Intravenously Transplanted Human Multilineage-Differentiating Stress-Enduring Cells Afford Brain Repair in a Mouse Lacunar Stroke Model.

Background and Purpose- Multilineage-differentiating stress-enduring cells are endogenous nontumorigenic reparative pluripotent-like stem cells found in bone marrow, peripheral blood, and connective tissues. Topically administered human multilineage-differentiating stress-enduring cells into rat/mouse stroke models differentiated into neural cells and promoted clinically relevant functional recovery. However, critical questions on the appropriate timing and dose, and safety of the less invasive intravenous administration of clinical-grade multilineage-differentiating stress-enduring cell-based product CL2020 remain unanswered. Methods- Using an immunodeficient mouse lacunar model, CL2020 was administered via the cervical vein in different doses (high dose=5×104 cells/body; medium dose=1×104 cells/body; low dose=5×103 cells/body) at subacute phase (≈9 days after onset) and chronic phase (≈30 days). Cylinder test, depletion of human cells by diphtheria toxin administration, immunohistochemistry, and human specific-genome detection were performed. Results- Tumorigenesis and adverse effects were not detected for up to 22 weeks. The high-dose group displayed significant functional recovery compared with the vehicle group in cylinder test in subacute-phase-treated and chronic-phase-treated animals after 6 weeks and 8 weeks post-injection, respectively. In the high-dose group of subacute-phase-treated animals, robust and stable recovery in cylinder test persisted up to 22 weeks compared with the vehicle group. In both groups, intraperitoneal injection of diphtheria toxin abrogated the functional recovery. Anti-human mitochondria revealed CL2020 distributed mainly in the peri-infarct area at 1, 10, and 22 weeks and expressed NeuN (neuronal nuclei)- and MAP-2 (microtubule-associated protein-2)-immunoreactivity. Conclusions- Intravenously administered CL2020 was safe, migrated to the peri-infarct area, and afforded functional recovery in experimental stroke.

Brain Stem Infarction Due to Basilar Artery Dissection in a Patient with Moyamoya Disease Four Years after Successful Bilateral Revascularization Surgeries.

Moyamoya disease (MMD) is a rare cerebrovascular disease with an unknown etiology and is characterized by intrinsic fragility in the intracranial vascular walls such as the affected internal elastic lamina and thinning medial layer. The association of MMD with intracranial arterial dissection is extremely rare, whereas that with basilar artery dissection (BAD) has not been reported previously. A 46-year-old woman developed brain stem infarction due to BAD 4 years after successful bilateral superficial temporal artery-middle cerebral artery anastomosis with indirect pial synangiosis for ischemic-onset MMD. She presented with sudden occipitalgia and subsequently developed transient dysarthria and mild hemiparesis. Although a transient ischemic attack was initially suspected, her condition deteriorated in a manner that was consistent with left hemiplegia with severe dysarthria. Magnetic resonance (MR) imaging revealed brain stem infarction, and MR angiography delineated a double-lumen sign in the basilar artery, indicating BAD. She was treated conservatively and brain stem infarction did not expand. One year after the onset of brain stem infarction, her activity of daily living is still dependent (modified Rankin Scale of 4), and there were no morphological changes associated with BAD or recurrent cerebrovascular events during the follow-up period. The association of MMD with BAD is extremely rare. While considering the common underlying pathology such as an affected internal elastic lamina and fragile medial layer, the occurrence of BAD in a patient with MMD in a stable hemodynamic state is apparently unique.

[A Case of Hydrocephalus in Listeria Meningitis Treated by Endoscopic Third Ventriculostomy].

A 69-year-old woman presented with anorexia, fever, and vomiting. The patient was not a compromised host. She was finally diagnosed with Listeria meningitis and treated with ampicillin and gentamicin. However, her condition worsened over time. Non-contrast head CT showed ventricular dilatation. As a result, continuous right ventricular drainage was performed. Non-contrast MRI revealed hydrocephalus due to stenosis of the fourth ventricle. She underwent endoscopic third ventriculostomy(ETV)to improve cerebrospinal fluid circulation. This procedure achieved a good result. The efficacy of ETV for post-infectious hydrocephalus has not been proven, but previous cases suggest that ETV would be effective in non-communicating hydrocephalus, even if it were a result of neuroinfection.

Clinical Impact of a Local Triage System Using the Emergent Large Vessel Occlusion Screen with a Rotation System of Thrombectomy-Capable Hospitals.

Objective: Early intervention with mechanical thrombectomy (MT) is expected to improve the functional outcome in patients with large vessel occlusion (LVO); however, a method for the effective detection of these patients in a prehospital setting and early transport to MT-capable hospitals has not been established. This study aimed to analyze the clinical impact and diagnostic performance of the emergent large vessel occlusion (ELVO) screen and its influence on the transportation time. Methods: The emergency medical services (EMS) in one of the secondary medical areas in Akita, Japan, introduced a prehospital triage system employing an ELVO screen and a rotation system of three MT-capable hospitals on December 1, 2021. Patients who were transferred to each of the three hospitals involved in the rotation system according to a predefined priority list from December 2021 to November 2022 were included in the triage group. Patients who underwent MT in the three hospitals before the introduction of the triage system were assigned to the pre-triage group. We compared the transportation time parameters between the two groups and analyzed the performance of the ELVO screen for the diagnosis of LVOs. This study was approved by the institutional review boards of all three hospitals. Results: Time parameters were compared between the 37 and 42 patients who underwent MT and had detailed data in the triage (n = 351) and pre-triage (n = 43) groups, respectively. The time from door to puncture tended to decrease in the triage group in all hospitals, with one hospital showing a statistically significant shortening of 14 min (p = 0.018). In the triage group, 209 ELVO screen-positive patients were present, with 60 (28.7%) of these having LVO. The sensitivity, specificity, positive and negative predictive values, and area under the curve of the ELVO screen to detect LVO under the present triage system were 87.0%, 47.2%, 28.7%, 93.7%, and 0.671, respectively. Conclusion: The present study demonstrated that the introduction of a triage system may have shortened the time required for MT. ELVO screen may be considered a useful marker for screening LVO in prehospital settings in terms of the sensitivity and negative predictive value; however, further improvement may be necessary to reduce the rate of false positive results.

Current Treatment Results of Intracranial Carotid Artery Dissection Causing Cerebral Ischemia: A Japanese Nationwide Survey.

Intracranial carotid artery dissection causing cerebral ischemia is a rare but important cause of cerebral infarction in children and adolescents. Although endovascular therapy has been reported to be effective, questions regarding the indications for intervention are yet to be addressed. Therefore, this study aimed to evaluate factors related to clinical outcomes through a nationwide survey. Overall, 35 neurosurgical centers reported patients within 2 weeks after ischemic onset due to intracranial carotid artery dissection causing cerebral ischemia treated between January 2015 and December 2020. Data on clinical and radiological findings were statistically analyzed. Twenty-eight patients met the inclusion criteria. The median age was 36 years (range, 7-59 years), without sex differences. Headache at onset was documented in 60.7% of the patients. Dissection findings were categorized into stenosis (71.4%) or occlusion (28.6%). Initial treatments, including various antithrombotic agent combinations in 23 (82.1%) patients, effectively improved or prevented aggravation in half of the patients. The patients with stenotic dissection were significantly more likely to experience aggravation during the initial treatment than did those with occlusive dissection (P = 0.03). In addition, the patients with moderate to severe neurological deficits on admission had poorer outcomes at discharge more frequently than did those with mild neurological deficits on admission. Eight patients undergoing endovascular therapy had no procedural complications or further aggravation after intervention. In conclusion, patients with intracranial carotid dissection causing cerebral ischemia who had a stenotic dissection were at risk of further aggravation, and endovascular therapy effectively improved or prevented aggravation.

Direct carotid puncture for endovascular surgery of intracranial aneurysms: Technical note for avoiding complications.

BACKGROUND: While the most intracranial aneurysms are approachable by femoral or brachial artery puncture during endovascular surgery, in some cases, the lesion is difficult to reach due to complications such as the presence of winding pathways. Direct carotid puncture (DCP) is an alternative access approach, despite the potential risk of fatal neck hematoma. Herein, we describe the DCP technique in a series of five patients with intracranial aneurysms, together with its technical considerations. METHODS: Patients with intracranial aneurysms who underwent endovascular surgery using DCP were reviewed retrospectively. We selected the 3F to 6F systems for DCP depending on the necessity of adjunctive techniques. To prevent DCP-associated complications, we (1) conducted a micropuncture before introducing the short sheaths,(2) selected the smallest possible size for the system, (3) reversed heparin postoperatively, and (4) performed perioperative intubation/sedation management. RESULTS: Five out of 535 patients underwent DCP in our hospital between 2015 and 2019; successful vascular access was achieved in all cases. Although a minor neck hematoma occurred in one case, the patient did not require additional treatment. According to a literature review, severe neck hematoma requiring rescue therapy occurs in 5 out of 95 cases (5.3%). CONCLUSION: Although the potential risk of neck hematoma is not negligible, the DCP technique appears to be a safe and effective approach in treating intracranial aneurysms with challenging access routes in cases where perioperative counter measurements are appropriately performed.

Association of intravenous administration of human Muse cells with deficit amelioration in a rat model of spinal cord injury.

OBJECTIVE: Multilineage-differentiating stress-enduring (Muse) cells are pluripotent stem cells, which can be harvested from the bone marrow. After transplantation, Muse cells can migrate to an injured site of the body and exert repair effects. However, it remains unknown whether Muse cell transplantation can be an effective treatment in spinal cord injury (SCI). METHODS: The authors used a rat model of thoracic spinal cord contusion injury. For Muse cell transplantation, the clinical product CL2020 containing 300,000 Muse cells was administered intravenously 1 day after midthoracic SCI. Animals were divided into CL2020 (n = 11) and vehicle-treated (n = 15) groups. Behavioral and histological evaluations were conducted over a period of 8 weeks to see whether intravenous CL2020 administration provided therapeutic effects for SCI. The effects of human-selective diphtheria toxin on reversion of the therapeutic effects of CL2020 were also investigated. RESULTS: Hindlimb motor function significantly improved after CL2020 transplantations. Importantly, the effects were reverted by the human-selective diphtheria toxin. In immunohistochemical analyses, the cystic cavity formed after the injury was smaller in the CL2020 group. Furthermore, higher numbers of descending 5-hydroxytryptamine (5-HT) fibers were preserved distal to the injury site after CL2020 administration. Eight weeks after the injury, Muse cells in CL2020 were confirmed to differentiate most predominantly into neuronal cells in the injured spinal cord. CONCLUSIONS: Following SCI, Muse cells in CL2020 can reach the injured spinal cord after intravenous administration and differentiate into neuronal cells. Muse cells in CL2020 facilitated nerve fiber preservation and exerted therapeutic potential for severe SCI.

Intentional Stent Herniation Technique Using Neuroform Atlas Stent System for Embolization of a Wide-Necked Basilar Tip Aneurysm.

Objective: Endovascular treatment for complex wide-necked basilar tip aneurysms is challenging. Multiple stenting may be an option to deal with such aneurysms; however, the risk of ischemic complications is reported to be relatively high. Here, we report a case of unruptured basilar tip aneurysm treated using the intentional stent herniation technique to preserve the aneurysmal neck branches. Case Presentation: A 65-year-old woman presented with a growing unruptured basilar tip aneurysm associated with bilateral posterior cerebral arteries (PCAs) arising from the aneurysmal dome. We intentionally selected a large-sized Neuroform Atlas stent (Stryker, Kalamazoo, MI, USA) compared to the parent artery and deployed it along the right PCA to the basilar artery. The stent was herniated into the aneurysmal dome near the origin of the left PCA, resulting in the preservation of the left PCA. Successful coil embolization was achieved with acceptable obliteration. Conclusion: The intentional stent herniation technique may be an effective approach to treat complex wide-necked basilar tip aneurysms.

Parent Artery Occlusion against Dissecting Aneurysm Involving the Proximal Anterior Inferior Cerebellar Artery: Case Report and Literature Review.

Dissecting aneurysms of the anterior inferior cerebellar artery (AICA) are rare. Few reports suggested that coil embolization and parent artery occlusion (PAO) would be valuable treatment options against dissecting AICA aneurysms. We report a case of PAO against dissecting aneurysm involving the proximal AICA and discuss the therapeutics and literature review of this pathology. A 69-year-old woman was referred to our hospital, and neurological examination revealed a semicoma (Hunt and Hess grade IV). Brain computed tomography (CT) established the diagnosis of Fisher group 3 subarachnoid hemorrhage (SAH), CT angiography revealed an extravasation near the clivus, while digital subtraction angiography showed no signs of dissection. Conservative treatment was administered, and repeated angiography on day 13 showed a pseudoaneurysm and false lumen in the left proximal AICA. The patient was in poor health condition, and endovascular therapy (EVT) of the left AICA was performed to minimize invasion. The PAO was successful with no severe ischemic damage to the brainstem and cerebellum. However, the general condition gradually deteriorated, and the patient expired on day 24. Since open surgery for dissecting AICA aneurysm is technically challenging and revascularization procedure is often required, the rapidly developing EVT is a viable alternative. Although preservation of the proximal AICA is usually necessary, PAO without revascularization procedure was performed to avoid the high risk of regrowth and re-rupture of the dissecting aneurysm with respect to the patient's poor health condition. Hence, EVT is a viable option when microsurgery is contraindicated for treating dissecting AICA aneurysms.

A Novel Type of Stem Cells Double-Positive for SSEA-3 and CD45 in Human Peripheral Blood.

Peripheral blood (PB) contains several types of stem/progenitor cells, including hematopoietic stem and endothelial progenitor cells. We identified a population positive for both the pluripotent surface marker SSEA-3 and leukocyte common antigen CD45 that comprises 0.04% ± 0.003% of the mononuclear cells in human PB. The average size of the SSEA-3(+)/CD45(+) cells was 10.1 ± 0.3 µm and ∼22% were positive for CD105, a mesenchymal marker; ∼85% were positive for CD19, a B cell marker; and ∼94% were positive for HLA-DR, a major histocompatibility complex class II molecule relevant to antigen presentation. These SSEA-3(+)/CD45(+) cells expressed the pluripotency markers Nanog, Oct3/4, and Sox2, as well as sphingosine-1-phosphate (S1P) receptor 2, and migrated toward S1P, although their adherence and proliferative activities in vitro were low. They expressed NeuN at 7 d, Pax7 and desmin at 7 d, and alpha-fetoprotein and cytokeratin-19 at 3 d when supplied to mouse damaged tissues of the brain, skeletal muscle and liver, respectively, suggesting the ability to spontaneously differentiate into triploblastic lineages compatible to the tissue microenvironment. Multilineage-differentiating stress enduring (Muse) cells, identified as SSEA-3(+) in tissues such as the bone marrow and organ connective tissues, express pluripotency markers, migrate to sites of damage via the S1P-S1P receptor 2 system, and differentiate spontaneously into tissue-compatible cells after homing to the damaged tissue where they participate in tissue repair. After the onset of acute myocardial infarction and stroke, patients are reported to have an increase in the number of SSEA-3(+) cells in the PB. The SSEA-3(+)/CD45(+) cells in the PB showed similarity to tissue-Muse cells, although with difference in surface marker expression and cellular properties. Thus, these findings suggest that human PB contains a subset of cells that are distinct from known stem/progenitor cells, and that CD45(+)-mononuclear cells in the PB comprise a novel subpopulation of cells that express pluripotency markers.

Metabolomic Analysis of Mouse Brain after a Transient Middle Cerebral Artery Occlusion by Mass Spectrometry Imaging.

We performed metabolomic analyses of mouse brain using a transient middle cerebral artery occlusion (tMCAO) model with Matrix Assisted Laser Desorption/Ionization (MALDI)-mass spectrometry imaging (MSI) to reveal metabolite changes after cerebral ischemia. We selected and analyzed three metabolites, namely creatine (Cr), phosphocreatine (P-Cr), and ceramides (Cer), because these metabolites contribute to cell life and death. Eight-week-old male C57BL/6J mice were subjected to tMCAO via the intraluminal blockade of the middle cerebral artery (MCA) and reperfusion 60 min after the induction of ischemia. Each mouse was randomly assigned to one of the three groups; the groups were defined by the survival period after reperfusion: control, 1 h, and 24 h. Corrected samples were analyzed using MALDI-MSI. Results of MSI analysis showed the presence of several ionized substances and revealed spatial changes in some metabolites identified as precise substances, including Cr, P-Cr, Cer d18:1/18:0, phosphatidylcholine, L-glutamine, and L-histidine. Cr, P-Cr, and Cer d18:1/18:0 were changed after tMCAO, and P-Cr and Cer d18:1/18:0 accumulated over time in ischemic cores and surrounding areas following ischemia onset. The upregulation of P-Cr and Cer d18:1/18:0 was detected 1 h after tMCAO when no changes were evident on hematoxylin and eosin staining and immunofluorescence assay. P-Cr and Cer d18:1/18:0 can serve as neuroprotective therapies because they are biomarker candidates for cerebral ischemia.

A case of ruptured infectious anterior cerebral artery aneurysm treated by interposition graft bypass using the superficial temporal artery.

BACKGROUND: To describe the application of an interposition graft bypass using superficial temporal artery (STA) for the treatment of a ruptured anterior cerebral artery (ACA) infectious aneurysm. CASE DESCRIPTION: A 30-year-old male suffered from severe headache with high fever. The patient's diagnosis was ruptured infectious ACA aneurysm at the A3 segment with a maximum diameter of 4.5 mm, caused by infectious endocarditis. The patient was initially treated with high-dose intravenous antibiotics. Follow-up digital subtraction angiography (DSA) revealed that the fusiform aneurysm had enlarged to a maximum diameter of 14.0 mm. A left paracentral artery, supplying the motor area of the left lower extremity, originated from the body of this aneurysm. Because the angiographic findings suggested a risk of recurrent bleeding, the patient underwent open surgery. Interposition graft bypass using the STA was performed to reconstruct the left A3 segment in an end-to-side manner (left proximal callosomarginal artery - STA graft - left distal pericallosal artery). Then, the origin of the left paracentral artery was cut and anastomosed to the STA graft in an end-to-side manner. The affected parent artery was trapped, and the aneurysm was resected. Postoperative magnetic resonance imaging showed no ischemic or hemorrhagic complications, and postoperative DSA revealed the patency of the interposition graft. Pathological diagnosis of the resected aneurysm revealed features corresponding to infectious cerebral aneurysm. The postoperative course was uneventful, and the patient was discharged without any neurological deficits. CONCLUSION: In the treatment of infectious cerebral aneurysms, revascularization should be considered when the affected artery supplies the eloquent area. Interposition graft bypass using the STA is one of the options for revascularization surgery for the treatment of infectious ACA aneurysms.