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.

Coil Embolization of Unruptured Distal Anterior Cerebral Artery Aneurysm Using a Marathon Microcatheter.

Marathon is rarely used in coil embolization for an aneurysm; particularly, there have been no reports about distal anterior cerebral artery aneurysms. We have reported a case of successful use of Marathon in coil embolization in case of a distal anterior cerebral artery aneurysm. The patient was an 83-year-old woman. She had undergone coil embolization for an unruptured distal anterior cerebral artery aneurysm, which was discovered by chance. Our initial approach involved the use of a combination of Traxcess and Excelsior SL-10, but the use of SL-10 could not follow Traxcess because the right anterior cerebral artery from the right internal carotid artery had a sharp bifurcation. However, by switching to a combination of TENROU and Marathon, we could access the aneurysm. We thereby decided to continue the use of Marathon in order to complete the coil embolization. In coil embolization for an aneurysm, Marathon was found to be useful, depending on the location of the aneurysm and access route.

Bilateral Magnetic Resonance Imaging-Guided Focused Ultrasound Thalamotomy for Essential Tremor.

INTRODUCTION: Essential tremor is the most common movement disorder in adults. Bilateral symptoms are typical; however, bilateral thalamotomy for essential tremor is associated with a high probability of adverse events. We retrospectively investigated the efficacy and safety of staged bilateral ventral intermediate nucleus thalamotomy for refractory essential tremor using magnetic resonance imaging-guided focused ultrasound. METHODS: We enrolled 5 consecutive patients with refractory essential tremor between September 2016 and March 2020. Patients underwent a second operation at least 1 year after the first operation. The second lesion was created asymmetrically to the first lesion. RESULTS: Mean patient age was 57.6 years, and the mean interval between the 2 operations was 27.8 months. The second lesion center was superior to the first lesion in all patients. The mean baseline, second preoperative, and second postoperative Clinical Rating Scale for Tremor total scores were 63.6, 49.2, and 21.8, respectively. The mean baseline, second preoperative, and second postoperative Clinical Rating Scale for Tremor part C scores were 18.4, 8.2, and 2.6, respectively. One patient had permanent adverse events of slight dysarthria and discomfort in the tongue. No patient experienced dysphagia or cognitive dysfunction after the second operation. Four of the 5 patients were satisfied with the results of the bilateral treatment, including the patient who had permanent adverse events. CONCLUSIONS: Magnetic resonance imaging-guided focused ultrasound is an effective method for bilateral thalamotomy when adhering to the following considerations: (1) asymmetrical lesions are created and (2) sufficient interval (>1 year) between operations.

4-Hydroxyl-2-Nonenal Localized Expression Pattern in Retrieved Clots is Associated with Large Artery Atherosclerosis in Stroke Patients.

OBJECTIVES: The relationship between stroke etiology and clot pathology remains controversial. MATERIALS AND METHODS: We performed histological analysis of clots retrieved from 52 acute ischemic stroke patients using hematoxylin and eosin staining and immunohistochemistry (CD42b and oxidative/hypoxic stress markers). The correlations between clot composition and the stroke etiological group (i.e., cardioembolic, cryptogenic, or large artery atherosclerosis) were assessed. RESULTS: Of the 52 clots analyzed, there were no significant differences in histopathologic composition (e.g., white blood cells, red blood cells, fibrin, and platelets) between the 3 etiological groups (P = .92). By contrast, all large artery atherosclerosis clots showed a localized pattern with the oxidative stress marker 4-hydroxyl-2-nonenal (P < .01). From all 52 clots, 4-hydroxyl-2-nonenal expression patterns were localized in 28.8% of clots, diffuse in 57.7% of clots, and no signal in 13.5% of clots. CONCLUSIONS: A localized pattern of 4-hydroxyl-2-nonenal staining may be a novel and effective marker for large artery atherosclerosis (sensitivity 100%, specificity 82%).

What factors impact the clinical outcome of magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor?

OBJECTIVE: Magnetic resonance imaging-guided focused ultrasound (MRgFUS) is a novel and useful treatment for essential tremor (ET); however, the factors impacting treatment outcome are unknown. The authors conducted this study to determine the factors affecting the outcome of MRgFUS. METHODS: From May 2016 through August 2017, 15 patients with ET were admitted to Ohnishi Neurological Center and treated with MRgFUS. To determine the factors impacting treatment outcome, the authors retrospectively studied correlations between the Clinical Rating Scale for Tremor (CRST) improvement rate and age, disease duration, baseline CRST score, skull density ratio (SDR), skull volume, maximum delivered energy, or maximum temperature. RESULTS: The mean CRST score was 18.5 ± 5.8 at baseline and 4.6 ± 5.7 at 1 year. The rate of improvement in the CRST score was 80% ± 22%. Younger age and lower baseline CRST score were correlated with a higher CRST improvement rate (p = 0.025 and 0.007, respectively). To obtain a CRST improvement rate ≥ 50%, a maximum temperature ≥ 55°C was necessary. There was no correlation between SDR and CRST improvement rate (p = 0.658). A lower SDR and higher skull volume required significantly higher maximum delivered energy (p = 0.014 and 0.016, respectively). A higher maximum temperature was associated with a significantly larger lesion volume (p = 0.026). CONCLUSIONS: Younger age and lower baseline CRST score were favorable outcome factors. It is important to assess predictive factors when applying MRgFUS.

A thread of hope for successful revascularization for acute embolic basilar artery occlusion due to miserable vertebral artery stump syndrome. A technical report.

Acute basilar artery occlusion (BAO) is associated with major morbidities and a high mortality rate. The prevalence of acute BAO is 10.4% among patients treated with thrombectomy for acute large vessel occlusion. Vertebral artery stump syndrome (VASS) reportedly causes ischemic stroke with tandem occlusions as vertebral artery (VA) origin occlusion and BAO. The pathogenesis of ischemic stroke due to VASS can be attributed to thrombi or emboli. Acute embolic BAO due to VASS accounted for 2 of 25 cases (8.0%) of BAO treated using thrombectomy between April 2014 and May 2019 in our registry. VASS must be considered as one cause of BAO. With the initial Magnetic resonance angiography on arrival, it is difficult to distinguish between BAO due to simple cardiogenic embolus and due to embolus caused by VASS rapidly. In patients suffering from acute embolic BAO due to VASS, the presence of VA origin occlusion makes endovascular therapy (EVT) difficult to perform. Here, we report consecutive cases of thrombectomy for acute embolic BAO due to VASS, showing markedly different outcomes. VA origin occlusion severely limits the technical options for EVT. Visualization or conjecture of the origin of both or dominant VAs conceivably offers the possibility of successful EVT and may allow good outcomes.

Diagnosing intra-cranial and cervical artery dissection using MRI as the initial modality.

Dissection of cranial and cervical arteries is a relatively frequent clinical condition. However, it is difficult to diagnose a dissection when patients present with relatively mild symptoms. Various radiological techniques are used as diagnostic tools. This study analyzed retrospectively the characteristics of cranial and cervical artery dissections using "MR first concept", with MRI as the first-choice diagnostic modality for all new patients with neurological symptoms. The patients who were admitted in Ohnishi neurological center between January 2001 and December 2014 were included. MRI was used as the initial investigation for all new patients, including those with mild symptoms such as headache or vertigo only. The patients were divided into carotid group and vertebral group. The statistical comparison was performed between these two groups. A total of 164 patient cases were analyzed. In 44 (26.8%) and 120 (73.2%) patients, dissection occurred in the carotid group and vertebral group, respectively. Concerning the type of onset, 52 patients presented with only subjective symptoms accompanied with ischemic or hemorrhagic lesions, 97 patients with ischemic symptoms and 15 patients with subarachnoid hemorrhage. There were statistically significant differences between the carotid and vertebral groups in terms of hemiparesis, aphasia, history of trauma, headache and vertigo. Patients with only a headache and those with no ischemic features had no worsening symptoms. The symptom of headache or neck pain only is more frequent than previously reported. The "MR first concept" would prove useful for early diagnosis of dissections and early treatment.

Cerebral and spinal cord tanycytic ependymomas in a young adult with a mutation in the NF2 gene.

We studied one frontal lobe tumor and multiple spinal cord tumors (one in an extramedullary location) that had been resected from a 24-year-old man. The frontal lobe tumor was well demarcated and non-infiltrating, and consisted of eosinophilic, elongated fibrillary cells arranged in a fascicular pattern. A similar histology was reproduced in the spinal cord tumors, with additional areas showing standard features of ependymoma. Immunohistochemical and ultrastructural observations revealed that all the tumors were ependymal in nature with positivity for GFAP and epithelial membrane antigen and negativity for oligodendrocyte transcription factor 2, showing intra- and intercellular microrosettes, leading us to a diagnosis of tanycytic ependymoma for the frontal lobe tumor and tanycytic ependymoma with ordinary ependymomatous component for the spinal cord tumors. The spinal extramedullary tumor was a schwannoma. Importantly, a heterozygous truncating mutation in the NF2 gene was identified in the blood lymphocytes from the patient. It is known that multiple nervous system tumors can occur in neurofibromatosis type 2 (NF2), which is caused by mutation in the NF2 gene, and that occurrence of ependymoma, including the tanycytic variant, can be associated with this genetic condition. The present case provides further information about the clinicopathology of tanycytic ependymoma with details of the immunohistochemical, ultrastructural and genetic features.

Classification of the superior petrosal veins and sinus based on drainage pattern.

BACKGROUND: The increasing number of reports of complications after sacrificing the superior petrosal veins, the largest veins in the posterior fossa, has led to a need for an increased understanding of the anatomy of these veins and the superior petrosal sinus into which they empty. OBJECTIVE: To examine the anatomy of the superior petrosal veins and their size, draining area, and tributaries, as well as the anatomic variations of the superior petrosal sinus. METHOD: Injected cadaveric cerebellopontine angles and 3-dimensional multifusion angiography images were examined. RESULTS: The 4 groups of the superior petrosal veins based on their tributaries, course, and draining areas are the petrosal, posterior mesencephalic, anterior pontomesencephalic, and tentorial groups. The largest group was the petrosal group. Its largest tributary, the vein of the cerebellopontine fissure, was usually identifiable in the suprafloccular cistern located above the flocculus on the lateral surface of the middle cerebellar peduncle. The medial or lateral segment of the superior petrosal sinus was absent in 40% of cerebellopontine angles studied with venography. CONCLUSION: The superior petrosal veins and their largest tributaries, especially the vein of the cerebellopontine fissure, should be preserved if possible. Obliteration of superior petrosal sinuses in which either the lateral or medial portion is absent may result in loss of the drainage pathway of the superior petrosal veins. Preoperative assessment of the superior petrosal sinus should be considered before transpetrosal surgery in which the superior petrosal sinus may be obliterated.

Platelet function and spontaneous thrombolytic activity of patients with cerebral infarction assessed by the global thrombosis test.

Measurements of platelet reactivity and assessment of the efficacy of antiplatelet drugs are widely recognized as pre-requisite for the diagnosis and treatment of stroke patients. A recently established shear-induced platelet reactivity test using non-anticoagulated blood (the Global Thrombosis Test) has facilitated measurements of physiologically relevant platelet function and thrombolytic activity. 195 healthy volunteers, not taking antiplatelet drugs or anticoagulants, and 185 patients with acute cerebrovascular diseases were enrolled. The effect of antiplatelet drugs on platelet function and thrombolytic activity was assessed using the Global Thrombosis Test after 14 days of medication. The occlusion time (OT), an index of platelet reactivity, in healthy controls was 284.9 ± 92.2 s. The lysis time (LT), an index of thrombolytic activity, in healthy controls was 2,231 ± 1,223 s. Both times had no significant difference between males and females. The OT of all stroke patients was 210.3 ± 140.8 s and was shorter than that of the healthy controls (284.9 ± 92.2, p < 0.0001). The LT of all stroke patients was 3,159 ± 1,549 s and was longer than that of the controls (2,231 ± 1,223, p < 0.0001). Medication significantly prolonged the OT from 184.5 ± 150.6 s (before) to 295.3 ± 208.1 s (after) in all patients, indicating a reversal of the hyper-platelet reactivity. In addition, medication shortened the LT from 3,924 ± 1,718 s (before) to 3,107 ± 1,794 s (after) in all patients. A prothrombotic state exists in stroke patients due to enhanced platelet function and suppressed thrombolytic activity. Medication improved these physiological parameters of haemostasis.

Cytologic feature by squash preparation of pineal parenchyma tumor of intermediate differentiation.

Pineal parenchyma tumor of intermediate differentiation (PPTID) is a very rare intracranial tumor, and pathological investigation limited to immunohistological and ultrastructural analyses have been published to date. Although intraoperative cytology is one of the important approaches for initial diagnosis in brain tumors, no or little studies on cellular morphology of PPTID have been demonstrated due to its rarity. We report here cytological features of PPTID obtained from stereotactic surgical specimens in a case of 27-year-old female manifested by dizziness and diplopia. Brain MRI revealed an unhomogeneously enhanced, large-sized tumor (56 x 52 x 60 mm) mainly located in the pineal region expanding from the midbrain to superior portion of the cerebellum and the fourth ventricle. Squash cytology showed increased nucleocytoplasmic ratio, hyperchromatic nuclei, and small rosette-like cell cluster but cellular pleomorphism was mild to moderate and necrotic background was not observed. Histology showed high cellularity, moderate nuclear atypia, and small rosette formation but neither bizarre tumor cells nor necrosis was present. Mitotic counts were very low (less than 1 per 10 high-power fields) and the MIB-1 labeling index was relatively high (10.1%). Tumor cells were immunohistochemically positive for neural markers such as synaptophysin, neurospecific enolase but not for glial fibrillary acidic protein or S-100. In some parts, cells were strongly reactive for neurofilament protein. Taken together, we made a final diagnosis of PPTID. This is the first presentation of cytological analysis by squash preparation that gives an important clue to accurate diagnosis of pineal parenchymal tumor and to understand its malignant potential.

A rare case of malignant glioma suspected to have arisen from a cavernous sinus.

A 55-year-old woman presented with a right trigeminal dysfunction (dysesthesia) initially, followed by right oculomotor and abducens paresis lasting 1 month. Neuroimaging studies showed an enhanced mass in the right cavernous sinus extending to the trigeminal ganglion. The extraparenchymal tumor located around the right trigeminal ganglion was totally removed, except for an intracavernous lesion, by the orbitozygomatic approach. The solid tumor was completely separated from the brainstem and seemed to be a trigeminal schwannoma arising from the trigeminal ganglion or cavernous sinus at surgery. A histological examination, however, found a typical malignant glioma that consisted primarily of astrocytic tumor cells. Immunohistochemical staining showed the tumor cells stained intensely for GFAP, S-100 protein, and vimentin, but not for NFP, Schwann/2E, CD34, and CD68. The mean MIB-1 index was 12.4%. The tumor recurred after a short time, and then it rapidly disseminated into the subarachnoid space and left the cerebral hemisphere. The patient died 1 year after the initial symptoms in spite of aggressive surgery, radiation, and chemotherapy with temozolomide. There are no previous reports of a malignant glioma arising from either the cavernous sinus or the trigeminal ganglion. From the pathogenetic point of view, this malignant glioma is an extremely rare case that developed clinically and neuroradiologically from the cavernous sinus and was suspected be being derived from ectopic glial tissue.

[Cranioplasty using autogenous bone cryopreserved with dimethylsulfoxide (DMSO)].

It is generally agreed that the autogenous bone flap which has been removed at the time of external decompression would be superior to any artificial material if it can be used in cranioplasty. Cranioplasty using autogenous frozen bone graft has been reported and showed good results except for infection and severe bone absorption. We conducted 39 cases of cranioplasty with cryopreserved autogenous bone in the presence of 10% of Dimethylsulfoxide (DMSO), which has been reported as a cryoprotective agent. Although no remarkable histological effects have been recognized in frozen bone with or without DMSO, we have obtained excellent clinical results without bone absorption in 24 of the cases. These results suggest that DMSO is helpful for frozen bone preservation.