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Objective: Motivated by the challenges raised by diagnosing poststroke epilepsy (PSE), especially in nonmotor onset seizure (non-MOS), we aimed to investigate the features of non-MOS, including seizure sequences, patient characteristics, and electrophysiological and imaging findings in PSE., Methods: This observational cohort study enrolled patients with PSE whose seizure onset was witnessed. According to the International League Against Epilepsy (ILAE) 2017 seizure classification, we classified seizure-onset symptoms into the non-MOS and MOS groups. We compared the different clinical characteristics between the two groups., Results: Between 2011 and 2018, we enrolled 225 patients with PSE (median age, 75 years), consisting of 97 (43%) with non-MOS and 128 (57%) with MOS. Overall, 65 (67%) of the patients without MOS had no subsequent convulsions. Multivariable logistic regression analysis showed significant associations of non-MOS with absence of poststroke hemiparesis (adjusted odds ratio [OR], 1.88; 95% confidence interval [CI], 1.03-3.42), frontal stroke lobe lesions (OR, 2.11; 95% CI, 1.14-3.91), and putaminal stroke lesions (OR, 2.51; 95% CI, 1.22-5.18) as negative indicators. Postictal single-photon emission computed tomography (SPECT) detected prolonged hyperperfusion in the temporal lobe more frequently in the non-MOS than in the MOS group (48% vs 31%; p = .02). The detection rate was higher than spikes/sharp waves in scalp electroencephalography, both in the non-MOS group (72% vs 33%; p < .001) and the MOS group (68% vs 29%; p < .001)., Significance: This study provides the clinical features of non-MOS in patients with PSE. Compared with the patients with MOS, patients with non-MOS showed less likely subsequent convulsive seizures, highlighting the clinical challenges. Postictal perfusion imaging and negative indicators of the non-MOS type may help diagnose and stratify PSE., (© 2022 International League Against Epilepsy.)

Background and Objectives: The functional outcome and mortality of patients with poststroke epilepsy (PSE) have not been assessed in a prospective study. Previous reports have suggested that patients with PSE may suffer from prolonged functional deterioration after a seizure. In this study, we prospectively investigated the functional outcome and mortality of patients with PSE and analyzed the effect of seizure recurrence on the outcomes., Methods: This is part of the Prognosis of Post-Stroke Epilepsy study, a multicenter, prospective observational cohort study, where 392 patients with PSE (at least 1 unprovoked seizure more than 7 days after the onset of the last symptomatic stroke) were followed for at least 1 year at 8 hospitals in Japan. This study included only PSE patients with a first-ever seizure and assessed their functional decline and mortality at 1 year. Functional decline was defined as an increase in modified Rankin Scale (mRS) score at 1 year compared with baseline, excluding death. The associations between the seizure recurrence and the outcomes were analyzed statistically., Results: A total of 211 patients (median age of 75 years; median mRS score of 3) were identified. At 1 year, 50 patients (23.7%) experienced seizure recurrence. Regarding outcomes, 25 patients (11.8%) demonstrated functional decline and 20 (9.5%) had died. Most patients died of pneumonia or cardiac disease (7 patients each), and no known causes of death were directly related to recurrent seizures. Seizure recurrence was significantly associated with functional decline (odds ratio [OR] 2.96, 95% CI 1.25-7.03, p = 0.01), even after adjusting for potential confounders (adjusted OR 3.26, 95% CI 1.27-8.36, p = 0.01), but not with mortality (OR 0.79, 95% CI 0.25-2.48, p = 0.68). Moreover, there was a significant trend where patients with more recurrent seizures were more likely to have functional decline (8.7%, 20.6%, and 28.6% in none, 1, and 2 or more recurrent seizures, respectively; p = 0.006)., Discussion: One-year functional outcome and mortality of patients with PSE were poor. Seizure recurrence was significantly associated with functional outcome, but not with mortality. Further studies are needed to ascertain whether early and adequate antiseizure treatment can prevent the functional deterioration of patients with PSE., (© 2022 American Academy of Neurology.)

Using dual single-photon emission computed tomography (SPECT) scanning, we recently found the postictal-interictal (P-I) subtraction method frequently detects prolonged postictal hyperperfusion in poststroke epilepsy (PSE) and thus may be valuable for auxiliary diagnosis. This study aimed to determine if the asymmetry method can localize hyperperfusion to reflect epileptic activity in PSE using a single postictal SPECT scan. Sixty-four patients with PSE who had undergone perfusion SPECT two times (postictal and interictal) were enrolled. We formulated a novel asymmetry method (subtraction analysis of reversed postictal SPECT from postictal SPECT, co-registered to magnetic resonance imaging) to identify paradoxical asymmetric increase, defined as a higher perfusion area adjacent to stroke lesions compared to the contralateral side. The postictal hyperperfusion area and detection rates were determined by the asymmetry and P-I subtraction methods independently. We subsequently calculated the sensitivity and specificity of the asymmetry method, compared to the gold standard P-I subtraction method. We also evaluated lateralization concordance between the asymmetry method and other clinical findings. Among 64 patients (median age, 75 years), prolonged postictal hyperperfusion was detected in 43 (67%) by the asymmetry, and 54 (84%) the P-I, method. The asymmetry method had high sensitivity (80%) and specificity (100%) in detecting postictal hyperperfusion, showing high lateralization concordance with seizure semiology (97%) and epileptiform electroencephalography findings (interictal/ictal epileptiform discharges or periodic discharges) (100%). The present study demonstrated the advantages of the objective asymmetry method for detecting prolonged hyperperfusion through using one postictal SPECT scan in PSE., Competing Interests: AI belongs to the Department of Epilepsy, Movement Disorders and Physiology, an Industry-Academia Collaboration Course, supported by a grant from Eisai Corporation, Nihon Kohden Corporation, Otsuka Pharmaceutical Co., and UCB Japan Co. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Fukuma, Tanaka, Takaya, Tojima, Kobayashi, Shimotake, Morita, Nishimura, Koga, Toyoda, Matsumoto, Takahashi, Ikeda and Ihara.)

Objective: To determine clinically ictal direct current (DC) shifts that can be identified by a time constant (TC) of 2 s and to delineate different types of DC shifts by different attenuation patterns between TC of 10 s and 2 s., Methods: Twenty-one patients who underwent subdural electrode implantation for epilepsy surgery were investigated. For habitual seizures, we compared (1) the peak amplitude and (2) peak latency of the earliest ictal DC shifts between TC of 10 s and 2 s. Cluster and logistic regression analyses were performed based on the attenuation rate of amplitude and peak latency with TC 10 s., Results: Ictal DC shifts in 120 seizures were analyzed; 89.1% of which were appropriately depicted even by a TC of 2 s. Cluster and logistic regression analyses revealed two types of ictal DC shift. Namely, a rapid development pattern was defined as the ictal DC shifts with a shorter peak latency and they also showed smaller attenuation rate of amplitude (73/120 seizures). Slow development pattern was defined as the ictal DC shifts with crosscurrent of a rapid development pattern, i.e., a longer peak latency and larger attenuation rate of amplitude (47/120 seizures). Focal cortical dysplasia (FCD) 1A tended to show a rapid development pattern (22/29 seizures) and FCD2A tended to show a slow development pattern (13 /18 seizures), indicating there might be some correlations between two types of ictal DC shift and certain pathologies., Conclusions: Ictal DC shifts, especially rapid development pattern, can be recorded and identified by the AC amplifiers of TC of 2 s which is widely used in many institutes compared to that of TC of 10 s. Two types of ictal DC shifts were identified with possibility of corresponding pathology., Significance: Ictal DC shifts can be distinguished by their attenuation patterns., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: To determine whether brain connectivity differs between focal cortical dysplasia (FCD) types I and II., Methods: We compared cortico-cortical evoked potentials (CCEPs) as measures of effective brain connectivity in 25 FCD patients with drug-resistant focal epilepsy who underwent intracranial evaluation with stereo-electroencephalography (SEEG). We analyzed the amplitude and latency of CCEP responses following ictal-onset single-pulse electrical stimulation (iSPES)., Results: In comparison to FCD type II, patients with type I demonstrated significantly larger responses in the electrodes near the ictal-onset zone (<50 mm). These findings persisted when controlling for the location of the epileptogenic zone, as noted in patients with temporal lobe epilepsies, as well as controlling for seizure type, as noted in patients with focal to bilateral tonic-clonic seizures (FBTCS). In type II, the root mean square (RMS) of CCEP responses dropped substantially from the early segment (10-60 ms) to the middle and late segments (60-600 ms). The middle and late CCEP latency segments showed the largest differences between FCD types I and II., Significance: Focal cortical dysplasia type I may have a greater degree of cortical hyperexcitability as compared with FCD type II. In addition, FCD type II displays a more restrictive area of hyperexcitability in both temporal and spatial domains. In patients with FBTCS and type I FCD, the increased amplitudes of RMS in the middle and late CCEP periods appear consistent with the cortico-thalamo-cortical network involvement of FBTCS. The notable differences in degree and extent of hyperexcitability may contribute to the different postsurgical seizure outcomes noted between these two pathological substrates., (© 2021 International League Against Epilepsy.)

Background: Benign adult familial myoclonus epilepsy (BAFME) is one of the diseases that cause cortical myoclonus (CM) with giant somatosensory evoked potentials (SEPs). There are no useful diagnostic biomarkers differentiating BAFME from other CM diseases., Objective: To establish reliable biomarkers including high-frequency oscillations (HFOs) with giant SEPs for the diagnosis of BAFME., Methods: This retrospective case study included 49 consecutive CM patients (16 BAFME and 33 other CM patients) who exhibited giant P25 or N35 SEPs. SEPs were processed by a band-pass filter of 400-1000 Hz to analyze HFOs. Clinical and SEP findings were compared between (1) BAFME and other CM groups and (2) patients with presence and absence of P25-HFOs (HFOs superimposed on giant P25). The diagnostic power of each factor for BAFME was calculated., Results: All 16 BAFME patients showed SEP P25-HFOs with significantly higher occurrence (P < 0.0001) compared with that of other CM groups. The presence of P25-HFOs significantly correlated with a BAFME diagnosis (P < 0.0001) and high SEP P25 and N35 amplitudes (P = 0.01 and P < 0.0001, respectively). BAFME was reliably diagnosed using P25-HFOs with high sensitivity (100%), specificity (87.9%), positive predictive value (80%), and negative predictive value (100%), demonstrating its superiority as a diagnostic factor compared to other factors., Conclusions: P25-HFOs with giant SEPs is a potential biomarker for BAFME diagnosis. P25-HFOs may reflect cortical hyperexcitability partly due to paroxysmal depolarizing shifts in epileptic neuronal activities and higher degrees of rhythmic tremulousness than those in ordinary CM. © 2021 International Parkinson and Movement Disorder Society., (© 2021 International Parkinson and Movement Disorder Society.)

Background and Purpose: The management of post-stroke epilepsy (PSE) should ideally include prevention of both seizure and adverse effects; however, an optimal antiseizure medications (ASM) regimen has yet been established. The purpose of this study is to assess seizure recurrence, retention, and tolerability of older-generation and newer-generation ASM for PSE., Methods: This prospective multicenter cohort study (PROgnosis of Post-Stroke Epilepsy [PROPOSE] study) was conducted from November 2014 to September 2019 at eight hospitals. A total of 372 patients admitted and treated with ASM at discharge were recruited. Due to the non-interventional nature of the study, ASM regimen was not adjusted and followed standard hospital practices. The primary outcome was seizure recurrence in patients receiving older-generation and newer-generation ASM. The secondary outcomes were the retention and tolerability of ASM regimens., Results: Of the 372 PSE patients with ASM at discharge (median [IQR] age, 73 [64-81] years; 139 women [37.4%]), 36 were treated with older-generation, 286 with newer-generation, and 50 with mixed-generation ASM. In older- and newer-generation ASM groups (n = 322), 98 patients (30.4%) had recurrent seizures and 91 patients (28.3%) switched ASM regimen during the follow-up (371 [347-420] days). Seizure recurrence was lower in newer-generation, compared with the older-generation, ASM (hazard ratio [HR], 0.42, 95%CI 0.27-0.70; p = .0013). ASM regimen withdrawal and change of dosages were lower in newer-generation ASM (HR, 0.34, 95% CI 0.21-0.56, p < .0001)., Conclusions: Newer-generation ASM possess advantages over older-generation ASM for secondary prophylaxis of post-stroke seizures in clinical practice., (© 2021 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

A 66 year-old right-handed female was admitted to our hospital presenting with recurrent episodes of catatonic symptoms consisting of stupor, waxy flexibility, and catalepsy lasting about 5-20 minutes. A brain MRI showed no significant abnormalities. An scalp-electroencephalography (EEG) concurrent with the symptoms showed ictal EEG activities arising from the left fronto-central area, which evolved into the bilateral frontal and bilateral parietal areas together. An 18 F-fluorodeoxy glucose positron emission tomography ( 18 F-FDG-PET) 4 days after improvement of the symptoms showed hypermetabolism in the bilateral frontal and parietal lobes. Her catatonic symptoms are assumed to be due to non-convulsive status epilepticus (NCSE), namely ictal catatonia. The introduction of several anti-epileptic drugs improved the symptoms and normalized the EEG and FDG-PET findings. NCSE must be considered as one of the underlying state of catatonic symptoms because the treatment plan for acute and chronic state is different from that of catatonic syndrome due to psychiatric disorders.

Objective: Cortico-cortical evoked potential (CCEP) by single-pulse electrical stimulation (SPES) is useful to investigate effective connectivity and cortical excitability. We aimed to clarify the safety of CCEPs., Methods: We retrospectively analyzed 29 consecutive patients with intractable partial epilepsy undergoing chronic subdural grid implantation and CCEP recording. Repetitive SPES (1 Hz) was systematically applied to a pair of adjacent electrodes over almost all electrodes. We evaluated the incidences of afterdischarges (ADs) and clinical seizures., Results: Out of 1283 electrode pairs, ADs and clinical seizures were observed in 12 and 5 pairs (0.94% and 0.39%, per electrode pair) in 7 and 3 patients (23.3% and 10.0%, per patient), respectively. Of the 18-82 pairs per patient, ADs and clinical seizures were induced in 0-4 and 0-3 pairs, respectively. Stimulating 4 SOZ (seizure onset zone) (2.5%) and 8 non-SOZ pairs (0.75%) resulted in ADs. We observed clinical seizures in stimulating 4 SOZ (2.5%) and 1 non-SOZ pair (0.09%). The incidence of clinical seizures varied significantly between SOZ and non-SOZ stimulations (p = 0.001), while the difference in AD incidence tended towards significance (p = 0.058)., Conclusion: Although caution should be taken in stimulating SOZ, CCEP is a safe procedure for presurgical evaluation., Significance: CCEP is safe under the established protocol., Competing Interests: Declaration of Competing Interest Department of Epilepsy, Movement Disorders and Physiology (Kyoto University Graduate School of Medicine) is the Industry-Academic Collaboration Courses, supported by Eisai Co., Ltd., NIHON KOHDEN CORPORATION, Otsuka Pharmaceutical Co., and UCB Japan Co., Ltd., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

We experienced 3 adult patients with intractable focal epilepsy treated by levetiracetam (LEV) as polytherapy, who showed paradoxical effect (PE). Starting dose of LEV was small (62.5, 250 mg/day) and we gradually increased by less than 250 mg/day, every more than 2 weeks. Within 6 months after LEV was added, LEV of 750 to 1,000 mg/day brought reduction of seizure frequency. Serum concentration of LEV was 13.3 and 14.0 μg/ml. In order to obtain better seizure control, LEV was increased up to 1,000-2,500 mg/day (19.3-35.0 μg/ml) within one year, and they developed PE. They all showed increased habitual seizures, occurring in cluster. Once dose of LEV deceased down to what produced the maximum seizure suppression, all of the patients regained the better seizure control. It is most likely that at least in some patients like present 3 cases, PE of LEV may express U curve association between dose and effect and that it was only delineated by slow titration.

The aim of this study was to clarify the effect of a stable concentration of propofol on interictal high-frequency oscillations (HFOs), which may contribute to identifying the epileptogenic zone intraoperatively for resection surgery. Nine patients with drug-resistant focal epilepsy who underwent invasive pre-surgical evaluation with chronic subdural electrodes were recruited. Five-minute electrocorticograms during wakefulness, slow-wave sleep, and under a stable brain concentration of propofol were recorded with the same electrodes. In each patient, 1-10 pairs of electrodes were selected for both electrodes with EEG changes within 5 seconds from the ictal onset (ictal pattern for 5 seconds [IP5]) and those outside the area of IP5 with no interictal epileptiform discharges (non-epileptiform [nEPI]). The numbers of ripples (80-250 Hz) and fast ripples (>250 Hz) were measured semi-automatically using an established algorithm. Statistical testing was performed with a mixed effect model. Thirty-seven pairs of electrodes from nine patients were analysed for IP5 and 29 pairs from seven patients were analysed for nEPI. The numbers of HFOs differed between the areas (IP5 and nEPI) and among the conditions (wakefulness, slow-wave sleep, propofol anaesthesia) (all p <0.01). The HFO occurrence rates were significantly higher for IP5 than those for nEPI in all conditions (for both ripples and fast ripples in all conditions; p <0.01). The occurrence rates of HFOs for IP5 were significantly higher than those for nEPI under propofol anaesthesia. These are fundamental findings for intraoperative HFO analysis, however, the following limitations should be considered: physiological HFOs could not be completely differentiated from pathological HFOs; in order to apply an HFO detector, an appropriate cut-off threshold is needed; an artefact of the impulse response filter appears as an HFO; and the series was comprised of a small number of heterogeneous patients.

Diagnosis of post-stroke epilepsy is often challenging because of a low incidence of epileptiform abnormalities on electroencephalography (EEG). Hence, this study evaluated whether postictal subtraction single-photon emission computed tomography (SPECT) could visualize epileptic activity and act as a diagnostic modality in post-stroke epilepsy. Fifty post-stroke epilepsy patients, who had undergone Tc-99m-ECD SPECT twice (postictal and interictal), were enrolled. The postictal hyperperfusion area was identified by subtraction (postictal-interictal) SPECT and classified into two distribution types: superficial or deep-seated. Laterality and distribution of postictal hyperperfusion on subtraction SPECT were compared with stroke lesions, seizure symptoms, and epileptiform EEG findings. Forty-three of the 50 patients (86%) had hyperperfusion on subtraction SPECT and 26 (52%) had epileptiform EEG findings. Subtraction SPECT showed prolonged postictal hyperperfusion despite the relatively long interval between seizure end and postictal SPECT (median: 19.1 h, range: 2.2-112.5 h). The laterality of the hyperperfusion area had a high concordance rate with the laterality of stroke lesions (97.7%), seizure symptoms (91.9%), and epileptiform EEG findings (100%). Scalp EEG identified epileptiform activity more frequently in superficial type of SPECT, but less frequently in deep-seated type (both, P  = 0.03). Postictal SPECT can be complementary to scalp EEG in endorsing the diagnosis and location of post-stroke epilepsy.

Objective: We aimed to delineate the engagement of cortico-cortical and cortico-subcortical networks in the generation of epileptic spasms (ES) using integrated neurophysiological techniques., Methods: Seventeen-year-old male patient with intractable ES underwent chronic subdural electrode implantation for presurgical evaluation. Networks were evaluated in ictal periods using high-frequency oscillation (HFO) analysis and in interictal periods using magnetoencephalography (MEG) and simultaneous electroencephalography, and functional magnetic resonance imaging (EEG-fMRI). Cortico-cortical evoked potentials (CCEPs) were recorded to trace connections among the networks., Results: Ictal HFO revealed a network comprising multilobar cortical regions (frontal, parietal, and temporal), but sparing the positive motor area. Interictally, MEG and EEG-fMRI revealed spike-and-wave-related activation in these cortical regions. Analysis of CCEPs provided evidence of connectivity within the cortico-cortical network. Additionally, EEG-fMRI results indicate the involvement of subcortical structures, such as bilateral thalamus (predominantly right) and midbrain., Conclusions: In this case study, integrated neurophysiological techniques provided converging evidence for the involvement of a cortico-cortical network (sparing the positive motor area) and a cortico-subcortical network in the generation of ES in the patient., Significance: Cortico-cortical and cortico-subcortical pathways, with the exception of the direct descending corticospinal pathway from the positive motor area, may play important roles in the generation of ES., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest or potential financial interests to disclose. Department of Epilepsy, Movement Disorders and Physiology is the Industry-Academia Collaboration Courses, supported by Eisai Co., Ltd., Nihon Kohden Corporation, Otsuka Pharmaceutical Co., and UCB Japan Co., Ltd. We confirm that we have read the journal's position on issues involving ethical publication and affirm that this report is consistent with those guidelines and all authors have approved the final article., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Using interictal epileptiform discharges (IEDs), consisting of spikes and post-spike slow waves (PSSs), and IED-related high-frequency activities (HFAs), we elucidated inhibitory effects of electrical cortical stimulation (ECS) on human epileptic foci., Methods: We recruited 8 patients with intractable focal epilepsy, and 50-Hz ECS was applied to the seizure-onset zone (SOZ) and non-SOZ. Before (5-min) and after (20-min) ECS, we evaluated the number of IED, the amplitudes of spikes and PSSs, spike-related HFA power, and PSS-related low gamma (30-50 Hz) activities., Results: SOZ stimulation significantly decreased the number of IEDs and amplitude of spikes. Spike-related HFA power values in fast ripple (200-300 Hz) and ripple (80-150 Hz) bands were significantly suppressed only by SOZ stimulation in 4 and 3 patients, respectively. Among 4 patients with discrete PSSs, the amplitude ratio of spike/PSS decreased and the PSS-related low gamma activity power increased significantly in 2 patients and marginally in 1 patient., Conclusions: ECS potentially modulates cortical excitability by reducing excitation and increasing inhibition, and monitoring IED-related HFAs may help achieve the optimal effects of ECS., Significance: IED and IED-related HFAs are dynamic, potential surrogate markers for epileptic excitability during the interictal period., Competing Interests: Declaration of Competing Interest None of the authors have any conflicts of interest or potential financial interests to disclose. Department of Epilepsy, Movement Disorders and Physiology is the Industry-Academia Collaboration Courses, supported by Eisai Co., Ltd., Nihon Kohden Corporation, Otsuka Pharmaceutical Co., and UCB Japan Co., Ltd. We confirm that we have read the journal’s position on issues involving ethical publication and affirm that this report is consistent with those guidelines and all authors have approved the final article., (Copyright © 2020 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

In the dual-stream model of language processing, the exact connectivity of the ventral stream to the anterior temporal lobe remains elusive. To investigate the connectivity between the inferior frontal gyrus (IFG) and the lateral part of the temporal and parietal lobes, we integrated spatiotemporal profiles of cortico-cortical evoked potentials (CCEPs) recorded intraoperatively in 14 patients who had undergone surgical resection for a brain tumor or epileptic focus. Four-dimensional visualization of the combined CCEP data showed that the pars opercularis (Broca's area) is connected to the posterior temporal cortices and the supramarginal gyrus, whereas the pars orbitalis is connected to the anterior lateral temporal cortices and angular gyrus. Quantitative topographical analysis of CCEP connectivity confirmed an anterior-posterior gradient of connectivity from IFG stimulus sites to the temporal response sites. Reciprocality analysis indicated that the anterior part of the IFG is bidirectionally connected to the temporal or parietal area. This study shows that each IFG subdivision has different connectivity to the temporal lobe with an anterior-posterior gradient and supports the classical connectivity concept of Dejerine; that is, the frontal lobe is connected to the temporal lobe through the arcuate fasciculus and also a double fan-shaped structure anchored at the limen insulae., (© The Author(s) 2020. Published by Oxford University Press.)

The pulmonary delivery of locked nucleic acid containing antisense oligonucleotides (LNA-ASOs) is expected to be a novel therapeutic approach for lung diseases. However, there are two concerns to be considered: immune responses, as the lung has a distinct immune mechanism to protect it from inhaled pathogens; and leakage into blood, since the lung is permeable to small molecules. As phagocytic alveolar macrophages reside in the alveolar space, it is hypothesized that inhaled LNA-ASOs effectively accumulate and exert a knockdown (KD) effect on these cells at low doses. Thus, targeting alveolar macrophages by inhaled LNA-ASOs may reduce these risks. To test this hypothesis, LNA-ASOs targeting Scarb1 or Hprt1 were intratracheally administered to mice. We confirmed the remarkable accumulation of intratracheally administered LNA-ASOs in murine alveolar macrophages and found that they exerted a significant and sequence-dependent KD effect. The dose required for KD in alveolar macrophages was lower than that required to induce KD in the whole lung. Furthermore, when a KD effect was observed in alveolar macrophages, no KD effect was observed in the liver or kidney; however, several inflammatory cytokines were increased in the lung. These results suggest the potential application of LNA-ASOs as an inhaled drug specific to alveolar macrophages. However, further studies on the immuno-stimulatory effects of LNA-ASOs will be necessary for the development of novel inhaled therapeutic agents.

Objective: Multispectrum electrocorticographic components are critical for mapping the nonprimary motor area (NPMA). The objective of this study was to derive and validate a reliable scoring system for electrocorticography-based NPMA mapping (NPMA score) to replace electrical cortical stimulation (ECS) during brain surgery., Methods: We analyzed 14 consecutive epilepsy patients with subdural electrodes implanted in the frontal lobe at Kyoto University Hospital. The NPMA score was retrospectively derived from multivariate analysis in the derivation group (patients = 7, electrodes = 713, during 2010-2013) and validated in the validation group (patients = 7, electrodes = 772, during 2014-2017). We assessed the accuracy and reliability of the score relative to ECS in determining the NPMA and predicting postoperative functional outcomes., Results: Multivariate analysis in the derivation group led to an 8-point score for predicting ECS-based NPMA (1 point for anatomical localization of the electrode and 1 or 2 points for movement-related electrocorticographic components regardless of somatotopy in very slow cortical potential shifts [<0.5 Hz], 40-80-Hz band power increase, and 8-24-Hz band power decrease), which was validated in the validation group. The area under the receiver operating characteristic curve (AUC) was 0.89 in the derivation group. Good prediction (specificity = 94%, sensitivity = 100%) and discrimination (AUC = 0.87) were reproduced in the validation group. Overall, higher NPMA scores identified 2 patients with postoperative deficits after frontal lobe resection., Significance: The NPMA score is reliable for NPMA mapping, potentially replacing ECS. It is a potential prognostic marker for postoperative functional deficits., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Objective: To elucidate the effects of perampanel (PER) on refractory cortical myoclonus for dose, etiology and somatosensory-evoked potential (SEP) findings., Methods: We examined 18 epilepsy patients with seizure and cortical myoclonus. Based on data accumulated before and after PER treatment, correlations among clinical scores in myoclonus and activities of daily life (ADL); early cortical components of SEP; and PER blood concentration, were analyzed., Results: PER (mean dose: 3.2 ± 2.1 mg/day) significantly improved seizures, myoclonus and ADL and significantly decreased the amplitude of and prolonged latency of giant SEP components. The degree of P25 and N33 prolongations (23.8 ± 1.6 to 24.7 ± 1.7 ms and 32.1 ± 4.0 to 33.7 ± 3.4 ms) were significantly correlated with improved ADL score (p = 0.019 and p = 0.025) and blood PER concentration (p = 0.011 and p = 0.025), respectively., Conclusions: Low-dose PER markedly improved myoclonus and ADL in patients with refractory cortical myoclonus. Our results suggest that SEP, particularly P25 latency, can be used as a potential biomarker for assessing the objective effects of PER on intractable cortical myoclonus., Significance: In this study, PER lessened the degree of synchronized discharges in the postsynaptic neurons in the primary motor cortex., (Copyright © 2019 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Wakefulness and sleep arise from global changes in brain physiology that may also govern the flow of neural activity between cortical regions responsible for perceptual processing versus planning and action. To test whether and how the sleep/wake cycle affects the overall propagation of neural activity in large-scale brain networks, we applied single-pulse electrical stimulation (SPES) in patients implanted with intracranial EEG electrodes for epilepsy surgery. SPES elicited cortico-cortical spectral responses at high-gamma frequencies (CCSRHG, 80-150 Hz), which indexes changes in neuronal population firing rates. Using event-related causality (ERC) analysis, we found that the overall patterns of neural propagation among sites with CCSRHG were different during wakefulness and different sleep stages. For example, stimulation of frontal lobe elicited greater propagation toward parietal lobe during slow-wave sleep than during wakefulness. During REM sleep, we observed a decrease in propagation within frontal lobe, and an increase in propagation within parietal lobe, elicited by frontal and parietal stimulation, respectively. These biases in the directionality of large-scale cortical network dynamics during REM sleep could potentially account for some of the unique experiential aspects of this sleep stage. Together these findings suggest that the regulation of conscious awareness and sleep is associated with differences in the balance of neural propagation across large-scale frontal-parietal networks., (© Sleep Research Society 2019. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

Electroencephalography (EEG) systems have been used for assessing cognitive function in dementia for several decades. Studies have demonstrated that EEG in Alzheimer's disease (AD) patients is generally characterized by significant and specific increases in delta and theta power, a decrease in alpha power, and a decrease in the coherence of the fast bands between different brain areas linked by long corticocortical fibers. Posterior EEG characteristics in dementia with Lewy bodies (DLB) allowed discrimination of DLB from AD and controls with high accuracy. Traditional EEG systems require a long application time and discomfort, which limited its use in dementia patients. Alternative tools for assessing cognition may be simple, low-cost, and mobile medical devices such as wireless and mobile EEG (wmEEG) sensor platforms with flexible electronics and stretchable electrode sheets that could be compatible with long-term EEG monitoring even in dementia patients. In this study, we review the utility of EEG in reflecting cognitive function and the prospects for clinical application of wmEEG monitoring for detecting early dementia and discriminating subtypes of dementia effectively and objectively assessing longitudinal cognitive changes. Repeated and longitudinal documentation of EEG using wmEEG will contribute to detection of specific sleep/wake EEG patterns for patients with sleep and wake-related problems related to dementia., Competing Interests: No competing financial interests exist., (Copyright 2019, Mary Ann Liebert, Inc., publishers.)

We herein report two epilepsy patients with the seizure focus in the non-dominant hemisphere manifesting secondarily generalized convulsion (sGC) with retained awareness characterized by a lack of autonomic signs although GC was complicated by respiratory arrest. Given the semiology and electrophysiological findings, the seizure activity was considered to propagate to the supplementary-motor area and the bilateral primary-motor area, with a clinical manifestation of sGC. The absence of autonomic signs during GC can be a key indicator that the seizure remains in the bilateral suprasylvian area and thus does not involve the region necessary for awareness preservation, which may assist in the diagnosis of this atypical epileptic seizure.

Objective: For future artificial intelligence-based brain mapping, development of a rational and safe scoring system for a brain motor mapping algorithm using electrocorticography (ECoG score), which contains various spectral, purely intrinsic brain activities, is necessary for either before or in the absence of electrical cortical stimulation (ECS)., Methods: We evaluated 1114 electrodes of 10 consecutive focal epilepsy patients who underwent subdural electrode implantation before epilepsy surgery at Kyoto University Hospital during 2011-2017. Data from ECoG-based mapping (bandpass filter of 0.016-300/600 Hz) to define the primary motor area (M1) localization were used to create an ECoG score (range = 0-4) by assigning 1 point each for the occurrence of ECoG components: very slow movement-related cortical potentials (<0.5-1.0 Hz), event-related synchronization (76-100 Hz or 100-200 Hz), and event-related desynchronization (8-12 Hz or 12-24 Hz). The ECoG score was assessed by calculating the sensitivity, specificity, and cutoff values of the score for localization concordance with M1 defined using only ECS as a reference., Results: With an area under the receiver operating characteristic curve (AUC) of 0.76, cutoffs of scores of 4 and 1 showed high specificity (94%) and sensitivity (98%) in concordance with ECS-based mapping, respectively. The ECoG score for mapping M1 of the upper limb achieved greater accuracy (AUC = 0.85) compared to that of the face (AUC = 0.64)., Significance: The ECoG score proposed in the present study is rational, simple, and useful to define M1, and it is spatially concordant with ECS. Although ECS is still widely employed for presurgical examination, our proposed application of the ECoG score may be suitable for future brain M1 mapping, and possibly beyond M1 mapping, independently of ECS., (Wiley Periodicals, Inc. © 2019 International League Against Epilepsy.)

Purpose: We reported the presence of interictal slow and high-frequency oscillations (HFOs) (IIS + HFO) and its temporal change so as to elucidate its clinical usefulness as a surrogate marker of epileptogenic zone in a patient with intractable focal epilepsy., Methods: We focused on one of the core electrodes of epileptogenicity, and investigated IIS + HFO in the pre- and post-segment of 30 minutes to all the 6 seizures. We adopted interictal slow in duration of 0.33 to 10 seconds, amplitude ≥50 μV and co-occurring with HFOs, and then divided into 5 groups depending on the amplitude of slow wave., Results: Before and after all the 6 seizures, the number of IIS + HFO was 2,890 at one electrode in the core epileptogenic zone. The number of IIS + HFO significantly decreased for 30 minutes after seizures. Furthermore, the number of IIS + HFO with the amplitude of 200 to 399 μV significantly decreased after seizures., Conclusions: IIS + HFO with the amplitude of 200 to 399 μV was influenced by and decreased after seizures. It may reflect the core part of epileptogenic area as similarly as ictal direct current shifts and ictal HFOs do. IIS + HFO could be called as the term "red slow," which may be useful to delineate at least a part of the epileptogenic zone.

Small interfering of RNA (siRNA) technology has the potential to be a next-generation therapy. However, naked siRNA does not have high transfection efficiency and is rapidly degraded after systemic injection, so an appropriate drug delivery system (DDS) is required for clinical use. Several potential systems have been assessed, clinically focusing on hepatocyte or cancer tissue using siRNA. However, targeting immune cells using siRNA is still challenging, and a new DDS is required. In this study, we prepared lipid nanoparticles (LNP) composed of original cationic lipid, neutral lipid of DOPE (1,2-dioleoyl-sn-glycero-3-phosphoethanolamine) and PEG2000-DMPE (N-(carbonyl-methoxypolyethyleneglycol 2000)-1,2-dimyristoyl-sn-glycero-3-phosphoethanolamine, sodium salt). Our LNP encapsulating siRNA (LNP/siRNA) exerted a knock-down (KD) effect on mouse inflammatory peritoneal macrophages in vitro. In addition, an in vivo KD effect by systemic administration of LNP/siRNA was observed in macrophages and dendritic cells (DCs) in mice. Furthermore, our LNP/siRNA showed in vitro KD effects not only on murine cells but also on human cells like monocyte-derived macrophages (MDMs) and monocyte-derived DCs (MDDCs). These results indicate the potential utility of our LNP for siRNA-based therapy targeting macrophages and DCs. Because these cells are known to have a significant role in several kinds of diseases, and siRNA can specifically suppress target genes that are closely associated with disease states and are untreatable by small molecules or antibodies. Therefore, delivering siRNA by our LNP to macrophages and DCs could provide novel therapies.

Hashimoto's encephalopathy (HE) is a steroid-responsive autoimmune encephalopathy associated with Hashimoto thyroiditis. We herein report a case of HE manifesting "smoldering" limbic encephalitis with persisting symptoms and abnormalities on examinations. Although our patient experienced partial clinical remission after treatment, hippocampal hypermetabolism on [ 18 F] fluorodeoxyglucose positron emission tomography (FDG-PET) and subclinical seizures on video electroencephalography persisted. Hypermetabolism on FDG-PET was improved by additional prednisolone therapy. Thus, as with other autoimmune limbic encephalitis cases, HE can take a course of "smoldering" encephalitis. FDG-PET and electroencephalogram findings can reflect the disease activity degree in such patients, although with certain neurophysiological and biochemical distinctions.

We report a 32-year-old female who presented myoclonus and generalized tonic-clonic seizure since she was 9 year-old. Thereafter, she was diagnosed as Unverricht-Lundborg disease by gene analysis. Although the epileptic seizures were controlled by multiple antiepileptic drugs, her cortical myoclonus remained intractable, which severely interfered her activity of daily living. On admission to our hospital, she presented mild cognitive impairment, dysarthria, severe postural and action myoclonus in all the limbs, severe impairment of coordinative movements, inability of standing and walking by herself, and severe basophobia. After administration of perampanel, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor antagonist, with initial dose of 1 mg/day, and then 16 days later it was increased up to 2 mg/day, the myoclonus dramatically improved and the basophobia also lessened about in 30 days since it started. Moreover, abnormally enlarged amplitudes of short latency somatosensory evoked potentials by median nerve stimulation decreased, which suggested the reduction of abnormal cortical hyperexcitability mainly in the primary sensori-motor cortices. We presented that perampanel is the effective drug for treating the refractory cortical myoclonus and basophobia even with small dosage.

The epilepsy syndrome of autoimmune etiology, namely, autoimmune epilepsy has attracted attention in recent years, as was reflected in the new etiology of "immunity" in the Epilepsy Classification of the International League Against Epilepsy (2017). However, no specific tests other than neuronal antibodies have been established. We proposed a diagnostic algorithm for autoimmune epilepsy and preliminarily investigated its clinical utility. We applied this algorithm to 70 patients who were suspected as having autoimmune epilepsy from clinical symptoms and laboratory findings in our institute. At least one of the three neuronal antibodies (antibodies to N-methyl-D-aspartic acid receptor (NMDAR), glutamic acid decarboxylase (GAD), and voltage-gated potassium channels (VGKC) complex) was evaluated. In this two-step algorithm, the patients were initially screened by clinical features and then evaluated by laboratory findings (neuronal antibodies, cerebrospinal fluid (CSF), MRI, FDG-PET). The results of preliminary application of the algorithm are described. One of the three neuronal antibodies was positive in 13 patients. In this preliminary investigation, it was suggested that two or more abnormal findings in the diagnostic tests (CSF, MRI, FDG-PET) favors the diagnosis of autoimmune epilepsy. On the other hand, two patients with a positive neuronal antibody test failed the first step (clinical features), partly because epilepsy was not the major manifestation of autoimmune encephalitis (VGKC complex antibody) or due to a relatively low titer of the antibody (GAD antibody). Recruitment of the patient cohort with comprehensive neuronal antibody testing and multivariate analysis of laboratory findings is warranted for validation and modification of the proposed algorithm.

Purpose: Benign adult familial myoclonus epilepsy (BAFME) is an autosomal dominant disease representing tremulous myoclonus or cortical tremor and infrequent generalized seizures. We aimed to delineate detailed epidemiological backgrounds in patients with Japanese BAFME and to establish diagnostic criteria based on clinical and electrophysiological findings., Methods: After a previous survey on the current nationwide state of myoclonus epilepsy of adults in Japan, we conducted this survey to delineate the clinical characteristics of Japanese BAFME patients, using a questionnaire to obtain details for individual patients. Based on clinical diagnostic criteria, we analyzed demographic and clinical characteristics of 101 BAFME patients in 74 families., Results: BAFME patients were predominantly female and were widely distributed throughout Japan. Ninety-two patients (91.1%) showed signs of cortical tremor and 84 (83.2%) showed epileptic seizures. Epileptic seizures were infrequent in BAFME patients, but 22.6% of patients had more than one seizure per year at the maximum. Three patients (3.0%) showed cerebellar ataxia, eight (7.9%) showed cognitive impairment, and 13 (12.9%) had psychiatric symptoms. Brain MRI was normal in 74% of patients, and the remaining patients had non-specific abnormal findings. Sodium valproate and clonazepam were the primary drugs used for BAFME patients. The older patients showed significantly more severe and higher rates of abnormal electrophysiological results, which were suggestive of cortical hyperexcitability., Conclusion: Our study successfully delineated the overall clinical characteristics of Japanese BAFME. The correlation between the genetic, clinical, and electrophysiological results will be very important to further elucidate the pathophysiology and treatment of BAFME in the future., (Copyright © 2018 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

In recent years, stereotactic electroencephalography(SEEG)has been focused on as a new invasive method for epileptic focus detection. Although the covering area of the brain surface is smaller than the invasive estimation with subdural electrodes, SEEG can evaluate foci that are deeply seated, noncontiguous leaves, and/or bilateral hemispheres. In addition, SEEG can capture consecutive changes in seizure activity in three dimensions. Due to the development of neuroimaging, computer-assisted, and robotic surgery technology, SEEG insertion began to be commonly used worldwide. Although the approximate complication rates of SEEG are estimated as 1% to 3%, which is lower than that of subdural electrode implantation, the risks of major complications, such as permanent neurological deficit and death, are equivalent. Therefore, meticulous procedure must be needed. To introduce SEEG for intractable partial epilepsy, we acquired approval from the institutional review board and concurrently imported surgical devices and electrodes from the manufacturer in the United States for two surgical candidates. We safely performed SEEG insertion, focal identification, and brain functional mapping by cortical electrical stimulation in two cases. Insertion was difficult for some electrodes, which could be due to the lack of adequate surgical device and large skull angle. Hopefully, the official installation of SEEG will be planned in the near future. We hereby reported tips and pitfalls of SEEG implantation through our own experience in a single institute.

Objective: To assess the feasibility of multi-component electrocorticography (ECoG)-based mapping using "wide-spectrum, intrinsic-brain activities" for identifying the primary sensori-motor area (S1-M1)., Methods: We evaluated 14 epilepsy patients with 1514 subdural electrodes implantation covering the perirolandic cortices at Kyoto University Hospital between 2011 and 2016. We performed multi-component, ECoG-based mapping (band-pass filter, 0.016-300/600 Hz) involving combined analyses of the single components: movement-related cortical potential (<0.5-1 Hz), event-related synchronization (76-200 Hz), and event-related de-synchronization (8-24 Hz) to identify the S1-M1. The feasibility of multi-component mapping was assessed through comparisons with single-component mapping and electrical cortical stimulation (ECS)., Results: Among 54 functional areas evaluation, ECoG-based maps showed significantly higher rate of localization concordances with ECS maps when the three single-component maps were consistent than when those were inconsistent with each other (p < 0.001 in motor, and p = 0.02 in sensory mappings). Multi-component mapping revealed high sensitivity (89-90%) and specificity (94-97%) as compared with ECS., Conclusions: Wide-spectrum, multi-component ECoG-based mapping is feasible, having high sensitivity/specificity relative to ECS., Significance: This safe (non-stimulus) mapping strategy, alternative to ECS, would allow clinicians to rule in/out the possibility of brain function prior to resection surgery., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Promnesia is a feeling of familiarity and foreknowledge and is a manifestation of simple partial seizures (focal aware seizures). It is similar to déjà vu and has been reported to be a rare symptom in patients with temporal lobe epilepsy. Here, we investigated the clinical characteristics in 4 patients with partial epilepsy presenting promnesia. Three out of 4 patients showed abnormal electroencephalography (EEG) and/or MRI findings in the temporal lobe. Furthermore, in 2 patients, promnesia was the only aura. It is important to actively obtain medical history of patients about promnesia because this is useful for identifying the epileptic focus. Further cases need to be analyzed to evaluate the sensitivity and specificity of promnesia for diagnosis and therapy of partial epilepsy.

Locked nucleic acid containing antisense oligonucleotides (LNA-ASOs) have the potential to modulate the disease-related gene expression by the RNaseH-dependent degradation of mRNAs. Pulmonary drug delivery has been widely used for the treatment of lung disease. Thus, the inhalation of LNA-ASOs is expected to be an efficient therapy that can be applied to several types of lung disease. Because the lung has a distinct immune system against pathogens, the immune-stimulatory effect of LNA-ASOs should be considered for the development of novel inhaled LNA-ASOs therapies. However, there have been no reports on the relationship between knock-down (KD) and the immune-stimulatory effects of inhaled LNA-ASOs in the lung. In this report, LNA-ASOs targeting Scarb1 (Scarb1-ASOs) or negative control LNA-ASOs targeting ApoB (ApoB-ASOs) were intratracheally administered to mice to investigate the KD of the gene expression and the immune-stimulatory effects in the lung. We confirmed that the intratracheal administration of Scarb1-ASOs exerted a KD effect in the lung without a drug delivery system. On the other hand, both Scarb1-ASOs and ApoB-ASOs induced neutrophilic infiltration in the alveoli and increased the expression levels of G-CSF and CXCL1 in the lung. The dose required for KD was the same as the dose that induced the neutrophilic immune response. In addition, in our in vitro experiments, Scarb1-ASOs did not increase the G-CSF or CXCL1 expression in primary lung cells, even though Scarb1-ASOs exerted a strong KD effect. Hence, we hypothesize that inhaled LNA-ASOs have the potential to exert a KD effect in the lung, but that they may be associated with a risk of immune stimulation. Further studies about the mechanism underlying the immune-stimulatory effect of LNA-ASOs is necessary for the development of novel inhaled LNA-ASO therapies.

Objective: We aimed to clarify that high frequency activity (HFA) of cortico-cortical evoked potentials (CCEPs), elicited by single pulse electrical stimulation (SPES), reflects cortical excitability., Methods: We recruited 16 patients with refractory partial epilepsy who had chronic subdural electrode implantation for presurgical evaluation. A repetitive SPES was given to (1) the seizure onset zone (SOZ) and (2) the control cortices (non-seizure onset zone: nSOZ). CCEPs were recorded from the neighboring cortices within SOZ and nSOZ. We applied short-time Fourier transform to obtain the induced responses for the timing of early (<50ms after SPES) and late CCEP components and analyzed the logarithmic power change for ripple (<200Hz) and fast ripple (>200Hz) bands., Results: Twenty-one clear CCEPs were recorded for both the SOZ and nSOZ. The HFA power of early CCEPs in SOZ significantly increased compared to that in nSOZ in both frequency bands, particularly in mesial temporal lobe epilepsy (MTLE)., Conclusion: Similar to the features of spontaneous pathological HFOs, the power of stimulus-induced HFAs in SOZ were greater than that outside SOZ, particularly in MTLE., Significance: HFA overriding CCEPs can be a surrogate marker of cortical excitability in epileptic focus., (Copyright © 2017 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Study Objectives: To investigate the changes in cortical neural responses induced by external inputs during phasic rapid eye movement (p-REM) sleep., Methods: Single-pulse electrical stimulation (SPES) was directly applied to the human cortex during REM sleep through subdural electrodes, in seven patients who underwent invasive presurgical evaluation for intractable partial epilepsy. SPES was applied to parts of the cortex through the subdural electrodes, and induced cortical responses were recorded from adjacent and remote cortical areas. Phase-locked corticocortical-evoked potentials (CCEPs) and nonphase-locked or induced CCEP-related high gamma activity (CCEP-HGA, 100-200 Hz), which are considered proxies for cortical connectivity and cortical excitability, respectively, were compared among wakefulness, p-REM (within ±2 seconds of significant bursts of REM), and tonic REM (t-REM) (periphasic REM) periods., Results: During REM sleep, SPES elicited a transient increase in CCEP-HGA, followed by a subsequent decrease or suppression. The HGA suppression during both p-REM and t-REM was stronger than during wakefulness. However, its suppression during p-REM was weaker than during t-REM. On the other hand, the CCEP waveform did not show any significant difference between the two REM periods., Conclusions: Cortical excitability to exogenous input was different between p-REM and t-REM. The change of the cortical excitability in p-REM was directed toward wakefulness, which may produce incomplete short bursts of consciousness, leading to dreams., (© Sleep Research Society 2017. Published by Oxford University Press on behalf of the Sleep Research Society. All rights reserved. For permissions, please e-mail journals.permissions@oup.com.)

A 69-year-old woman undergoing treatment for hypertension and epilepsy was scheduled to undergo cataract surgery. All preoperative examination results were within normal limits. Despite being tense, she walked to the operating room. Approximately 2 minutes after an intravenous line was established by an anesthesia resident, severe hypoxia and bradycardia developed, and she lost consciousness. Cardiopulmonary resuscitation was initiated immediately, and after 1 minute, she regained consciousness, and her breathing and circulation recovered. After admission to the intensive care unit, emergency coronary angiography was performed. The blood flow in all the coronary arteries was normal. However, a decrease in the apical left ventricular wall motion and an increase in the basal wall motion were observed. Based on these findings, Takotsubo cardiomyopathy was diagnosed. The wall motion gradually improved and the patient was discharged from the hospital on postoperative day 15. The respiratory depression and bradycardia were thought to be due to an inadvertent bolus of remifentanil. We surmised that the patient had received a slight amount of retained medication when the anesthesia resident established the intravenous line, which caused severe respiratory depression. It is important to note that adverse effects such as severe respiratory depression and bradycardia can be caused by even small doses of remifentanil., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Brain dysfunction in Japanese benign adult familial myoclonus epilepsy (BAFME) has not been elucidated. To clarify diffuse brain dysfunction as indicated by posterior dominant rhythm (PDR) slowing in patients with BAFME. The frequency of PDR on EEG was studied in 19 BAFME patients (50.6±15.7 years) and 38 age-matched control subjects (50.1±14.5 years). We investigated the relationship between age and PDR in both groups. PDR frequency in the patient group (9.1±0.7 Hz) was significantly slower than that of age-matched control subjects (10.4±1.1 Hz; p<0.0001), regardless of the use of anticonvulsants. There was no significant difference in PDR slowing with age between groups. These findings suggest that Japanese patients with BAFME have mild diffuse brain dysfunction with minimal progression.

Objective In hematological malignancy patients, the complication of acute respiratory failure often reaches a degree of severity that necessitates mechanical ventilation. The objective of the present study was to investigate the therapeutic outcomes of mechanical ventilation in hematological malignancy patients with respiratory failure and to analyze the factors that are associated with successful treatment in order to identify the issues that should be addressed in the future. Methods The present study was a retrospective analysis of 71 hematological malignancy patients with non-cardiogenic acute respiratory failure who were treated with mechanical ventilation at Nippon Medical School Hospital between 2003 and 2014. Results Twenty-six patients (36.6%) were treated with mechanical ventilation in an intensive care unit (ICU). Non-invasive positive pressure ventilation (NPPV) was applied in 29 cases (40.8%). The rate of successful mechanical ventilation treatment with NPPV alone was 13.8%. The rate of endotracheal extubation was 17.7%. A univariate analysis revealed that the following factors were associated with the successful extubation of patients who received invasive mechanical ventilation: respiratory management in an ICU (p=0.012); remission of the hematological disease (p=0.011); female gender (p=0.048); low levels of accompanying non-respiratory organ failure (p=0.041); and the non-use of extracorporeal circulation (p=0.005). A subsequent multivariate analysis revealed that respiratory management in an ICU was the only variable associated with successful extubation (p=0.030). Conclusion The outcomes of hematological malignancy patients who receive mechanical ventilation treatment for respiratory failure are very poor. Respiratory management in an ICU environment may be useful in improving the therapeutic outcomes of such patients.

Sleep-induced changes in human brain connectivity/excitability and their physiologic basis remain unclear, especially in the frontal lobe. We investigated sleep-induced connectivity and excitability changes in 11 patients who underwent chronic implantation of subdural electrodes for epilepsy surgery. Single-pulse electrical stimuli were directly injected to a part of the cortices, and cortico-cortical evoked potentials (CCEPs) and CCEP-related high-gamma activities (HGA: 100-200 Hz) were recorded from adjacent and remote cortices as proxies of effective connectivity and induced neuronal activity, respectively. HGA power during the initial CCEP component (N1) correlated with the N1 size itself across all states investigated. The degree of cortical connectivity and excitability changed during sleep depending on sleep stage, approximately showing dichotomy of awake vs. non-rapid eye movement (REM) [NREM] sleep. On the other hand, REM sleep partly had properties of both awake and NREM sleep, placing itself in the intermediate state between them. Compared with the awake state, single-pulse stimulation especially during NREM sleep induced increased connectivity (N1 size) and neuronal excitability (HGA increase at N1), which was immediately followed by intense inhibition (HGA decrease). The HGA decrease was temporally followed by the N2 peak (the second CCEP component), and then by HGA re-increase during sleep across all lobes. This HGA rebound or re-increase of neuronal synchrony was largest in the frontal lobe compared with the other lobes. These properties of sleep-induced changes of the cortex may be related to unconsciousness during sleep and frequent nocturnal seizures in frontal lobe epilepsy., (© 2015 Wiley Periodicals, Inc.)

Tacrolimus ointment is prescribed for patients with atopic dermatitis, although it is known to cause transient burning sensations and hot flashes in the applied skin. The aim of this study was to evaluate the effects of olopatadine hydrochloride (olopatadine), an antiallergic agent with a histamine H1 receptor (H1R) antagonistic activity, on the incidence of hot flashes induced by topical treatment with tacrolimus ointment in rats. Consequently, the skin temperature was increased by the topical application of tacrolimus ointment in rats, and the rise in skin temperature was inhibited by pretreatment with olopatadine in a dose-dependent manner. Inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation was significantly more potent than that of cetirizine hydrochloride, other antiallergic agent with H1R antagonistic activity, at doses in which both agents exhibit comparable H1R antagonistic activity in rats. These results suggest that H1R antagonistic activity-independent mechanism contribute to the inhibitory effect of olopatadine on tacrolimus-induced skin temperature elevation. Olopatadine also significantly inhibited increases in vascular permeability and nerve growth factor production in the skin induced by topical tacrolimus treatment. Thus, the onset of hot flashes in rats is quantitatively determined by measuring the skin temperature and olopatadine attenuates hot flashes induced by topical tacrolimus ointment in rats, suggesting that the combination application with olopatadine and tacrolimus ointment is useful for improving medication adherence with tacrolimus ointment treatment in patients with atopic dermatitis., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A 62-year-old male was admitted to our hospital due to left lower abdominal pain. Three days before admission, he ate seafood in a Japanese restaurant. Two days before admission, he suffered from intermittent left lower abdominal pain. One day before admission, he developed a high fever and subsequently visited our hospital the following day. Localized tenderness and rebound pain were observed in the left lower abdomen, and C-reactive protein was elevated. Computed tomography revealed a linear high-density object in the distal portion of the small intestine accompanied by edema of the wall, suggesting penetration by something like a fishbone. On the ninth hospital day, double-balloon endoscopy was performed via the transanal route. Yellow foreign material was found in the ileum and was then successfully removed with biopsy forceps. The removed material measured 3 mm in width, 3 cm in length and was slightly curved. It proved to be a bone of the forefoot of a soft-shelled turtle, which had been included on the menu of the restaurant. The patient was completely cured and discharged on the 14th hospital day.

Purpose: To delineate chronological changes of cortical hyperexcitability by long-term follow-up of the amplitudes of somatosensory evoked potentials (SEPs) in patients with Japanese Unverricht-Lundborg disease (ULD)., Method: SEPs to median nerve stimulation were repeatedly examined in 7 genetically diagnosed ULD patients with the mean interval of 11.9 years. The degree of temporal changes in the amplitude of 3 early cortical components, N20, P25 and N35, to the age was analyzed and compared with that of healthy subjects., Results: Their clinical course was almost stable during the follow-up period, namely cessation of generalized tonic-clonic seizures and little or no progression of myoclonus. SEP amplitudes of P25 and N35 were enlarged in all patients and were gradually decreased with aging in ULD on average. The degree of temporal changes of P25 and N35 in ULD was similar or even lower than that of healthy subjects., Conclusion: Enlarged but relatively stable SEP amplitudes had a consistency with so-called self-limited clinical course in Japanese ULD. SEP amplitude could be one of the surrogate markers of the degree of cortical hyperexcitability in ULD during the long-term follow-up period., (Copyright © 2014 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.)

The preservation of language function during brain surgery still poses a challenge. No intraoperative methods have been established to monitor the language network reliably. We aimed to establish intraoperative language network monitoring by means of cortico-cortical evoked potentials (CCEPs). Subjects were six patients with tumors located close to the arcuate fasciculus (AF) in the language-dominant left hemisphere. Under general anesthesia, the anterior perisylvian language area (AL) was first defined by the CCEP connectivity patterns between the ventrolateral frontal and temporoparietal area, and also by presurgical neuroimaging findings. We then monitored the integrity of the language network by stimulating AL and by recording CCEPs from the posterior perisylvian language area (PL) consecutively during both general anesthesia and awake condition. High-frequency electrical stimulation (ES) performed during awake craniotomy confirmed language function at AL in all six patients. Despite an amplitude decline (≤32%) in two patients, CCEP monitoring successfully prevented persistent language impairment. After tumor removal, single-pulse ES was applied to the white matter tract beneath the floor of the removal cavity in five patients, in order to trace its connections into the language cortices. In three patients in whom high-frequency ES of the white matter produced naming impairment, this "eloquent" subcortical site directly connected AL and PL, judging from the latencies and distributions of cortico- and subcortico-cortical evoked potentials. In conclusion, this study provided the direct evidence that AL, PL, and AF constitute the dorsal language network. Intraoperative CCEP monitoring is clinically useful for evaluating the integrity of the language network., (Copyright © 2014 Wiley Periodicals, Inc.)

We recently reported clinical anticipation in Japanese families with benign adult familial myoclonus epilepsy (BAFME). However, it remains unknown whether clinical anticipation is predominantly associated with paternal or maternal transmission. We investigated the relationship between gender of the transmitting parent and clinical anticipation in nine BAFME families. Clinical anticipation regarding either cortical tremor or generalised seizures was observed in all 12 parent/child pairs (8 mother/child pairs and 4 father/child pairs). Moreover, a higher degree of clinical anticipation was associated with maternal transmission than with paternal transmission (p=0.03). Although a causative gene for BAFME still remains unknown, our finding suggests that BAFME and diseases with unstable expanding repeats, including those in non-coding regions, might share a similar molecular mechanism because such diseases often show clinical anticipation with maternal transmission.

Although the survival rate of H1N1-related severe respiratory failure following ECMO therapy was high in several countries, the rate in Japan has been low. Efforts should be made to supply suitable equipments, to train the physicians, and to establish transport system for the patient.

The clinical anticipation in Japanese benign adult familial myoclonus epilepsy (BAFME), defined as earlier onset age of either cortical tremor or generalized seizures or new appearance of those symptoms in the next generation, remains unknown. The onset age and the degree of both cortical tremor and generalized seizures were investigated in nine patients of four BAFME families (mean age: 46.6 ± 18.7 years). Clinical anticipation in the onset age of cortical tremor or generalized seizures was observed in three families, and generalized seizures newly appeared in the next generation in those two families and in another family. Clinical anticipation was observed in four families, which suggests the clinical progression over generation in Japanese BAFME families., (Wiley Periodicals, Inc. © 2011 International League Against Epilepsy.)

Objective: To delineate long-term change of cortical excitability by measuring somatosensory evoked potentials (SEPs) in patients with Unverricht-Lundborg disease (ULD)., Methods: SEPs to median nerve stimulation were repeatedly examined in two genetically proven ULD patients manifesting stable condition over 16 years, namely disabling but non-progressive myoclonus and cessation of generalised tonic-clonic seizures., Results: In both patients, five sets of early cortical components were identified 16 years ago: two tangential components of N20-P20 and P30-N30 and three radial components of P25, N35 and N40. Cortical SEPs were regarded as abnormally enhanced 'giant' based on the N35 amplitude (>mean+3 SD of normal controls). The bimodal negative peaks of N35 and N40 showed different spatial distribution: N35 maximum in the central area and N40 in the centro-parietal area. At present, N35 remained giant while N40 disappeared in both patients., Conclusions: It is possible that currently preserved giant SEPs at least at N35 reflect disabling cortical myoclonus and that disappearance of N40 might reflect a lesser degree of increased cortico-cortical connectivity and/or decreased cortical hyperexcitability in the association cortices. It might possibly have resulted in the disappearance of GTCSs., Significance: We delineated long-term change of giant SEP in ULD., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)