. The spatial distribution of oscillatory changes related to silent reading was shown tomographically with SAM as statistical images. Language dominance was estimated by the laterality index, which scales the lateralization of the beta (13-25 Hz) and low gamma (25-50 Hz) band desynchronizations in the inferior frontal gyrus (IFG) or middle frontal gyrus (MFG). Oscillatory changes were distributed multifocally and bilaterally in the occipital cortex, IFG or MFG, and temporo-parieto-occipital border regions. In 19 patients (95%), language lateralization estimated by the laterality index was congruent with the result of the Wada test. In left-handed patients, SAM analysis clearly differentiated language dominance (left, right, or bilateral), and the findings were confirmed by the Wada test. Lateralization of beta or low gamma band desynchronizations in the IFG or MFG is a good indicator of the side of language dominance. Reliability of MEG imaging with SAM is sufficient to evaluate language dominance preoperatively in neurosurgical patients.

[Application of synthetic aperture magnetometry for epilepsy surgery].

Recently developed synthetic aperture magnetometry (SAM) is a new MEG signal analysis introducing a high performance spatial filtering technique. SAM is not an inverse solution like dipole analysis, but rather an adaptive beamformer for estimating source activity at each selected voxel inside of the brain. SAM can estimate source changes as a function of time, or power changes subjected to statistical analysis from the non-averaged raw MEG data. Thus this method enables to display the regional currentodensitogram of the arbitrary selected brain tissue as if depth electrodes were inserted (SAM virtual sensor), and to detect the origin of epileptic discharges and their spread. By applying statistical discrimination, SAM can also demonstrate the spatial distribution of event-related changes of brain rhythm (SAM statistical method), in other words activated cerebral cortex during task performance. We will present the usefulness of noninvasive SAM methods in epilepsy surgery detecting the epileptogenic zone by SAM virtual sensor method as well as eloquent brain by SAM statistical method.

Neuromagnetic gamma-band activity in the primary and secondary somatosensory areas.

To evaluate the gamma-band activity related to somatosensory processing, we recorded neuromagnetic signals from seven healthy subjects. The source power changes evoked by electrical stimulation of the median nerve were estimated with synthetic aperture magnetometry (SAM). Source power in the low gamma band (40 Hz) decreased in the contralateral primary somatosensory cortex (SI) for a few hundred milliseconds (i.e. middle and long latency) and then increased inversely. Source power in the high gamma band (70-90 Hz) increased simultaneously both in the contralateral SI and contra/ipsilateral secondary somatosensory cortex (SII) in 80-180 ms. These results suggest that low and high gamma oscillations work under independent mechanisms during somatosensory processing. In particular, high gamma oscillations may play an essential role in making a functional connection between SI and SII.

Frequency-dependent spatial distribution of human somatosensory evoked neuromagnetic fields.

Using synthetic aperture magnetometry (SAM), we examined the spatial distribution of frequency changes in magnetoencephalography signal rhythms on individual magnetic resonance images following somatosensory stimulation. SAM is a novel statistical spatial filtering method that uses an adaptive beamformer. Electrical stimulation of the right median nerve demonstrated high-frequency event-related synchronization (ERS) in the 50-200-Hz range, consistently localized in the contralateral primary sensorimotor area in all subjects (n=7). Event-related desynchronization (ERD) was demonstrated in the 8-13, 13-25 and 25-50-Hz ranges bilaterally in the area surrounding the central sulcus. The differences in the spatial distribution as well as the frequency bands between ERS and ERD suggest that ERS and ERD reflect the responses of different cell assemblies rather than a frequency shift of the same cell assembly.