川合 謙介

薬剤抵抗性で難治に経過するてんかん症例に対しては、成人・小児に関わらず、積極的な外科手術適応を考慮すべきであるが、特に小児においてはより早期の手術施行が望まれる。なぜなら、重症てんかん発作の持続が小児の精神運動発達を遅滞、時に退行させうるからである。術後無発作を達成するためには、てんかん原性領域を確実に同定し完全に切除する必要がある。重要な脳機能に関与する部位を含んだ根治的切除は重篤な神経学的後遺症を引き起こす可能性があるが、小児期の脳は可塑性が高く術後神経機能の代償性改善が期待しやすい。さらに、抗てんかん薬の長期内服が患児に及ぼしうる悪影響も早期手術が望まれる要因である。一方で、小児てんかん外科手術が、患児のIQや併存する精神神経疾患などに及ぼす影響については今後更なる検討が必要である。本稿では、小児てんかん外科治療の最も適切なタイミングについて、自験例と文献的考察を交えながら述べる。(著者抄録)

Neuromodulation achieved by vagus nerve stimulation (VNS) induces various neuropsychiatric effects whose underlying mechanisms of action remain poorly understood. Innervation of neuromodulators and a microcircuit structure in the cerebral cortex informed the hypothesis that VNS exerts layer-specific modulation in the sensory cortex and alters the balance between feedforward and feedback pathways. To test this hypothesis, we characterized laminar profiles of auditory-evoked potentials (AEPs) in the primary auditory cortex (A1) of anesthetized rats with an array of microelectrodes and investigated the effects of VNS on AEPs and stimulus specific adaptation (SSA). VNS predominantly increased the amplitudes of AEPs in superficial layers, but this effect diminished with depth. In addition, VNS exerted a stronger modulation of the neural responses to repeated stimuli than to deviant stimuli, resulting in decreased SSA across all layers of the A1. These results may provide new insights that the VNS-induced neuropsychiatric effects may be attributable to a sensory gain mechanism: VNS strengthens the ascending input in the sensory cortex and creates an imbalance in the strength of activities between superficial and deep cortical layers, where the feedfoward and feedback pathways predominantly originate, respectively.

＜Key Points＞(1)小児の薬剤抵抗性てんかんに対しては、成長運動発達に及ぼす影響を考慮すると、できるだけ早期に根治的外科治療が施行されるべきである。(2)外科治療適応とその施行時期決定にあたっては、確実なてんかん病型診断と正確なてんかん焦点局在の同定、各てんかん疾患群の自然歴や予後の把握が必須である。(3)外科治療適応の決定とその施行には、小児科医とてんかん外科医の緊密な連携が必須であるが、てんかん外科医の絶対数は不足しており、各地域における体系的なてんかん診療システムの構築が課題である。(著者抄録)

PURPOSE: The Japanese authorities require a 2-year seizure-free period for a driver's license in people with epilepsy. To evaluate the stringency of the criteria, we calculated the risk of fatal traffic crashes by epileptic seizure and compared that to the risk of fatal traffic crashes among the general population. METHODS: Nation-wide questionnaire surveys to physicians and their patients with epilepsy were conducted to determine the rate of seizure recurrence after given seizure-free periods, average driving time and the rate of traffic crashes by epileptic seizures. The risk of fatal traffic crashes by epileptic seizures was calculated using the method proposed by the Driving License Committee of the EU. The risk of fatal traffic crashes among subgroups of the general population was calculated using the national statistics available. RESULTS: Valid answers were obtained from a total of 548 patients of 138 epilepsy-specialists and 102 non epilepsy-specialist physicians. The relative risks of fatal traffic crashes in people with epilepsy with 1-year and 2-year seizure-free periods were 1.22 and 1.15, compared to the general population, while the ones in males in their twenties, people aged 60 and over, people aged 65 and over, and people aged 75 and over among the general population were 1.71, 1.31, 1.52 and 2.69, respectively. CONCLUSION: The risk of fatal traffic crashes in people with epilepsy for 1-year and 2-year seizure-free periods was estimated to be lower than that of some age groups in the general population. The increased risk in 1-year seizure freedom from that in 2-year seizure freedom was relatively small.

An epileptic seizure during the course of driving can result in a serious car accident. However, basic data on how epileptic seizures actually affect driving performance is significantly lacking. To understand the relationship, it is crucial to conduct not only behavioral but also electroencephalogram (EEG) analysis during epileptic seizures. Therefore, we developed a mobile driving simulator which makes it possible to record driving-related parameters time-lined with video-EEG. We report a case in which behavioral and EEG changes were successfully recorded during ictal periods of focal impaired awareness seizure in a patient engaged with the system. With the current lack of objective data describing how seizures impair driving performance, such an accumulation of information could improve personalized medical management, influence legal adjudication and assist in the development of driving support systems for people with epilepsy.

薬剤抵抗性てんかん患者に対する迷走神経刺激療法(vagus nerve stimulation:VNS)は、米国では1997年から、本邦では2010年から施行されており、発作軽減を目的とした緩和療法として確立した治療法である。一方で、てんかん患者に対する使用経験から、VNSがうつ病に対しても有効である可能性が注目され、米国では2005年に薬剤抵抗性うつ病(treatment-resistant depression:TRD)に対するVNSの施行が米国食品医薬品局(FDA)により認可された。ただ、TRDに対するVNSの有効性を高いエビデンスレベルで示した研究は少なく、本邦では未承認である。また、うつ病のみならず、そもそもてんかんに対するVNSの作用機序も未だに明らかになっていない。本稿では、TRDに対するVNSの有効性と、主に動物実験から得られたVNSの作用機序に関する知見について、文献的考察を交えて述べる。(著者抄録)

Data presented in this article are related to our article entitled "Unilateral posterior reversible encephalopathy syndrome: A case report" [1]. Cases of Posterior Reversible Encephalopathy Syndrome (PRES) involving unilateral lesions are very rare. We searched the PubMed database using keywords such as PRES, unilateral, and asymmetric and found a small number of cases to include in our review. We summarized the characteristics of these reported cases of unilateral PRES, including our case.

Both frame-based stereotaxy and frameless stereotaxy are established surgical procedures. However, they each have their respective disadvantages when used in the biopsy of a deep-seated lesion. To overcome the drawbacks associated with these procedures, we evaluated the feasibility of applying augmented reality (AR) to stereotactic biopsy. We applied our trans-visible navigator (TVN) to frame-based stereotactic biopsy in five cases of deep-seated lesions. This navigation system uses the AR concept, allowing surgeons to view three-dimensional virtual models of anatomical structures superimposed over the surgical field on a tablet personal computer. Using TVN, we could easily confirm a clear trajectory avoiding the important structures as well as the target point's location in the lesion. Use of the stereotactic apparatus allowed the surgeon to easily advance the biopsy probe to the target point. Consequently, a satisfactory histopathological diagnosis without complication was achieved in all cases. In conclusion, applying AR to stereotactic biopsy is feasible and may improve the safety of the procedure.

INTRODUCTION: Epileptologists could benefit from a diagnosis support system that automatically detects seizures because visual inspection of long-term electroencephalograms (EEGs) is extremely time-consuming. However, the diversity of seizures among patients makes it difficult to develop universal features that are applicable for automatic seizure detection in all cases, and the rarity of seizures results in a lack of sufficient training data for classifiers. METHODS: To overcome these problems, we utilized an autoencoder (AE), which is often used for anomaly detection in the field of machine learning, to perform seizure detection. We hypothesized that multichannel EEG signals are compressible by AE owing to their spatio-temporal coupling and that the AE should be able to detect seizures as anomalous events from an interictal EEG. RESULTS: Through experiments, we found that the AE error was able to classify seizure and nonseizure states with a sensitivity of 100% in 22 out of 24 available test subjects and that the AE was better than the commercially available software BESA and Persyst for half of the test subjects. CONCLUSIONS: These results suggest that the AE error is a feasible candidate for a universal seizure detection feature.

Directing attention to movement outcomes (external focus; EF), not body movements (internal focus; IF), is a better cognitive strategy for motor performance. However, EF is not effective in some healthy individuals or stroke patients. We aimed to identify the neurological basis reflecting the individual optimal attentional strategy using functional near-infrared spectroscopy. Sixty-four participants (23 healthy young, 23 healthy elderly, and 18 acute stroke) performed a reaching movement task under IF and EF conditions. Of these, 13 healthy young participants, 11 healthy elderly participants, and 6 stroke patients showed better motor performance under EF conditions (EF-dominant), whereas the others showed IF-dominance. We then measured prefrontal activity during rhythmic hand movements under both attentional conditions. IF-dominant participants showed significantly higher left prefrontal activity than EF-dominant participants under IF condition. In addition, receiver operating characteristic analysis supported that the higher activity in the left frontopolar and dorsolateral prefrontal cortices could detect IF-dominance as an individual's optimal attentional strategy for preventing motor performance decline. Taken together, these results suggest that prefrontal activity during motor tasks reflects an individual's ability to process internal body information, thereby conferring IF-dominance. These findings could be applied for the development of individually optimized rehabilitation programs.

Auditory contextual processing has been assumed to be based on a hierarchical structure consisting of the primary auditory cortex, superior temporal gyrus (STG), and frontal lobe. Recent invasive studies on mismatch negativity (MMN) have revealed functional segregation for auditory contextual processing such as neural adaptation in the primary auditory cortex and prediction in the frontal lobe. However, the role of the STG remains unclear. We obtained induced activity in the high gamma band as mismatch response (MMR), an electrocorticographic (ECoG) counterpart to scalp MMN, and the components of MMR by analyzing ECoG data from patients with refractory epilepsy in an auditory oddball task paradigm. We found that MMR localized mainly in the bilateral posterior STGs, and that deviance detection largely accounted for MMR. Furthermore, adaptation was identified in a limited number of electrodes on the superior temporal plane. Our findings reveal a mixed contribution of deviance detection and adaptation depending on location in the STG. Such spatial considerations could lead to further understanding of the pathophysiology of relevant psychiatric disorders.

Survivin, a member of the inhibitors of apoptosis protein gene family, inhibits the activity of caspase, leading to a halt of the apoptotic process. Our study focused on the neuroprotective effect of survivin after transient middle cerebral artery occlusion (MCAO) with intraparenchymal administration of an adeno-associated virus (AAV) vector. His-tagged survivin was cloned and packaged into the AAV-rh10 vector. Four-week-old Sprague-Dawley rats were injected with 4 × 109  vg of AAV-GFP or AAV-His-survivin into the right striatum and were treated 3 weeks later with transient MCAO for 90 min. Twenty-four hours after MCAO, functional and histological analyses of the rats were performed. The result showed that rats that had been treated with AAV-green fluorescent protein (GFP) and those that had been treated with AAV-His-survivin did not show a significant difference in neurological scores 24 hr after MCAO, however, infarction volume was significantly reduced in the AAV-His-survivin group compared to that in the AAV-GFP group. Although the neutrophil marker myeloperoxidase did not show a significant difference in the ischemic boundary zone, cells positive for active caspase-3 and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling were significantly decreased in the AAV-His-survivin group. In conclusion, survivin overexpression in the ischemic boundary zone induced by using an AAV vector has the potential for amelioration of ischemic damage via an antiapoptotic mechanism.

Adeno-associated virus (AAV) is an ideal vector for gene transduction into the central nervous system because of its safety and efficiency. While it is currently widely used for clinical trials and is expected to become more widespread, the appropriate combination of viral serotypes and promoters have not been fully investigated. In this study, we compared the transduced gene expression of AAVrh10 to AAV5 in gerbil hippocampus using three different promoters, including cytomegalovirus (CMV), chicken β-actin promoter with the CMV immediate-early enhancer (CAG), and the Synapsin 1 (Syn1) promoter. Four-week-old male gerbils underwent stereotaxic injection with 1 × 1010 viral genome of AAV carrying green fluorescent protein (GFP). Quantification of the GFP-positive areas 3 weeks after injection showed that AAVrh10-CMV and AAVrh10-CAG were the most efficient (p < 0.001, compared with the control) and AAVrh10-Syn1 and AAV5-CMV were the next most efficient (p < 0.05, compared with the control). On the other hand, AAV5-Syn1 showed little expression, which was only observed at the injected site. In conclusion, we should note that some combinations of viral capsids and promoters can result in failure of gene delivery, while most of them will work appropriately in the transgene expression in the brain.

Background: In superficial temporal artery−middle cerebral artery (STA-MCA) anastomosis, there is a certain risk of intraoperative acute occlusion of the bypass that can cause operative complications. Objective: We sought to assess the efficacy of resuturing at the same site after intraoperative acute occlusion of the bypass. Methods: In total, 129 STA-MCA anastomosis operations were performed on 125 patients at our institution. The electronic medical records of each patient were reviewed to gather information regarding intraoperative occlusion events, and the operative videos and postoperative radiologic images were also reviewed. Results: Twelve intraoperative acute occlusions were identified. In each case, resuturing was performed after cutting all knots, flushing the thrombus, and trimming the edges of the STAs. In 11 cases, indocyanine green videoangiography and/or Doppler sonography revealed patency during the operation, which was confirmed by postoperative magnetic resonance angiography. None of the 12 cases exhibited high-signal intensities in the MCA area on diffusion-weighted images. Conclusion: If intraoperative acute occlusion of STA-MCA anastomosis occurs, reanastomosis at the site should be the first option.

Restoration of speech communication for locked-in patients by means of brain computer interfaces (BCIs) is currently an important area of active research. Among the neural signals obtained from intracranial recordings, single/multi-unit activity (SUA/MUA), local field potential (LFP), and electrocorticography (ECoG) are good candidates for an input signal for BCIs. However, the question of which signal or which combination of the three signal modalities is best suited for decoding speech production remains unverified. In order to record SUA, LFP, and ECoG simultaneously from a highly localized area of human ventral sensorimotor cortex (vSMC), we fabricated an electrode the size of which was 7 by 13 mm containing sparsely arranged microneedle and conventional macro contacts. We determined which signal modality is the most capable of decoding speech production, and tested if the combination of these signals could improve the decoding accuracy of spoken phonemes. Feature vectors were constructed from spike frequency obtained from SUAs and event-related spectral perturbation derived from ECoG and LFP signals, then input to the decoder. The results showed that the decoding accuracy for five spoken vowels was highest when features from multiple signals were combined and optimized for each subject, and reached 59% when averaged across all six subjects. This result suggests that multi-scale signals convey complementary information for speech articulation. The current study demonstrated that simultaneous recording of multi-scale neuronal activities could raise decoding accuracy even though the recording area is limited to a small portion of cortex, which is advantageous for future implementation of speech-assisting BCIs.

＜文献概要＞I.はじめに 難治性てんかんに対してさまざまな刺激療法が行われてきたが,現在,普及し拡大を続けている植込み型デバイスは,迷走神経刺激療法(vagus nerve stimulation:VNS)のシステム(VNS Therapy System. LivaNova USA, Inc., Houston, TX, USA)である.1980年代から基礎研究が進められ,欧州では1994年,米国では1997年に正式に認可された.VNSの治験は本邦においても1993〜1997年にかけて行われ,認可申請されたが,承認を得るには時間を要した.2006年10月から始まった厚生労働省の「医療ニーズの高い医療機器等の早期導入に関する検討会」の第2回会合(2007年2月)でVNSが取り上げられ,これによって本邦においてもようやく日の目を見ることとなった.2010年1月に薬事法承認,同年7月に保険適用となったことで保険償還が可能となり,急速に普及していった.VNSのデバイスは,本邦での治験の頃はNeuroCybernetic Prosthesis(Model 100)というプロトタイプであったが,2010年から実際に使われ始めたのは小型化されたDemipulse(Model 103)で

Objectives To develop an in vitro model for studying the biological effect of complex-flow stress on endothelial cells in three-dimensional (3D) patient-specific vascular geometry. Materials and methods A vessel replica was fabricated with polydimethylsiloxanes using 3D printing technology from vascular image data acquired by rotational angiography. The vascular model was coated with fibronectin and immersed in a tube filled with a cell suspension of endothelium, and then cultured while being slowly rotated in three dimensions. Culture medium with viscosity was perfused in the circulation with the endothelialized vascular model. A computational fluid dynamics (CFD) study was conducted using perfusion conditions used in the flow experiment. The morphology of endothelial cells was observed under a confocal microscope. Results The CFD study showed low wall shear stress and circulating flow in the apex of the basilar tip aneurysm, with linear flow in the parent artery. Confocal imaging demonstrated that the inner surface of the vascular model was evenly covered with monolayer endothelial cells. After 24 h of flow circulation, endothelial cells in the parent artery exhibited a spindle shape and aligned with the flow direction. In contrast, endothelial cells in the aneurysmal apex were irregular in shape and size. Conclusions A geometrically realistic intracranial aneurysm model with live endothelial lining was successfully developed. This in vitro model enables a new research approach combining study of the biological impact of complex flow on endothelial cells with CFD analysis and patient information, including the presence of aneurysmal growth or rupture.

Purpose: Proper judgement of the aptitude of people with epilepsy (PWE) for driving is a critical issue, both medically and socially. One thus far reported approach is a quantitative comparison of the risk of fatal traffic accidents caused by PWE drivers and that by subgroups of drivers in the general population. We propose a new approach that compares the risk posed by PWE drivers and that by sud-den death of occupational drivers, and the maximum driving time for PWE based on that comparison. Method: The risk of fatal traffic accidents was estimated using four variables. The value assigned to each variable was determined using reports and statistics. Results: The risk of fatal traffic accidents caused by sudden death of occupational drivers was estimated to be 7.6×10-5/year, 4.9×10-5/year, and 1.7×10-5/year for large-sized, mid-sized and normal-sized vehicles. The risk of fatal traffic accidents caused by PWE drivers was estimated to be 5.3×10-5/year and 3.2×10-5/year for PWE with seizure-free periods of 1 year and 2 years, respectively. The maxi-mum acceptable driving time for PWE having a 2-year seizure-free period at the equivalent risk caused by sudden death of occupational drivers of mid-sized vehicles was estimated to be 304 min/week. Conclusion: The risk of fatal traffic accidents caused by PWE drivers can be evaluated by com-paring to that caused by sudden death of occupational drivers. Such risk posed by PWE drivers having a 2-year seizure-free period was less than that caused by sudden death of occupational drivers of mid-sized vehicles. Assuming that the society accepts the latter risk, PWE may be permitted to drive for an estimated maximum time at the equivalent risk of causing a fatal accident.

Introduction Self-made devices composed of agar and gelatin gel were used for resident training in intra-axial brain tumor resection. The mixture gel of agar and gelatin is retractable and can be suctioned. Hardness of the gel depends on the concentration of the solution. Therefore, by changing the concentration, it is easy to make gels of various hardness. Methods In this study, a mass of gel that looked like a tumor was placed into another gel that looked like the brain. A part of the “brain” was regarded as the eloquent area. Three types of “tumor” were prepared: hard, moderately hard, and soft tumors. Residents tried to remove the tumor entirely with minimal brain invasion. The training was repeated with 3 types of gel. After resection, the weight of the residual tumor, resected normal brain, and resected eloquent area were measured, and the time taken for removal was recorded. Results These data were compared between residents and neurosurgeons. We also analyzed how these data improved with repeated practice. In most cases, residual tumor, resected normal brain, resected eloquent area, and time taken for removal were less in neurosurgeons than in residents. Repeated training made residents more skillful. The responses of the trainees were almost all favorable. Conclusions Our devices with “tumors” of various hardness appear to be suitable for resident training in each surgical skill. For the next step of this study, we will attempt to fabricate more practical 3-dimensional gel models for presurgical simulation.

Background: The lesionectomy is a general surgical procedure for treating focal epilepsy resulting from a structural abnormality, but a favorable outcome cannot be achieved in some patients, especially patients whose symptomatogenic zone is located in remote regions. Herein we propose the surgical disconnection of the seizure propagation pathway, which consists of short and long associating fibers linking the epileptogenic zone to the remote symptomatogenic zone, as an effective method of achieving favorable seizure outcomes in patients with posterior cortex epilepsy. Methods: Three patients with intractable epilepsy showing a structural abnormality in the medial posterior cortex participated in this study. Their habitual seizures were complex partial seizures stemming from remote symptomatogenic zones. Seizure propagation-related fibers were assumed by non-invasive examination and semiology. Results: Cingulum and superior/inferior longitudinal fasciculus were considered to form main seizure propagation pathway. Based on the preoperative assumption and the intraoperative intracranial electroencephalogram findings, a lesionectomy and corticectomy were performed for 2 patients while a clusterectomy and corticectomy were performed for the remaining patient. The resection area was extended in the direction of the association fibers to disconnect the remote symptomatogenic zone completely from the epileptogenic zone. Engel class I was achieved in all the patients. Conclusion: The current study suggested that assuming the presence of association fibers was an important factor for achieving a favorable outcome in the surgical treatment of posterior cortex epilepsy. Though further study is required, disconnection surgery is recommended as a treatment option for cases in which the epileptogenic zone is located in an eloquent area.

BACKGROUND: Safe entry to the inferior horn is required for a selective approach to the medial temporal region. This can be challenging sometimes for inexperienced surgeons. Our objective was to verify the usefulness of the deep medullary vein (DMV) as an intraoperative landmark for safely entering the inferior horn during the transsylvian selective approach to the mesial temporal region. METHODS: Videos of 8 cases of transsylvian selective amygdalohippocampectomies performed at the University of Tokyo Hospital from 2013 to 2015 were reviewed. Consistency of the DMV and time required to open the inferior horn via the temporal stem through the inferior limiting sulcus were retrospectively evaluated. RESULTS: DMVs were identified in all cases; the average number identified was 2.5 +/- 0.3 (mean +/- SE). The inferior horn was opened without disorientation in all cases, with mean dissecting time of 7.0 minutes +/- 1.1. No complications were caused by disorientation within the temporal stem white matter. CONCLUSIONS: Consideration of the venous system within the white matter and following the DMV could reduce the risk of disorientation and enable the surgeon to reach the inferior horn in a straightforward manner without accidental white matter damage.

ObjectivesThe purpose of this study was to examine the feasibility of an optical see-through head-mounted display (OST-HMD) to improve ergonomics during ultrasound-guided fine-needle aspiration (FNA) in the neck region. MethodsThis randomized controlled study compared an OST-HMD with a normal ultrasound monitor during an ultrasound-guided FNA in the neck region. Patients with a neck tumor were recruited and randomized into one of two groups. Two practitioners performed ultrasound-guided FNA with or without the HMD, as indicated. An independent researcher measured the procedure time, the number and time of head movements, as well as the number of needle redirections. In addition, practitioners completed questionnaires after performing the FNA on each patient. ResultsIn 93% of the sessions with the OST-HMD, practitioners performed ultrasound-guided FNA without turning the patients' heads. There was no difference in procedural time and number of needle redirections between the two groups. Results from the questionnaire revealed not only good wearability and low fatigue, but also the practitioners' preference for the HMD. ConclusionsThe OST-HMD improved the practitioners' ergonomics and can be adopted for performing ultrasound-guided interventional procedures in clinical settings.