Impact of Cilostazol Pharmacokinetics on the Development of Cardiovascular Side Effects in Patients with Cerebral Infarction.

This study investigated the impact of polymorphisms of metabolic enzymes on plasma concentrations of cilostazol and its metabolites, and the influence of the plasma concentrations and polymorphisms on the cardiovascular side effects in 30 patients with cerebral infarction. Plasma concentrations of cilostazol and its active metabolites, and CYP3A5*3 and CYP2C19*2 and *3 genotypes were determined. The median plasma concentration/dose ratio of OPC-13213, an active metabolite by CYP3A5 and CYP2C19, was slightly higher and the median plasma concentration rate of cilostazol to OPC-13015, another active metabolite by CYP3A4, was significantly lower in CYP3A5*1 carriers than in *1 non-carriers (p = 0.082 and p = 0.002, respectively). The CYP2C19 genotype did not affect the pharmacokinetics of cilostazol. A correlation was observed between changes in pulse rate from the baseline and plasma concentrations of cilostazol (R = 0.539, p = 0.002), OPC-13015 (R = 0.396, p = 0.030) and OPC-13213 (R = 0.383, p = 0.037). A multiple regression model, consisting of factors of the plasma concentration of OPC-13015, levels of blood urea nitrogen, and pulse rate at the start of the therapy explained 55.5% of the interindividual variability of the changes in pulse rate. These results suggest that plasma concentrations of cilostazol and its metabolites are affected by CYP3A5 genotypes, and plasma concentration of OPC-13015, blood urea nitrogen, and pulse rate at the start of therapy may be predictive markers of cardiovascular side effects of cilostazol in patients with cerebral infarction.

Safety profile of clozapine: Analysis using national registry data in Japan.

Clozapine is the only effective antipsychotic drug used for the treatment of treatment-resistant schizophrenia. Although it has been shown that the frequency of clozapine use is very low in Japan, our previous study revealed that the number of clozapine prescriptions has been increasing in recent years, and that risk factors leading to discontinuation of clozapine were also identified as age ≥40 years, poor tolerability to olanzapine, previous treatment with clozapine, and white blood cell count <6000/mm3. The main cause for discontinuation of clozapine is the occurrence of a wide range of adverse events, including neutropenia/leukopenia and fatal cardiac disorders. In this study, we analyzed the physical details and backgrounds of patients with adverse events that led to clozapine discontinuation using a national registry database of more than 8000 Japanese patients. The physical adverse events that led to discontinuation of clozapine were neutropenia/leukopenia, glucose intolerance, cardiac disorders, gastrointestinal disorders, neuroleptic malignant syndrome, pleurisy, pulmonary embolism, sedation/somnolence, and seizures. Neutropenia/leukopenia had the highest incidence (5.0%). Neutropenia/leukopenia and cardiac disorders tended to occur early in the treatment period, indicating the need for careful monitoring for these adverse events in the early stages of clozapine treatment. Gastrointestinal disorders occurred over a long period of time, suggesting the need for careful observation during the maintenance period. The data obtained in our study will lead to the optimal and safe use of clozapine treatment.

A descriptive study of 10-year clozapine use from the nationwide database in Japan.

This survey was conducted to identify the actual usage of clozapine and changes required to increase the number of patients with schizophrenia who would benefit from clozapine. We obtained Clozaril® Patient Monitoring Service (CPMS) data for 8,263 patients that received clozapine between July 2009 and January 2020. Patients were divided into the early (n=3,696 cases, which have been analyzed previously) and late groups (n=4,567 cases) according to the date of the treatment initiation. In total, 417 facilities offered the drug, with a surge in cases in the late group (40.0 hospitals/year, 568.6 cases/year vs. 39.3 hospitals/year, 1,141.8 cases/year). We found a significant between-group difference in the mean dosage during treatment (early group: 309.1 mg/day; late group: 247.9 mg/day). The treatment continuation rates at 1 and 4 years in all study participants were 77.2% and 65.1%, respectively. The incidences of granulocytopenia and agranulocytosis were 5.5% and 1.0%, respectively. The discontinuation rate because of granulocytopenia was significantly lower in the late group. There were no differences in the discontinuation rate because of glucose intolerance between the groups. An assessment of the current CPMS regulations may be required to further examine the clozapine use effectiveness.

Clozapine Is Better Tolerated in Younger Patients: Risk Factors for Discontinuation from a Nationwide Database in Japan.

OBJECTIVE: The effectiveness of clozapine is clearly superior to other antipsychotics in the treatment of refractory schizophrenia. Clozapine leads to various side effects, and therefore many patients are forced to discontinue. In this study, we analyzed the registry database of all cases in Japan to identify risk factors for discontinuation of clozapine. METHODS: The Clozaril patient monitoring service® (CPMS) database from July 31, 2009 to January 26, 2020 was acquired. We defined the following exclusion criteria: patients who had ever taken clozapine by a non-CPMS method, such as an individual import or clinical trial, patients who did not receive clozapine after being enrolled in CPMS, and patients with initial doses other than 12.5 mg (outside the current protocol). Therefore, all patients in this study are new users. Multivariate Cox regression analysis was used to investigate independent risk factors associated with time to discontinuation of clozapine. RESULTS: We identified 8,263 patients as the study population. Clozapine discontinuation was significantly associated with age 40 and older [hazard ratio (HR)=1.66, p<0.001], intolerance to olanzapine (HR=1.31, p=0.018), previous treatment with clozapine (HR=1.30, p=0.001), and leukocyte counts <6,000/mm3 (HR=1.24, p<0.001). The Kaplan-Meier curves for clozapine discontinuation by age group revealed that older age at the time of clozapine introduction tended to have lower continuation rates. CONCLUSION: Careful administration is important because patients with these factors have a high risk of discontinuation. In addition, the initiation of clozapine during the younger period was more effective and more tolerated.

Remote hemorrhage after burr-hole surgery for chronic subdural hematoma: A report of two cases.

BACKGROUND: The standard neurosurgical procedure for chronic subdural hematoma is a burr-hole surgery. Postoperative hemorrhage is one of the complications after burr-hole surgery. The hemorrhage generally occurs at the surgical site; however, remote hemorrhage is rare. Here, we report two cases of remote hemorrhage after burr-hole surgery for chronic subdural hematoma and discuss the possible mechanism underlying this rare complication. CASE DESCRIPTION: Two patients presented remote hemorrhages after burrhole surgery for chronic subdural hematoma. In the first case, hemorrhage occurred in the interhemispheric fissure and contralateral subdural space. In the second case, hemorrhage occurred in the subdural space of the posterior fossa. CONCLUSION: Postoperative remote hemorrhage is a rare complication, and it can occur after both craniotomy surgery and burr-hole surgery. Neurosurgeons should consider the possibility of this rare complication, and sufficient care should be taken to select the most appropriate surgical procedure to prevent remote hemorrhage.

A novel technique to visualize true lumen in endovascular treatment of the occlusive carotid dissection and the usefulness of external-internal carotid collateral channel.

Background Dissection of the internal carotid artery (ICA) can cause occlusion or severe stenosis and is known to be one of the major causes of ischemic stroke in the young. Endovascular treatment is one of the useful options for carotid dissections, but passing the guidewire through the occlusion (lesion-cross) and confirmation of the true lumen are sometimes difficult. Case presentation A 40-year-old right-handed man complaining of dysarthria and gait disturbance consulted our hospital. Magnetic resonance imaging and angiography revealed right ICA dissection. Because of worsening symptoms with conservative treatment, we performed endovascular treatment. Prior to the lesion-cross, a microcatheter was navigated to the third segment of the internal maxillary artery and a balloon-guiding catheter was navigated to the proximal ICA. Under balloon occlusion of the ICA, superselective angiography via the ipsilateral maxillary artery and slow evacuation from the balloon-guiding catheter were performed. Thereafter, the course of the true lumen was clearly visualized, and we were able to navigate another microcatheter without difficulty. Subsequently, angioplasty and stent placement were successfully accomplished. Conclusion We presented a case of ICA dissection and demonstrated a novel technique for a safe lesion-cross for occlusive ICA dissection.

Choroid plexus AVM with anomalous origin of the capsulothalamic artery: A case report.

Background and importance Traditionally, it has been believed that the plexal segment of the anterior choroidal artery (AChoA) can be sacrificed safely. Here, we present a case of choroid plexus arteriovenous malformation (AVM) in which the capsulothalamic artery originated from distal plexal segment of the AChoA. Clinical presentation A 45-year-old man was diagnosed with arteriovenous malformation involving the left inferior horn in screening MRI. Preceding stereotactic radiosurgery, transarterial target embolization was performed. In this procedure, 20% n-butyl-2-cyanoacrylate (NBCA) was successfully injected from the lateral plexal branch of the AChoA. After embolization, right homonymous hemianopsia developed due to cerebral infarction on the left optic radiation. This infarction was considered to be within the territory of the capsulothalamic artery. Conclusion This anomalous capsulothalamic artery might be formed by hemodynamic compromise of the brain surrounding AVM in early gestation. We must be aware of this unusual anatomical variation to avoid ischemic complication in embolization of the AChoA.

Standardization of Assistive Products with Robotic Technology - From a Perspective of ISO/TC173.

ISO/TC173 is a technical committee, in charge of international standardization of assistive products (APs). Robotic technology (RT) is currently an important topic in this field. APs with RT will be included in future revisions of the scope of TC173. Cooperation between the AP and RT space is essential to reach suitable solutions of future standardization.

Fatal cerebral swelling immediately after cranioplasty: A case report.

BACKGROUND: Cranioplasty is a standard neurosurgical procedure which is performed after decompressive craniotomy. Fatal complications associated with this procedure are not well documented. Here, we report a case of fatal cerebral swelling after cranioplasty and discuss the possible mechanism of this complication. CASE DESCRIPTION: A 64-year-old man was admitted with the diagnosis of cerebral hemorrhage, and emergency surgery for hemorrhage removal and decompressive craniotomy were performed. One month after surgery, cranioplasty was performed using a titanium mesh plate. Sixteen hours after the surgery, the patient became comatose with bilateral dilated pupils followed by blood pressure lowering. Computed tomography of the brain showed bilateral massive cerebral edema. The titanium mesh plate was immediately removed, however, the patient's neurological condition did not recover and he died 7 days after the surgery. We speculated that the negative pressure difference and increase in cerebral blood flow after cranioplasty may have attributed to the fatal cerebral swelling. CONCLUSION: Fatal cerebral swelling after cranioplasty is a rare but devastating complication. Although it is rare, neurosurgeons should keep in mind that this fatal complication can follow cranioplasty.

Correlation between frontal lobe oxy-hemoglobin and severity of depression assessed using near-infrared spectroscopy.

INTRODUCTION: The search for objective biomarkers of psychiatric disorders has a long history. Despite this, no universally accepted instruments or methods to detect biomarkers have been developed. One potential exception is near-infrared spectroscopy, although interpreting the measures of blood flow recorded with this technique remains controversial. In this study, we aimed to investigate the relationship between recorded blood flow and depression severity assessed using the Hamilton depression scale in patients with various psychiatric disorders. METHODS: Enrolled patients (n=43) had DSM-IV diagnoses of major depressive disorder (n=25), bipolar disorder I (n=5), schizophrenia (n=3), dysthymic disorder (n=3), psychotic disorder (n=3), panic disorder (n=2), and Obsessive Compulsive Disorder (n=2). The verbal fluency task was administered during blood flow recording from the frontal and temporal lobes. RESULTS: We found that severity of depression was negatively correlated with the integral value of blood flow in the frontal lobe, irrespective of psychiatric diagnosis (F=5.94, p=0.02). DISCUSSION: Our results support blood flow in the frontal lobe as a potential biomarker of depression severity across various psychiatric disorders. LIMITATION: Limited sample size, no replication in the second set.

Usefulness of interventional embolization of the middle meningeal artery for recurrent chronic subdural hematoma: Five cases and a review of the literature.

PURPOSE: Although several strategies against recurrent chronic subdural hematoma (CSDH) have been proposed, no consensus has been established. Recently, middle meningeal artery (MMA) embolization has been proposed as radical treatment for recurrent CSDH. We wanted to estimate the usefulness of MMA embolization for recurrent CSDH. METHODS: From February 2012 to June 2013, 110 patients with CSDH underwent single burr-hole surgery with irrigation and drainage. Among these patients, 13 showed recurrent hematoma formation and were retreated surgically. Furthermore, repeated recurrence of CSDH was observed in six patients. Five of these six patients underwent middle meningeal artery (MMA) embolization with polyvinyl alcohol particles. All five patients with interventional treatment were observed for four to 60 weeks. RESULTS: No more recurrence of CSDH was observed in any of the patients. During the follow-up period, no patients suffered from any side effects or complications from the interventional treatment. CONCLUSION: MMA embolization with careful attention paid to the procedure might be a treatment of choice for recurrent CSDH.

An innovative technique for detecting the caudal end of occluded inferior petrosal sinus in cavernous arteriovenous fistula using intravascular ultrasonography--technical note.

INTRODUCTION: Although cavernous sinus (CS) dural arteriovenous fistulas (d-AVFs) are usually treated with transvenous embolization (TVE) via the inferior petrosal sinus (IPS), IPSs are sometimes thrombosed and angiographically invisible. In such cases, the first obstacle to TVE is detecting the entry to the IPS. We report a new technique for TVE via IPS using intravascular ultrasonography (IVUS). METHODS: Three consecutive cases of CS d-AVF with ipsilateral or bilateral IPS occlusion were involved in this study. On TVE, the orifice of the IPS was investigated with IVUS placed in the jugular vein or jugular bulb. RESULTS: This technique has been successfully adapted in all three cases. In two of these cases, IPS was well visualized with the help of IVUS, and TVE was successfully performed. CONCLUSION: To our knowledge, this is the first report to mention the usefulness of IVUS for detecting angiographically occult IPS.

Adult classical glioblastoma with a BRAF V600E mutation.

The B-Raf proto-oncogene serine/threonine kinase (B-Raf) is a member of the Raf kinase family. The BRAF V600E mutation occurs frequently in certain brain tumors such as pleomorphic xanthoastrocytoma, ganglioglioma, and pilocytic astrocytoma, and less frequently in epithelioid and giant cell glioblastoma. BRAF V600E mutation in these cases has been canonically detected using Sanger sequencing or immunohistochemistry but not with next-generation sequencing (NGS). Moreover, to our knowledge, there is no detailed report of the BRAF V600E mutation in an adult glioblastoma with classical histologic features (c-GBM). Therefore, we performed NGS analysis to determine the mutational status of BRAF of 13 glioblastomas (GBMs) (11 primary and 2 secondary cases) and detected one tumor harboring the BRAF V600E mutation. We report here the detection of the BRAF V600E mutation in a patient with c-GBM and describe the patient's clinical course as well as the results of histopathological analysis.

Usefulness of 11C-methionine positron emission tomography for detecting intracranial ameloblastic carcinoma: A case report.

Ameloblastic carcinoma, secondary type, is an extremely rare odontogenic malignant tumor. The present study reports the case of a 58-year-old male with ameloblastic carcinoma that extended into the intracranial space close to the internal carotid artery. Surgical excision was performed, as headaches were being caused via compression by the mass. Small remnants of the tumor remained surrounding the internal carotid artery following surgical resection. Although the remnant tissue was not detected on magnetic resonance imaging or 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET), it was clearly visualized on 11C-methionine PET in the early post-operative follow-up period. No neurological deficits were exhibited during the follow-up period, and 11C-methionine PET was able to detect the remnant lesion distribution in the intracranial space. The current study presents a rare case of ameloblastic carcinoma that extended into the intracranial space. In addition, several diagnostic imaging tools were compared in order to determine the most suitable imaging modality. At present, the patient is continuing a therapeutic course of radiation and evident mass reduction has been observed. However, the therapeutic effects are currently under consideration. To the best of our knowledge, this is the first study on the effectiveness of using 11C-methionine PET for detecting ameloblastic carcinoma with intracranial extension.

The usefulness of subcutaneous infiltration of epinephrine-containing lidocaine for curative transarterial embolization of dural arteriovenous fistula. A technical note.

Recently, transarterial embolization (TAE) with liquid embolic materials has been recognized as one of the curative therapeutic options for non-sinus type dural arteriovenous fistula (d-AVF). To prevent glue fragmentation and incomplete obliteration, flow reduction of transosseous high-flow feeders is one of the key points of this therapy. However, flow reduction of transosseous feeders is sometimes difficult with previously reported techniques such as particle embolization, manual compression, or proximal balloon occlusion. This report introduces a new technique to reduce the flow of transosseous feeders using epinephrine-containing lidocaine, and describes a case of intracranial d-AVF successfully treated with this technique. The usefulness and efficacy of the technique are discussed.

Reversible splenial lesion in postpartum cerebral angiopathy: a case report.

Reversible lesions on magnetic resonance imaging that transiently restrict diffusion in the splenium of the corpus callosum (SCC) without any other accompanying lesions have been reported in various clinical conditions. We offer the first report of postpartum cerebral angiopathy with reversible SCC lesions.

[A case of the myelitis due to Toxocara canis infection complicated with cervical spondylosis].

A 59-year-old male had suffered from numbness of the hands for 7 months. With a diagnosis of cervical spondylosis, he had been treated conservatively at a nearby clinic. After he fell off his bicycle, the numbness intensified and limb weakness developed. Cervical MRI revealed spinal cord compression at the C4/5 and C5/6 levels due to cervical spondylosis with prominent edema in the spinal cord spreading from the C4 to C6 level. The edema was very serious. Therefore, we suspected that the traumatic spinal injury underlying the cervical spondylosis was complicated by another disease. Cervical spinal angiography revealed no apparent vascular disorder. Contrast enhanced MRI showed a small enhanced area in the spinal cord at the C5 level. Because of the rapid progression of gait disturbance, expansive laminoplasty was performed without further examination. Although remarkable amelioration of the symptoms was seen just after the surgery, the symptoms worsened again about 1 month later. The patient's clinical history was reconsidered, revealing that he likes raw bovine liver. Serological examination, because of suspicion of parasitic infection showed elevated titers of anti-Toxocara canis antibody in the serum and cerebrospinal fluid. Administration of albendazole improved the clinical symptoms, and normalized the serological and MRI findings. Myelitis due to T canis infection is a rare disease. For an early and accurate diagnosis, it is important to be fully aware of this disease and to include detailed information on food preferences and pet-keeping in the process of compiling a clinical history.

Histone deacetylase inhibitor, FK228, induces apoptosis and suppresses cell proliferation of human glioblastoma cells in vitro and in vivo.

We investigated the effects of FK228 on cell proliferation and apoptosis against human glioblastoma (GM) T98G, U251MG, and U87MG cells. Upon exposure to FK228, cell proliferation was inhibited, and apoptosis detected by the cleavage of CPP32 was induced. FK228 increased the expression levels of p21 (WAF-1) and of pro-apoptotic Bad protein in all GM cells. Furthermore, FK228 treatment also reduced the anti-apoptotic protein Bcl-xL in all GM cells and anti-apoptotic Bcl-2 in U87MG cells, thereby shifting the cellular equilibrium from life to death. An increased accumulation of histone H4 was detected in the p21 (WAF-1) promoter and the structural gene (exon 2) and the Bad structural gene (exon 2 and 3) upon treatment with FK228, as assessed by chromatin immunoprecipitation (ChIP) assay. Thus, the results indicated that an increased expression of p21 (WAF1) and Bad due to FK228 is regulated, at least in part, by the degree of acetylation of the gene-associated histone. We also found that FK228 inhibits cellular invasiveness and decreases MMP-2 activity. In addition, the growth of transplanted human GM m-3 cells into the subcutaneous tissue of hereditary athymic mice was significantly inhibited, and apoptosis was induced with FK228 treatment. The results suggested that FK228 might be useful in the treatment of human GM, although further studies will be needed.