Effective Epilepsy Surgery for Post-Traumatic West Syndrome Following Abusive Head Trauma.

West syndrome, an infantile developmental and epileptic encephalopathy with a deleterious impact on long-term development, requires early treatment to minimize developmental abnormality; in such cases, epilepsy surgery should be considered a powerful therapeutic option. We describe a 10-month-old female admitted with West syndrome associated with a hemispheric lesion following abusive head trauma. Her seizures were suppressed by hemispherotomy at 12 months of age, leading to developmental improvement. Surgical treatment of West syndrome following traumatic brain injury has not been reported previously but is worth considering as a treatment option, depending on patient age and brain plasticity.

Usefulness of Transcranial Motor Evoked Potential in Clipping Surgery for Cerebral Aneurysms-Introduction of a New Protocol for Stable Monitoring.

The usefulness of transcranial motor evoked potentials (Tc-MEPs) in clipping surgery has been reported. However, numerous false positive and false negative cases were reported. We report the usefulness of a new protocol compared with direct cortical MEP (Dc-MEP).Materials were 351 patients who underwent aneurysmal clipping under simultaneous monitoring of Tc- and Dc-MEPs. A total of 337 patients without hemiparesis and 14 with hemiparesis were separately analyzed. Intraoperative changes of Tc-MEP thresholds were examined in the first 50 patients without hemiparesis. The stimulation strength of Tc-MEP was set at +20% of the stimulation threshold. As thresholds changed intraoperatively, thresholds were examined every 10 min and changed stimulation strength.Stimulation thresholds of Tc-MEP were significantly decreased after craniotomy and significantly increased after CSF aspiration. The recording ratios of Tc- and Dc-MEPs were 98.8% and 90.5%, respectively. Out of 304 patients without MEP change, 5 patients developed transient or mild hemiparesis with infarction of the territory of the perforating artery arising from the posterior communicating artery. Out of 31 patients whose MEP transiently disappeared, 3 patients developed transient or mild hemiparesis. The other two patients without MEP recovery manifested persistent hemiparesis. In 14 patients with preoperative hemiparesis, 3 patients whose healthy/affected ratio of Tc-MEP was large developed severe persistent hemiparesis.We clarified the intraoperative changes of Tc-MEP thresholds for the first time. A new protocol of Tc-MEP that followed thresholds and changed stimulation strength to +20% of thresholds is useful for stable monitoring. The usefulness of Tc-MEP is the same as that or better than that of Dc-MEP.

[Settings and Decisions of Monitoring].

Since the beginning of the 21st century, as intraoperative monitoring has been steadily spreading in Japan and globally, the values of motor-evoked potentials, visual-evoked potentials, and cortical-evoked potentials have been described. There are a wide variety of monitoring methods; the diseases handled are not limited to brain lesions, but extend also to spinal cord and spinal lesions; and there are many problems that have not yet been solved. Possible precautions are indicated by means of a video of an actual case site. Considerations are presented regarding the setting of this monitoring method, utilized in relatively frequent diseases and associated intraoperative judgments.

IDH-mutant Astrocytoma Arising in the Brainstem with Symptom Improvement by Foramen Magnum Decompression: A Case Report.

Diffusely infiltrative midline gliomas are known to have a poor prognosis. The standard treatment for typical diffuse midline glioma in the pons is local radiotherapy as surgical resection is inappropriate. This case reports a brainstem glioma in which stereotactic biopsy and foramen magnum decompression were concomitantly performed to confirm the diagnosis and improve symptoms. A 23-year-old woman was referred to our department with a chief complaint of headache for six months. Magnetic resonance imaging (MRI) showed diffuse T2 hyperintense swelling of the brainstem with the pons as the main locus. Enlargement of the lateral ventricles was observed because of cerebrospinal fluid obstruction out of the posterior fossa. This was atypical for a diffuse midline glioma in terms of the longstanding slow progression of symptoms and patient age. Stereotactic biopsy was performed for diagnosis, and foramen magnum decompression (FMD) was concomitantly performed to treat the obstructive hydrocephalus. The histological diagnosis was astrocytoma, IDH-mutant. Post-surgery, the patient's symptoms were relieved, and she was discharged on the fifth day after surgery. The hydrocephalus was resolved, and the patient returned to normal life without any symptoms. The tumor size follow-up with MRI demonstrated no marked change for 12 months. Even though diffuse midline glioma is considered to have a poor prognosis, clinicians should contemplate if it is atypical. In atypical cases like the one described herein, surgical treatment may contribute to pathological diagnosis and symptom improvement.

Synergistic therapeutic effects of intracerebral transplantation of human modified bone marrow-derived stromal cells (SB623) and voluntary exercise with running wheel in a rat model of ischemic stroke.

BACKGROUND: Mesenchymal stromal cell (MSC) transplantation therapy is a promising therapy for stroke patients. In parallel, rehabilitation with physical exercise could ameliorate stroke-induced neurological impairment. In this study, we aimed to clarify whether combination therapy of intracerebral transplantation of human modified bone marrow-derived MSCs, SB623 cells, and voluntary exercise with running wheel (RW) could exert synergistic therapeutic effects on a rat model of ischemic stroke. METHODS: Wistar rats received right transient middle cerebral artery occlusion (MCAO). Voluntary exercise (Ex) groups were trained in a cage with RW from day 7 before MCAO. SB623 cells (4.0 × 105 cells/5 µl) were stereotactically injected into the right striatum at day 1 after MCAO. Behavioral tests were performed at day 1, 7, and 14 after MCAO using the modified Neurological Severity Score (mNSS) and cylinder test. Rats were euthanized at day 15 after MCAO for mRNA level evaluation of ischemic infarct area, endogenous neurogenesis, angiogenesis, and expression of brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF). The rats were randomly assigned to one of the four groups: vehicle, Ex, SB623, and SB623 + Ex groups. RESULTS: SB623 + Ex group achieved significant neurological recovery in mNSS compared to the vehicle group (p < 0.05). The cerebral infarct area of SB623 + Ex group was significantly decreased compared to those in all other groups (p < 0.05). The number of BrdU/Doublecortin (Dcx) double-positive cells in the subventricular zone (SVZ) and the dentate gyrus (DG), the laminin-positive area in the ischemic boundary zone (IBZ), and the mRNA level of BDNF and VEGF in SB623 + Ex group were significantly increased compared to those in all other groups (p < 0.05). CONCLUSIONS: This study suggests that combination therapy of intracerebral transplantation SB623 cells and voluntary exercise with RW achieves robust neurological recovery and synergistically promotes endogenous neurogenesis and angiogenesis after cerebral ischemia, possibly through a mechanism involving the up-regulation of BDNF and VEGF.

Two Cases of Monozygotic Twins with Early-onset Isolated (DYT1) Dystonia Effectively Treated with Bilateral Globus Pallidus Internus Stimulation.

Early-onset isolated (DYT1) dystonia is one of the most common forms of primary dystonia in childhood, and deep brain stimulation of the globus pallidus internus (GPi-DBS) is a highly effective treatment for it. However, the effectiveness of GPi-DBS in monozygotic twins with DYT1 dystonia has never been reported globally. Here, we report the cases of monozygotic twins with DYT1 dystonia who were treated using GPi-DBS, and we include a literature review. The younger brother showed an abnormal gait, with external rotation of the right lower leg at 6 years old. The symptoms gradually became so severe that he had difficulty walking on his own at 9 years of age. Treatment with levodopa-carbidopa partially resolved his symptoms, but most of the symptoms remained. Meanwhile, the older brother developed dystonia in both upper limbs at 8 years of age, with gradual symptom progression. At 13 years of age, they were diagnosed with DYT1 dystonia. Bilateral GPi-DBS was performed in both patients at 16 years of age. Their symptoms remarkably improved after surgery. The Burke-Fahn-Marsden dystonia rating scale (BFMDRS) movement score was reduced from 52 to 2 points for the younger brother and from 35 to 1 point for the older brother. Even if monozygotic twins have the same genes, the onset and severity of symptoms might vary in accordance with differences in epigenomic profiles. However, GPi-DBS treatment was very effective for the two cases; thus, we should consider the surgical interventions for each patient.

[Infections in Functional Neurosurgery:Focusing on Device-based Surgery].

Functional neurosurgery for epilepsy, movement disorders, and spasticity includes some device-based surgeries such as deep brain stimulation, subdural electrode placement, vagus nerve stimulation, and baclofen pump implantation. These surgeries have a higher risk of surgical site infection(SSI)than other general neurological surgeries. Furthermore, because device removal after infection can significantly impair patients'activities of daily living and quality of life, SSI in functional neurosurgery is a worrisome surgical complication. In this study, we conducted a mini-review of the risk of infection in each device-based surgery and described associated surgical procedures and preparations performed at our institution, with a focus on infection prevention.

Transplantation of modified human bone marrow-derived stromal cells affords therapeutic effects on cerebral ischemia in rats.

AIMS: SB623 cells are human bone marrow stromal cells transfected with Notch1 intracellular domain. In this study, we examined potential regenerative mechanisms underlying stereotaxic transplantation of SB623 cells in rats with experimental acute ischemic stroke. METHODS: We prepared control group, empty capsule (EC) group, SB623 cell group (SB623), and encapsulated SB623 cell (eSB623) group. Transient middle cerebral artery occlusion (MCAO) was performed on day 0, and 24 h after MCAO, stroke rats received transplantation into the envisioned ischemic penumbra. Modified neurological severity score (mNSS) was evaluated, and histological evaluations were performed. RESULTS: In the mNSS, SB623 and eSB623 groups showed significant improvement compared to the other groups. Histological analysis revealed that the infarction area in SB623 and eSB623 groups was reduced. In the eSB623 group, robust cell viability and neurogenesis were detected in the subventricular zone that increased significantly compared to all other groups. CONCLUSION: SB623 cells with or without encapsulation showed therapeutic effects on ischemic stroke. Encapsulated SB623 cells showed enhanced neurogenesis and increased viability inside the capsules. This study reveals the mechanism of secretory function of transplanted SB623 cells, but not cell-cell interaction as primarily mediating the cells' functional benefits in ischemic stroke.

A Case of a Solitary Cortical Tuber with No Other Manifestations of Tuberous Sclerosis Complex Mimicking Focal Cortical Dysplasia Type II with Calcification.

Cortical tubers are one of the typical intracranial manifestations of tuberous sclerosis complex (TSC). Multiple cortical tubers are easy to diagnose as TSC; however, a solitary cortical tuber without any other cutaneous or visceral organ manifestations can be confused with other conditions, particularly focal cortical dysplasia. We report a surgical case of refractory epilepsy caused by a solitary cortical tuber mimicking focal cortical dysplasia type II, and describe the radiological, electrophysiological, and histopathological findings of our case.

[Essential Tremor That is Difficult to Improve with Standard Medical Treatment-Suppression: Surgical Treatment of Tremor].

Drug-refractory essential tremors, especially those in the upper extremities, may benefit from surgical treatment. Currently, three main treatment methods are available: deep brain stimulation (DBS), radiofrequency coagulation (RF), and magnetic resonance -guided focused ultrasound surgery (MRgFUS). DBS is a device-based therapy, and its effects are reversible, whereas RF and FUS create irreversible coagulation lesions. DBS and RF require the direct puncturing of the target, whereas FUS focuses ultrasound from extracranial sources. The primary target is the ventralis intermedius of the thalamus (Vim); however, the posterior subthalamic area (PSA) is also reportedly an effective target site. In this article, we will summarize the features of the three treatments for essential tremors, and discuss the treatment strategies and methods for each symptom.

Spinal Surgery after Bilateral Subthalamic Stimulation for Patients with Parkinson's Disease: A Retrospective Outcome Analysis of Pain and Functional Control.

Parkinson's disease (PD) patients often suffer from spinal diseases requiring surgeries, although the risk of complications is high. There are few reports on outcomes after spinal surgery for PD patients with deep brain stimulation (DBS). The objective of this study was to explore the data on spinal surgery for PD patients with precedent DBS. We evaluated 24 consecutive PD patients with 28 spinal surgeries from 2007 to 2017 who received at least a 2-year follow-up. The characteristics and outcomes of PD patients after spinal surgery were compared to those of 156 non-PD patients with degenerative spinal diseases treated in 2013-2017. Then, the characteristics, outcomes, and spinal alignment of PD patients receiving DBS were analyzed in degenerative spinal/lumbar diseases. The mean age at the time of spinal surgery was 68 years. The Hoehn and Yahr score regarding PD was stage 1 for 8 patients, stage 2 for 2 patients, stage 3 for 8 patients, stage 4 for 10 patients, and stage 5 for 0 patient. The median preoperative L-DOPA equivalent daily dose was 410 mg. Thirteen patients (46%) received precedent subthalamic nucleus (STN) DBS. Lumbar lesions with pain were common, and operation and anesthesia times were long in PD patients. Pain and functional improvement of PD patients persisted for 2 years after surgery with a higher complication rate than for non-PD patients. PD patients with STN DBS maintained better lumbar lordosis for 2 years after spinal surgery. STN DBS significantly maintained spinal alignment with subsequent pain and functional amelioration 2 years after surgery. The outcomes of spinal surgery for PD patients might be favorably affected by thorough treatment for PD including DBS.

[Programing of Deep Brain Stimulation and Features of Devices].

Deep brain stimulation(DBS)is an effective therapy for conditions involving drug-resistant involuntary movements, such as Parkinson's disease, tremor, and dystonia. Programming of DBS, as well as strict surgical indications, appropriate target selection, and accurate electrode placement, is one of the most important factors in the success of DBS. To obtain effective stimulation for a long period, it is important to expand the therapeutic window and reduce side effects. Recent advances in DBS devices have dramatically expanded the variety of stimulus settings. While the indication criteria of DBS and surgical techniques have been established, the details of the programming algorithm are not yet unified. In this paper, we describe the features of each device, basic programming methods, management of DBS-related side effects, and advanced stimulus methods.

Preoperative Risks of Cerebral Infarction in Pediatric Moyamoya Disease.

Background and Purpose: In pediatric moyamoya disease, there have been few reports of the risk factors for preoperative cerebral infarction, especially during the waiting period before surgery. The clinical and radiological findings of surgically treated pediatric moyamoya patients were evaluated to analyze the risk factors for cerebral infarction seen from onset to surgery. Methods: Between August 2003 and September 2019, 120 hemispheres of 71 patients under 18 years of age with moyamoya disease were surgically treated by direct and indirect bypass procedures. The mean age of all surgical hemispheres at diagnosis was 6.7±3.9 years (6 months­17 years). The potential risk factors for preoperative infarction were examined statistically. Results: Multivariate logistic regression analysis showed that risk factors for infarction at the time of diagnosis were age at diagnosis (odds ratio [OR], 0.68 [95% CI, 0.57­0.82]; P<0.0001) and the magnetic resonance angiography (MRA) score (OR, 2.29 [95% CI, 1.40­3.75]; P=0.001). Univariate analysis showed that risk factors for infarction while waiting for surgery were age at diagnosis (OR, 0.61 [95% CI, 0.46­0.80]; P<0.0001), the MRA score (OR, 1.75 [95% CI, 1.26­2.41]; P=0.0003), and onset of infarction (OR, 40.4 [95% CI, 5.08­322.3]; P<0.0001). Multiple comparisons showed that patients under 4 years of age were at a significantly high risk of infarction at the time of diagnosis and while waiting for surgery. Time from diagnosis to surgery of >2 months was a significant risk factor for infarction while waiting for surgery in patients under 6 years of age. Conclusions: Young age at diagnosis and a high MRA score may be associated with rapid disease progression and result in preoperative infarction. We recommend that surgery be performed within 2 months of diagnosis for the patients under 4 years of age with a high MRA score (>5) and cerebral infarction. Further study is needed to define the optimal timing of surgery.

[What Is the Key Point for Intraoperative Monitoring in Cerebral Aneurysm Surgery?]

Intraoperative monitoring, which has advanced in the 21st century, consists of the motor evoked potential(MEP)and visual evoked potential(VEP). Transcranial stimulation has become the mainstream of MEP from cortical stimulation, and reports of MEP monitoring for the face and lower limbs are increasing. The biggest problem with VEP is poor reproducibility due to inhalation anesthetics. With the increase use of of MEP, total intravenous anesthesia has become common and reproducibility has improved, making it a clinically useful method. I will mention the key points of current intraoperative monitoring in cerebral aneurysm surgery. 1. Selection of type of intraoperative monitoring: Is MEP cortical stimulation or transcranial stimulation, upper limb or lower limb? What is VEP? What is somatosensory evoked potential? 2. What to do when the waveform deteriorates or disappears? Remove the clip after clipping. If the blood flow is temporarily occluded, release the occlusion as soon as possible. When the deterioration improves after this maneuver, it should be stopped until the waveform is restored. 3. Pitfall and coping method: Anesthesia method. Changes in the stimulation threshold of the transcranial stimulation MEPs. Deterioration/disappearance of MEP waveform after release of brain traction.

Paracrine CCL17 and CCL22 signaling regulates hematopoietic stem/progenitor cell migration and retention in mouse fetal liver.

Fetal liver (FL) is the major embryonic hematopoietic organ and a site where circulating hematopoietic stem/progenitor cells (HSPCs) reside. However, HSPC migration/retention mechanisms in FL remain unclear. A chemokine screen revealed that the CCR4 ligands CCL17 and CCL22 are highly expressed in mouse embryonic day (E) 12.5 FL. Flow cytometric analysis confirmed CCR4 expression in FL HSPCs. To identify sources of CCL17 and CCL22, we fractionated FL into various cell types and found that Ccl17 and Ccl22 were predominantly expressed in HPCs/matured HCs. In vitro cell migration analysis confirmed enhanced HSPC migration in the presence of HPCs/matured HCs. Furthermore, exo-utero injection of anti-CCR4 neutralizing antibody into pregnant mice significantly reduced the number of FL HSPCs in embryos. These data demonstrate a paracrine mechanism by which HSPC migration/retention is regulated by CCL17 and CCL22 secreted from HPCs or matured HCs in FL.

Study protocol of a Phase I/IIa clinical trial of Ad-SGE-REIC for treatment of recurrent malignant glioma.

Malignant glioma is one of the most common brain cancers in humans, which is very devastating. The expression of reduced expression in immortalized cells/Dickkopf-3 (REIC/Dkk-3) is decreased in various human cancers. Lately, we have developed a novel second-generation adenoviral vector that expresses REIC/Dkk-3 (Ad-SGE-REIC) and revealed its antiglioma efficacy. The present investigator-initiated clinical trial is a single-arm, prospective, nonrandomized, noncomparative, open-label, single-center trial performed at Okayama University Hospital, Okayama, Japan. The primary end points are dose-limiting toxicities and the incidence of adverse events. The secondary end points are the objective response rate and immunological assessment. Use of Ad-SGE-REIC will help to improve the prognosis of patients with malignant brain tumors.

Cell encapsulation enhances antidepressant effect of the mesenchymal stem cells and counteracts depressive-like behavior of treatment-resistant depressed rats.

Despite the advances in pharmacological therapies, only the half of depressed patients respond to currently available treatment. Thus, the need for further investigation and development of effective therapies, especially those designed for treatment-resistant depression, has been sorely needed. Although antidepressant effects of mesenchymal stem cells (MSCs) have been reported, the potential benefit of this cell therapy on treatment-resistant depression is unknown. Cell encapsulation may enhance the survival rate of grafted cells, but the therapeutic effects and mechanisms mediating encapsulation of MSCs remain unexplored. Here, we showed that encapsulation enhanced the antidepressant effects of MSCs by attenuating depressive-like behavior of Wistar Kyoto (WKY) rats, which are considered as a promising animal model of treatment-resistant depression. The implantation of encapsulated MSCs (eMSCs) into the lateral ventricle counteracted depressive-like behavior and enhanced the endogenous neurogenesis in the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus, whereas the implantation of MSCs without encapsulation or the implantation of eMSCs into the striatum did not show such ameliorative effects. eMSCs displayed robust and stable secretion of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor, fibroblast growth factor-2, and ciliary neurotrophic factor (CNTF), and the implantation of eMSCs into the lateral ventricle activated relevant pathways associated with these growth factors. Additionally, eMSCs upregulated intrinsic expression of VEGF and CNTF and their receptors. This study suggests that the implantation of eMSCs into the lateral ventricle exerted antidepressant effects likely acting via neurogenic pathways, supporting their utility for depression treatment.

Cell therapy for central nervous system disorders: Current obstacles to progress.

Cell therapy for disorders of the central nervous system has progressed to a new level of clinical application. Various clinical studies are underway for Parkinson's disease, stroke, traumatic brain injury, and various other neurological diseases. Recent biotechnological developments in cell therapy have taken advantage of the technology of induced pluripotent stem (iPS) cells. The advent of iPS cells has provided a robust stem cell donor source for neurorestoration via transplantation. Additionally, iPS cells have served as a platform for the discovery of therapeutics drugs, allowing breakthroughs in our understanding of the pathology and treatment of neurological diseases. Despite these recent advances in iPS, adult tissue-derived mesenchymal stem cells remain the widely used donor for cell transplantation. Mesenchymal stem cells are easily isolated and amplified toward the cells' unique trophic factor-secretion property. In this review article, the milestone achievements of cell therapy for central nervous system disorders, with equal consideration on the present translational obstacles for clinic application, are described.

First-in-human phase I study of E7090, a novel selective fibroblast growth factor receptor inhibitor, in patients with advanced solid tumors.

Fibroblast growth factor receptors (FGFR) are a family of transmembrane receptor tyrosine kinases involved in regulating cellular processes. FGFR mutations are implicated in oncogenesis, representing therapeutic potential in the form of FGFR inhibitors. This phase I, first-in-human study in Japan evaluated safety and tolerability of E7090, a potent selective FGFR1-3 inhibitor, in patients with advanced solid tumors. Dose escalation (daily oral dose of 1-180 mg) was carried out to assess dose-limiting toxicity (DLT), maximum tolerated dose, and pharmacokinetics. Pharmacodynamic markers (serum phosphate, fibroblast growth factor 23, and 1,25-(OH)2 -vitamin D) were also evaluated. A total of 24 patients refractory to standard therapy or for whom no appropriate treatment was available were enrolled. No DLT were observed up to the 140-mg dose; one patient in the 180-mg cohort experienced a DLT (increased aspartate aminotransferase/alanine aminotransferase, grade 3). The maximum tolerated dose was not reached. Dose-dependent increases in the maximum concentration and area under the curve from time 0 to the last measurable concentration were observed up to 180 mg. Dose-dependent increases were observed in all pharmacodynamic markers and plateaued at 100-140 mg, indicating sufficient FGFR pathway inhibition at doses ≥100 mg. In conclusion, E7090 showed a manageable safety profile with no DLT at doses ≤140 mg. Maximum tolerated dose was not determined. The recommended dose for the follow-up expansion part, restricted to patients with tumors harboring FGFR alterations, was determined as 140 mg, once daily.