Allogeneic Stem Cell Therapy for Acute Ischemic Stroke: The Phase 2/3 TREASURE Randomized Clinical Trial.

Importance: Cell therapy is a promising treatment approach for stroke and other diseases. However, it is unknown whether MultiStem (HLCM051), a bone marrow-derived, allogeneic, multipotent adult progenitor cell product, has the potential to treat ischemic stroke. Objective: To assess the efficacy and safety of MultiStem when administered within 18 to 36 hours of ischemic stroke onset. Design, Setting, and Participants: The Treatment Evaluation of Acute Stroke Using Regenerative Cells (TREASURE) multicenter, double-blind, parallel-group, placebo-controlled phase 2/3 randomized clinical trial was conducted at 44 academic and clinical centers in Japan between November 15, 2017, and March 29, 2022. Inclusion criteria were age 20 years or older, presence of acute ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score of 8-20 at baseline), confirmed acute infarction involving the cerebral cortex and measuring more than 2 cm on the major axis (determined with diffusion-weighted magnetic resonance imaging), and a modified Rankin Scale (mRS) score of 0 or 1 before stroke onset. Data analysis was performed between May 9 and August 15, 2022. Exposure: Patients were randomly assigned to either intravenous MultiStem in 1 single unit of 1.2 billion cells or intravenous placebo within 18 to 36 hours of ischemic stroke onset. Main Outcomes and Measures: The primary end points were safety and excellent outcome at day 90, measured as a composite of a modified Rankin Scale (mRS) score of 1 or less, a NIHSS score of 1 or less, and a Barthel index score of 95 or greater. The secondary end points were excellent outcome at day 365, mRS score distribution at days 90 and 365, and mRS score of 0 to 1 and 0 to 2 at day 90. Statistical analysis of efficacy was performed using the Cochran-Mantel-Haenszel test. Results: This study included 206 patients (104 received MultiStem and 102 received placebo). Their mean age was 76.5 (range, 35-95) years, and more than half of patients were men (112 [54.4%]). There were no between-group differences in primary and secondary end points. The proportion of excellent outcomes at day 90 did not differ significantly between the MultiStem and placebo groups (12 [11.5%] vs 10 [9.8%], P = .90; adjusted risk difference, 0.5% [95% CI, -7.3% to 8.3%]). The frequency of adverse events was similar between treatment groups. Conclusions and Relevance: In this randomized clinical trial, intravenous administration of allogeneic cell therapy within 18 to 36 hours of ischemic stroke onset was safe but did not improve short-term outcomes. Further research is needed to determine whether MultiStem therapy for ischemic stroke has a beneficial effect in patients who meet specific criteria, as indicated by the exploratory analyses in this study. Trial Registration: ClinicalTrials.gov Identifier: NCT02961504.

Surgical aspects using an exoscope for corpus callosotomy: initial experience for epilepsy surgery.

The exoscope is a new form of optic device that has begun to be used in the last decade. The exoscope provides high-quality magnification and illumination at depth, allowing easy manipulation of surgical instruments even in narrow surgical fields. Exoscopic corpus callosotomy (CC) has not been reported. We report herein our initial experience with the utility of exoscopic CC. A 3-year-old boy diagnosed with West syndrome at 4 months old was referred to our hospital. As the seizure spasms were considered to carry a risk of severe traumatic injury, we performed exoscopic CC as palliative therapy. An EX VITOM 3D exoscope and 4K-3D surgical monitor were used during the procedure. No surgical complications that could be related to exoscope use were noted. Operative time for exoscopic CC was comparable to that for microscopic CC, despite a lack of previous experience with the equipment. Stereoscopic vision was easily obtained. The exoscope was perceived as providing higher quality magnification. We report our first clinical experience of exoscopic CC. The exoscope appears useful in the field of epilepsy surgery.

Effectiveness of radiation therapy on brain invasion by human papillomavirus-related multiphenotypic sinonasal carcinoma: A case report.

Human papillomavirus (HPV)-related multiphenotypic sinonasal carcinoma (HMSC) is newly suggested and characterized by HPV-related tumors. HMSC has a relatively good prognosis. No cases of brain invasion have been reported to date. We encountered a case of brain invasion by HMSC, in which we assessed the effectiveness of radiotherapy in comparison with biopsy and autopsy. A 69-year-old man was referred to a hospital three months after intracerebral hemorrhage (ICH). Contrast magnetic resonance imaging revealed a tumor in the ethmoid sinus involving the brain. We performed transnasal biopsy and intensity-modulated radiotherapy for sinonasal and intracranial lesions. Despite radiotherapy, the patient died on day 41 after radiation. Biopsy specimens displayed mixed findings of epithelial and mesenchymal components. The tumor was immunoreactive for p16, and the RNA in situ hybridization for HPV was positive. Finally, we diagnosed the patient as having HMSC. Autopsy of the sinonasal tissue revealed a reduction in the number of tumor cells. There was a marked reduction in the number of tumor cells in the sinonasal tissue compared to that in the invaded brain tissue. The effectiveness of radiotherapy could depend on the histopathological components and location of the lesion, even in the same patient.

Non-Ruptured Temporal Lobe Dermoid Cyst Concomitant with Focal Cortical Dysplasia Causing Temporal Lobe Epilepsy-A Case Report and Literature Review.

BACKGROUND: Intracranial dermoid cyst is a rare, benign, nonneoplastic tumor-like lesion that could cause seizures, headache, and hydrocephalus. We hypothesized that the temporal lobe dermoid cyst in combination with other factors were causing the epileptic seizure. METHODS: We encountered a 17-year-old girl with anti-seizure medication-resistant epilepsy secondary to dermoid cyst located in the temporal region depicted on magnetic resonance imaging (MRI). She showed neither symptoms of meningitis nor rupture of the cyst according to serial MRI. We hypothesized that temporal lobe dermoid cyst in combination with other factors, such as focal cortical dysplasia (FCD), etc., was causing epileptic seizures in this case. She underwent dermoid cyst removal surgery with resection of the tip of the antero-inferior temporal lobe. RESULTS: Histopathological study showed multiple small intramedullary dermoid cysts in the left antero-inferior temporal lobe in addition to MRI lesions and FCD. CONCLUSION: A patient with medically intractable epilepsy secondary to left temporal lobe dermoid cyst showed multiple intramedullary dermoid cysts and focal cortical dysplasia that might have interacted to create epileptogenicity. To our knowledge, this is the first case report of dermoid cyst concomitant with FCD.

Experience using mTOR inhibitors for subependymal giant cell astrocytoma in tuberous sclerosis complex at a single facility.

BACKGROUND: Subependymal giant cell astrocytoma (SEGA) is occasionally seen in tuberous sclerosis complex (TSC). Two main options are currently available for treating SEGA: surgical resection or pharmacotherapy using mammalian target of rapamycin inhibitors (mTORi). We hypothesized that opportunities for surgical resection of SEGA would have reduced with the advent of mTORi. METHODS: We retrospectively reviewed the charts of patients treated between August 1979 and July 2020, divided into a pre-mTORi era group (Pre-group) of patients treated before November 2012, and a post-mTORi era group (Post-group) comprising patients treated from November 2012, when mTORi became available in Japan for SEGA. We compared groups in terms of treatment with surgery or mTORi. We also reviewed SEGA size, rate of acute hydrocephalus, recurrence of SEGA, malignant transformation and adverse effects of mTORi. RESULTS: In total, 120 patients with TSC visited our facility, including 24 patients with SEGA. Surgical resection was significantly more frequent in the Pre-group (6 of 7 patients, 86 %) than in the Post-group (2 of 17 patients, 12 %; p = 0.001). Acute hydrocephalus was seen in 1 patient (4 %), and no patients showed malignant transformation of SEGA. The group treated using mTORi showed significantly smaller SEGA compared with the group treated under a wait-and-see policy (p = 0.012). Adverse effects of pharmacotherapy were identified in seven (64 %; 6 oral ulcers, 1 irregular menstruation) of the 11 patients receiving mTORi. CONCLUSIONS: The Post-group underwent surgery significantly less often than the Pre-group. Since the treatment option to use mTORi in the treatment of SEGA in TSC became available, opportunities for surgical resection have decreased in our facility.

Posttraumatic epilepsy may be a state in which underlying epileptogenicity involves focal cortical dysplasia.

INTRODUCTION: The occurrence rate of posttrauma epilepsy ranges widely from 1% to 30%. Little is known about the underlying epileptogenesis of traumatic brain injury (TBI)-related epilepsy (TRE), because no comparison between TRE and TBI without epilepsy has been performed in terms of neuropathology. Therefore, we postulated that different neuropathological factors may be present between TRE and TBI without epilepsy. The purpose of this study was to clarify differences between TRE and TBI without epilepsy. METHODS: We studied patients who experienced severe head trauma and underwent brain surgery. The age range of the patients was 9-71 years old. Patients with medically resistant epilepsy were included in the Epilepsy group, and patients without epilepsy were included in the nonepilepsy group. Pathological findings, age, sex, and cause of head trauma were statistically compared between these two groups. RESULTS: This study involved 10 patients, nine of whom met the inclusion criteria. Pathological findings for all patients in the Epilepsy group included focal cortical dysplasia (FCD) (p = 0.012). CONCLUSION: The difference between TRE and TBI without epilepsy was underlying FCD in patients with TRE.

The Fornix May Play a Key Role in Korsakoff's Amnesia Secondary to Subcallosal Artery Infarction.

BACKGROUND: Subcallosal artery infarction injures the fornix and anterior corpus callosum and sometimes causes Korsakoff's amnesia. We hypothesized that Korsakoff's amnesia might be caused by fornix dysfunction rather than anterior corpus callosum dysfunction in subcallosal artery infarction. METHODS: A systematic review approach was applied to search PubMed and Google Scholar for articles to compare patients who had both bilateral fornix and corpus callosum infarction due to subcallosal artery territory ischemia (vascular event group; V group) with patients who had undergone anterior corpus callosotomy (callosotomy group; C group). RESULTS: The V group comprised 10 patients (mean age, 63 years; median, 69 years; standard deviation (SD), 14.5 years; 5 males, 5 females). The C group comprised 6 patients (mean age, 23.7 years; median, 20 years; SD, 7.3 years; 3 males, 3 females). Six of 10 patients (60%) with subcallosal artery infarction exhibited Korsakoff's amnesia. One patient showed neither confabulation nor amnesia. Conversely, no amnesia episodes were seen in any patients from the C group (p = 0.034). CONCLUSION: Fornix injury, rather than anterior corpus callosum injury, might be the major cause of Korsakoff's amnesia in patients with subcallosal artery infarction.

What Part of the Brain Controls Contralateral Fine Finger Movement in a Normally Developed Patient With a Deficit of Primary Motor Cortices?

BACKGROUND: Malformations of cortical development (MCDs) often result in mental retardation, intractable epilepsy, neurodevelopmental delay, and contralateral hemiparesis. We describe herein a rare patient with MCD who had developed normally in spite of diffuse hemispheric anomaly of the brain. CASE DESCRIPTION: We report a left-handed 20-year-old healthy man. A magnetic resonance image scan revealed congenital left cerebral hemispheric dysplasia and deficit of the normal anatomical primary motor cortices although he was normally developed without hemiparesis nor aphasia. Diffusion tensor tractography showed unusual fiber radiation from the left cerebral peduncle to the much more rostral and lateral cerebral cortices compared with normal anatomy. Right finger flexion-extension task showed activation in that area on functional magnetic resonance imaging. CONCLUSIONS: Even in a congenital hemispheric dysplasia, the contralateral fine finger movement may still depend on the dysplastic hemisphere. On the other hand, speech and the other gross movements including leg, foot, and arm can be compensated with the ipsilateral normal cerebral cortices.

Neuroendoscopic Surgery with a Combination of Image Detectable Sheath, Intraoperative Computed Tomography Scan, and Navigation System Improves Accuracy and Safety in Minimally Invasive Evacuation of Intracerebral Hematoma: Technical Note.

BACKGROUND: Recent studies have confirmed the effectiveness of minimally invasive endoscopic surgery for intracerebral hematoma (ICH). However, improvements are needed because incomplete hematoma removal may offset the surgical benefits of the technique. We describe a technique of neuroendoscopic surgery using an image detectable sheath, intraoperative computed tomography (iCT) scan, and a navigation system. METHODS: This is a retrospective study of 15 consecutive patients with spontaneous ICH who received neuroendoscopic surgery. During the surgery, a transparent sheath was fastened tightly to the scalp with 3.0 nylon. The patient's head was covered with a sterilized vinyl sheet and subsequent iCT scan visualized the orientation of the endoscopic sheath and the extent of residual hematoma, allowing the surgeon to decide to continue to remove the hematoma or to finish the treatment. RESULTS: The median hematoma evacuation rate was 93% (interquartile range, 82.2%-95.9%). The Glasgow Coma Scale score of all patients significantly improved at 1 week after the operation (P < 0.05). No complications associated with the procedure were observed. CONCLUSIONS: The combination of our techniques improves accuracy and safety of minimally invasive surgical evacuation of hematoma. Performing surgery with iCT scan also improves the spatial recognition of surgeons and therefore may be of educational value.

Intracranial Multiple Pseudotumor Due to Immunoglobulin G4-Related Disease without Other Lesions: Case Report and Literature Review.

BACKGROUND: Immunoglobulin (Ig)G4-related disease (IgG4-RD) was defined only recently and can be found in many organs. As intracranial lesions, hypophysitis and pachymeningitis are well known, whereas intracranial pseudotumor is unusual. This case involved multiple intracranial pseudotumors without extracranial lesions, mimicking multiple meningioma. CASE DESCRIPTION: A 72-year-old woman was referred to our hospital with an incidental mass lesion at the craniocervical junction on magnetic resonance imaging (MRI). MRI showed diffuse enhanced extra-axial nodules around the medulla and middle cranial fossa. Surgery was performed for the gradually enlarging tumor. Intraoperative findings showed hard nodules around the vertebral artery. We performed subtotal resection. Neuropathological findings showed diffuse lymphoplasmacytic infiltration with lymphoid follicles. Immunohistochemical studies for IgG4 and IgG showed the histological criteria for IgG4-RD were met. Given the high IgG4 serum level, we diagnosed IgG4-RD. Steroid was administered initially but was then tapered, and nodules have since remained small. CONCLUSIONS: This case demonstrates IgG4-RD mimicking meningioma with multiple masses but without extracranial lesions. This case and previous descriptions suggest the possibility of pseudotumor due to IgG4-RD in the presence of multiple extra-axial lesions at the dura and supplying artery, hard nodules with thickening of the artery, and frozen section findings of lymphoplasmacytes surrounded by rich collagen fibers. In such cases, the pseudotumor due to IgG4-RD should be resected, and total resection might not be warranted.

Cerebellar Metastasis of Unknown Primary Neuroendocrine Carcinoma: Report of Case Mimicking Hemangioblastoma.

BACKGROUND: Neuroendocrine carcinoma (NEC) originates with neuroendocrine cells and is mainly found in the pancreas, lungs and gastrointestinal tract. We surgically treated a case of primary unknown NEC with only cerebral metastasis that mimicked hemangioblastoma. Recurrence was seen at the fornix, and no primary lesion had been identified as of 2 years after treatments despite careful examination. CASE DESCRIPTION: A 61-year-old man presented with dizziness. Past medical history included hypertension, dyslipidemia, hyperuricemia and colon polyp. We performed magnetic resonance imaging (MRI) to examine the cause of dizziness, revealing tumor with enhancement and peritumoral edema at the right cerebral lesion. Contrast-enhanced whole-body computed tomography (CT) showed no other lesions. We suspected hemangioblastoma from examinations and decided on surgical resection. Neuropathologically, the resected tumor was diagnosed as brain metastasis of NEC, but CT, fluorodeoxyglucose-positron emission tomography, gastrointestinal endoscopy, and somatostatin receptor scintigraphy all failed to reveal the primary lesion. As postoperative MRI showed enhancement around the resection cavity and at the right fornix, radiotherapy was performed. No other lesions were seen at 24 months postoperatively. We are continuing careful monitoring and no chemotherapy has been administered. CONCLUSIONS: We treated brain metastasis from NEC of unknown primary and mimicking hemangioblastoma using only local treatment. When an enhancing, single, solid tumor is seen in the cerebellum, brain metastasis from NEC of unknown primary is 1 differential diagnosis.

An Unusual Case of Lhermitte-Duclos Disease Manifesting with Intratumoral Hemorrhage.

BACKGROUND: Lhermitte-Duclos disease (LDD) is a rare neurologic disease that causes a hamartomatous lesion in the cerebellum. LDD is usually associated with mass lesion effects, but with appropriate surgical treatment, the clinical course is usually benign. We report a rare case of a patient with LDD with contrast enhancement on magnetic resonance imaging (MRI) who died as a result of intratumoral hemorrhage. CASE DESCRIPTION: LDD was diagnosed in a 59-year-old woman after a routine MRI. She did not present with any symptoms initially or after follow-up MRI suggested minor hemorrhage in the tumor. Eleven months after her first visit to our department, she suddenly lost consciousness, and computed tomography revealed massive intratumoral hemorrhage. Surgical decompression was done, but she died 17 days after surgery. Histopathologic findings were consistent with LDD. CONCLUSIONS: Hemorrhagic events can occur with LDD, even though the growth of the lesion is slow. Long-term close follow-up of patients with LDD is needed, especially patients in whom MRI shows atypical enhancement. To avoid possible hemorrhagic events, surgical treatment should be considered even if only subtle changes are seen on neuroimaging.

A Potential New Risk Factor for Stroke: Streptococcus Mutans With Collagen-Binding Protein.

BACKGROUND: Among human oral bacteria, particular kinds of Streptococcus mutans (SM) known as dental caries pathogens contain a collagen-binding protein, Cnm, and show platelet aggregation inhibition and matrix metalloproteinase-9 activation. We have previously reported that these strains may be a risk factor for intracerebral hemorrhage. As a major sample-providing hospital, we report the clinical details, including intracranial aneurysms and ischemic stroke. METHODS: After the study received approval from the Ethical Committee, 429 samples of whole saliva were obtained from patients who were admitted to or visited our hospital between February 16, 2010, and February 28, 2011. The study cohort comprised 48 patients with cardioembolic stroke (CES), 151 with non-CES infarct, 54 with intracerebral hemorrhage (ICH), 43 with ruptured intracranial aneurysm (RIA), and 97 with unruptured intracranial aneurysm (UIA). Cultured SM was identified as Cnm-positive when the corresponding gene was positive. The results were compared with those from 79 healthy volunteers. Relationships between Cnm-positive SM and known risk factors, including hypertension, diabetes, hyperlipidemia, smoking, and alcohol consumption, were analyzed. RESULTS: A statistically significant high Cnm-positive rate was observed in patients with CES, non-CES infarct, ICH, and RIA (P = 0.002, 0.039, 0.013, and 0.009, respectively). There were no relationships between Cnm-positive SM and known risk factors. CONCLUSIONS: Specific types of oral SM can be a risk factor for cardioembolic infarct, intracerebral hemorrhage, and intracranial aneurysm rupture. Further study is needed.

Endoscopic Removal of Neonatal Acute Epidural Hematoma via Strip-Bending Osteoplastic Craniotomy. Technical Note.

We present a rare case of an acute epidural hematoma extending through a skull fracture into a cephalohematoma in a neonate. The epidural hematoma was caused by a fall after delivery. The neonate remained neurologically asymptomatic. A computed tomography scan 12 days after delivery showed the large-volume epidural hematoma with midline shift. We performed a strip-bending osteoplastic craniotomy and removed the epidural hematoma and external cephalohematoma under neuroendoscopic control. This is the first reported case of an acute epidural hematoma in a neonate treated successfully neuroendoscopically via a strip-bending craniotomy.

Chordoid glioma of the third ventricle: a report of two cases, one with ultrastructural findings.

Chordoid glioma, which generally occurs in adults, is a rare CNS tumor arising in the anterior part of the third ventricle. We report two cases of chordoid glioma of the third ventricle in a 42-year-old woman and a 51-year-old man, respectively. Both tumors showed essentially the same histological and immunohistochemical features; the tumors were composed of cords and nests of epithelioid, GFAP-immunoreactive cells in a mucinous stroma with lymphoplasmacytic infiltrates at the tumor periphery. Ultrastructural examination in one case revealed that the tumor cells were characterized by the presence of hemidesmosomes and associated focal basal lamina formation, intermediate junctions, microvilli and cilia, and intercellular microrosettes with microvilli. Of interest was that small blood vessels with fenestrated endothelial cells were present in the stroma. In the brain, the presence of fenestrated endothelial cells is a feature of the circumventricular organs (except the subcommissural organ), among which the organum vasculosum of the lamina terminalis is located in the anterior part of the third ventricular floor that is lined by specialized ependymal cells known as tanycytes. These findings further strengthen the hypothesis that chordoid glioma may represent a peculiar clinicopathological subtype of ependymoma (chordoid ependymoma) originating from the lamina terminalis area.

Synovial chondromatosis of the temporomandibular joint with intracranial extension.

A 52-year-old man presented with an extremely rare case of synovial chondromatosis in the temporomandibular joint (TMJ) with extension into the middle cranial fossa manifesting as swelling and exacerbation of pain. He had a long history of right TMJ disorders. Computed tomography and magnetic resonance imaging showed a mass in the right TMJ with extension into the intracranial part through the destroyed temporal skull base. The preoperative diagnosis was chondrosarcoma or osteosarcoma. The patient underwent surgery via combined trans-zygomatic temporal skull base and pre-auricular approaches and the mass was totally removed. Histological examination found an enormous number of closely packed loose bodies of various sizes, consisting of hyaline chondrocytes. The histological diagnosis was synovial chondromatosis. This rare lesion is difficult to discriminate from chondrosarcoma, so total removal is essential for correct diagnosis and cure.

Frontal anaplastic oligodendroglioma showing multi-organ metastases after a long clinical course. Case report.

A 17-year-old woman presented with an anaplastic oligodendroglioma manifesting as generalized seizure. Neuroimaging studies revealed a right frontal tumor. Histological examinations of biopsy specimens revealed that the tumor was oligodendroglial in nature. Total resection was repeated four times, and malignant change was evident within the tissues. The final diagnosis was anaplastic oligodendroglioma. Despite irradiation, combination chemotherapy, and interstitial hyperthermia, the tumor grew rapidly but was confined to the cavity created by previous removal operations. She suffered bone pain in the last 3 months of her life, when neuroimaging examinations disclosed multiple bone lesions. She died at the age of 29 years. At autopsy, generalized metastases from the tumor were identified at various sites, including the dura mater covering the frontal lobes and thoracic cord, cavernous sinus, tuberculum sellae, spleen, liver, pancreas, lungs, paratracheal lymph nodes, vertebral bodies, ribs, sternum, pelvis, dorsal root ganglia, and iliopsoas muscle. This rare case of cerebral anaplastic oligodendroglioma developed in adolescence, and rapid hematogenous spread of the glioma cells into the systemic organs occurred after a relatively long clinical course.

Monitoring of singlet oxygen is useful for predicting the photodynamic effects in the treatment for experimental glioma.

PURPOSE: Singlet oxygen ((1)O(2)) generated in photodynamic therapy (PDT) plays a very important role in killing tumor cells. Using a new near-IR photomultiplier tube system, we monitored the real-time production of (1)O(2) during PDT and thus investigated the relationship between the (1)O(2) production and photodynamic effects. EXPERIMENTAL DESIGN: We did PDT in 9L gliosarcoma cells in vitro and in an experimental tumor model in vivo using 5-aminolevulinic acid and nanosecond-pulsed dye laser. During this time, we monitored (1)O(2) using this system. Moreover, based on the (1)O(2) monitoring, we set the different conditions of laser exposure and investigated whether they could affect the tumor cell death. RESULTS: We could observe the temporal changes of (1)O(2) production during PDT in detail. At a low fluence rate the (1)O(2) signal gradually decreased with a low peak, whereas at a high fluence rate it decreased immediately with a high peak. Consequently, the cumulative (1)O(2) at a low fluence rate was higher, which thus induced a strong photodynamic effect. The proportion of apoptosis to necrosis might therefore be dependent on the peak and duration of the (1)O(2) signal. A low fluence rate tended to induce apoptotic change, whereas a high fluence rate tended to induce necrotic change. CONCLUSIONS: The results of this study suggested that the monitoring of (1)O(2) enables us to predict the photodynamic effect, allowing us to select the optimal laser conditions for each patient.