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.

The Prediction of Neurological Prognosis for Cervical Spondylotic Myelopathy Using Diffusion Tensor Imaging.

OBJECTIVE: Although cervical spondylotic myelopathy (CSM) can be easily diagnosed using magnetic resonance imaging (MRI), prediction of surgical effect using preoperative radiological examinations remains difficult. In previous studies, it was reported that diffusion tensor imaging (DTI) may be used for the prediction of surgical effect; however, these studies did not consider the influences of spinal cord compression even though the values of DTI indexes can be distorted by compressive lesions in patients with CSM. Therefore, it is uncertain whether preoperative DTI indexes can actually predict the surgical effect. The aim of this study was to investigate DTI metrics that are hardly affected by spinal cord compression and can accurately predict neurological status after decompressive surgery. METHODS: Twenty-one patients with CSM who underwent surgery and 10 healthy volunteers were enrolled in this study. The subjects underwent cervical MRI, and values of DTI indexes including axial diffusivity (AD), radial diffusivity (RD), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were recorded at each intervertebral level. Further, the Japanese Orthopaedic Association (JOA) score of each patient with CSM was recorded before and after surgery for neurological status evaluation. Preoperative and postoperative values of DTI indexes were compared, and correlations between preoperative DTI parameters and postoperative neurological recovery were assessed. RESULTS: After surgery, the lesion-adjacent (LA) ratios of RD and ADC increased (p = 0.04 and p = 0.062, respectively), while the LA ratio of FA decreased (p = 0.075). In contrast, the LA ratio of AD hardly changed. A negative correlation was observed between preoperative LA ratio of AD and JOA recovery rate 6 months after surgery (r = -0.379, p = 0.091). Based on preoperative LA ratio of AD, the patients were divided into a low AD group and a high AD group, and JOA recovery rate 6 months after surgery was found to be higher in the low AD group than in the high AD group (p = 0.024). CONCLUSION: In patients with CSM, preoperative LA ratio of AD is seldom affected by spinal cord compression, and it negatively correlates with JOA recovery rate 6 months after surgery.

[A Case of Positional Vertebral Artery Occlusion due to Physiological Cervical Extension with Occipital Condylar Spur].

Positional vertebral artery occlusion(PVAO)is a mechanical occlusion of the extracranial vertebral artery(VA)due to physiological movement of the head and neck. However, only a few cases of mechanical VA compression due to routine flexion-extension of the neck have been reported. We present a unique case of PVAO due to neck extension with an occipital condylar spur. A 78-year-old man was admitted to our hospital for sudden onset of right hemiparesis and dysarthria. Magnetic resonance imaging(MRI)revealed bilateral occipital and cerebellar infarctions and vessel occlusion extending from the VA to the basilar artery. Mechanic thrombectomy resulted in partial recanalization. Computed tomography angiography(CTA)performed the next day showed spontaneously recanalized left VA with some wall irregularity. CTA in the neck-extended position revealed a severely compressed left VA in its V3 segment, which was attributed to the left occipital condylar spur with degenerative changes of the condyle-C1 facet. Cervical MRI also showed a pseudotumor from the lower clivus to the odontoid process that indicated mechanical stress on the occipitocervical ligaments. An occiput to C2 fusion was performed to stabilize and avoid dynamic vascular compression. Postoperative CTA revealed no evidence of restricted flow with flexion or extension movements of the neck. It should be noted that physiological head and neck movements accompanied by condylar degenerative changes could be a cause of vertebrobasilar insufficiency.

[Successful Total Resection with Preceding Arterial Coil Embolization of Intradural Extramedullary Tumor at Craniovertebral Junction Encasing Dominant-side Vertebral Artery].

OBJECTIVE: The surgical resection of craniovertebral junction(CVJ)meningioma is challenging because of the neighboring brainstem, lower cranial nerves, and vertebral artery(VA). Moreover, encasement of the VA by the tumor can raise the risk of complications and require cautious manipulation during surgery. CASE: A 46-year-old woman presented with a one-year history of neck pain. She had temporal hemiplegia and numbness on her left side. Magnetic resonance imaging(MRI)showed a CVJ meningioma pushing the brainstem from the right vertebral side and encasing the right VA. Digital subtraction angiography(DSA)showed two feeding arteries arising from the right VA and a sunburst sign. The right VA was the dominant side but did not have the right posterior inferior cerebellar artery(PICA). The anterior spinal artery(ASA)was dominant in the left VA. We performed a balloon test occlusion(BTO)for 20 min and it did not cause any complications;therefore, we occluded the VA using endovascular coils. After 4 days, we removed the meningioma in the prone position, using a far-lateral approach and C1-laminectomy. The laterally located meningioma pushed the brainstem. After detaching the tumor from the dura, we cut the encased VA and the tumor was resected safely(Simpson grade II). Postoperatively, she developed temporal thermal hypoalgesia on the left side of her body. Magnetic resonance imaging showed a microinfarction in the medulla. CONCLUSION: If the VA test occlusion provides a clear result, pre-operative endovascular sacrifice of the VA encased by CVJ meningioma is a feasible treatment strategy.

Decreased Value of Highly Accurate Fractional Anisotropy Using 3-Tesla ZOOM Diffusion Tensor Imaging After Decompressive Surgery in Patients with Cervical Spondylotic Myelopathy: Aligned Fibers Effect.

BACKGROUND: Diffusion tensor imaging (DTI) is widely used; however, most of the prior studies have resulted in presurgical decreased fractional anisotropy (FA) values in patients with cervical spondylotic myelopathy (CSM). We used ZOOM DTI and could acquire highly accurate FA values during perioperative periods, which indicated different insights than preceding studies. The objective of this study was to assess the perioperative FA change in patients with CSM and determine the prognostic factor. METHODS: Twenty-eight patients with CSM and healthy control subjects were enrolled in this study. Twenty patients (71%) had intracordal high intensity before surgery. All patients underwent decompressive surgery. ZOOM DTI and the Japanese Orthopaedic Association (JOA) assessment were performed before and after surgery. The region of interest was manually contoured to omit the surrounding cerebrospinal fluid. The axial plane of the most stenotic cervical level was assessed. RESULTS: FA values before surgery and at 1 week after surgery, and FA values at 1 week after surgery and at 6 months after surgery differed significantly as determined. The FA values of patients with intracordal high intensity significantly decreased after surgery and significantly increased from 1 week to 6 months, whereas those of patients without intracordal high intensity did not significantly change. JOA scores at 6 months after surgery (13.1) improved significantly compared with JOA scores before surgery (10.8). Only FA values at 1 week after surgery had a significant positive relationship with JOA scores presurgery and at 6 months after surgery. CONCLUSIONS: The presurgical FA value in patients with CSM did not differ from that of normal control subjects, but significantly decreased after surgery, and significantly increased 6 months after surgery. We concluded that the postsurgical FA value approximates the proper state of the damaged cord and the presurgical FA value includes a masked effect as an aligned fiber effect because of compression by degenerative construction. Only the FA value at 1 week had a significant positive relationship with the JOA score presugery and at 6 months, which established that the postsurgical FA value may be a more accurate prognostic factor than the presurgical FA value.

Mollaret Meningitis with a High Level of Cytokines in the Cerebrospinal Fluid Successfully Treated by Indomethacin.

A rare case of Mollaret meningitis characterized by four recurrent episodes of aseptic meningitis during a three-year period is reported. The patient showed a high fever and severe headache accompanied by a high level of cerebrospinal fluid (CSF) cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α). The symptoms and high CSF cytokines were resolved immediately after introducing indomethacin treatment. Reactivation of the latent virus is considered to be the cause of this rare disease, and indomethacin is believed to inhibit the periodic abnormal generation of eicosanoid in the brain, resulting in a reduction in the fever and subsequent inflammation.

[A Case of Onion-Skin Hemifacial Dysesthesia Caused by Ossification of the Cervical Posterior Longitudinal Ligament].

BACKGROUND: The spinal trigeminal nucleus is a cranial nerve which extends caudally from the medulla to the upper cervical segment of the spinal cord. An upper cervical lesion can cause pain or dysesthesia of the face sparing the central area, which is called onion-skin pattern. CASE PRESENTATION: We present a rare case of a 73-year-old man with cervical ossification of the posterior longitudinal ligament(OPLL)causing onion-skin pattern dysesthesia. No other brain lesion was detected by MRI. He had received adequate medication for six months, but his dysesthesia persisted. Cervical radiographic studies showed OPLL with slight instability at the C2-3 level and mild spinal cord compression at the C3 vertebral level. The lesion was considered solely responsible for the onion-skin pattern dysesthesia, and it resulted in posterior cervical decompression. Immediately after the surgery, his dysesthesia disappeared. CONCLUSION: The onion-skin pattern dysesthesia could have been caused by the C2-3 lesion.

Double Crush of L5 Spinal Nerve Root due to L4/5 Lateral Recess Stenosis and Bony Spur Formation of Lumbosacral Transitional Vertebra Pseudoarticulation: A Case Report and Review.

We present a case of double-crushed L5 nerve root symptoms caused by inside and outside of the spinal canal with spur formation of the lumbosacral transitional vertebra (LSTV). A 78-year-old man presented with 7-year history of moderate paresis of his toe and left leg pain when walking. Magnetic resonance imaging (MRI) revealed spinal stenosis at the L3/4 and 4/5 spinal levels and he underwent wide fenestration of both levels. Leg pain disappeared and 6-min walk distance (6MWD) improved after surgery, however, the numbness in his toes increased and 6MWD decreased 9 months after surgery. Repeated MR and 3D multiplanar reconstructed computed tomography (CT) images showed extraforaminal impingement of the L5 root by bony spur of the left LSTV. He underwent second decompression surgery of the L5/S via the left sided Wiltse approach, resulting in the improvement of his symptoms. The impingement of L5 spinal nerve root between the transverse process of the fifth lumbar vertebra and the sacral ala is a rare entity of the pathology called "far-out syndrome (FOS)". Especially, the bony spur formation secondary to the anomalous articulation of the LSTV (LSPA) has not been reported. These articulations could be due to severe disc degeneration, following closer distance and contact between the transverse process and the sacral ala. To our knowledge, this is the first report describing a case with this pathology and may be considered in cases of failed back surgery syndromes (FBSS) of the L5 root symptoms.

[Radiotherapy for Alleviation of Paraparesis due to Leptomeningeal and Cauda Equina Metastasis of HER2-Positive Breast Cancer: A Case Report].

Leptomeningeal metastasis is a rare entity and its diagnosis is often difficult. Moreover, evidence-based therapeutic strategies have not yet been established. A 52-year-old woman presented with high fever and was diagnosed with bacterial meningitis at first examination;although her fever was alleviated, she experienced motor weakness in both of her lower extremities. Ga scintigraphy highlighted the hot-spot areas of the disease in the cranial bone. She was then transferred to our department. Open biopsy of the skull showed metastasis of the cancer. Chest CT results indicated right breast cancer and Gd-DTPA imaging showed obvious enhancement of the pia mater around the conus medullaris and cauda equina. However, cerebrospinal fluid(CSF)cytological examination did not show the presence of any positive cells;consequently, mastectomy was performed in the thoracic surgical department. The severity of paraparesis and pain in her legs increased;however, repeat MRI 1 month later showed no evidence of any change. Therefore, we performed biopsy of the cauda equina and arachnoid lesions. The pathological diagnosis was metastasis of breast cancer with positive human epidermal growth factor receptor 2(HER2)immunological staining. The results of a repeat cytological examination of the CSF during the surgery were negative. Local radiotherapy(25 Gy/5 Fr)as a monotherapy was selected for the patient, because her family did not approve of the combination of radiotherapy and chemotherapy. The severity of both paraparesis and limb pain decreased immediately after the radiotherapy.

Pituitary apoplexy manifesting as massive intracerebral hemorrhage. Case report.

A 68-year-old man presented with severe conscious disturbance caused by pituitary apoplexy resulting in massive intracerebral hemorrhage (ICH). He had been periodically followed up for asymptomatic pituitary adenoma at another hospital for 8 years. Neuroimaging examination revealed pituitary apoplexy and massive ICH located in the left frontal lobe, and the ICH was directly connected to the intratumoral hemorrhage. The diagnosis was massive ICH from pituitary apoplexy. The patient underwent emergent evacuation of hematoma and removal of the pituitary adenoma via bi-frontal craniotomy. Postoperatively, he continued to exhibit deep consciousness disturbance and died 1 month after the operation. Pituitary apoplexy is usually characterized by intra-tumoral hemorrhage. The treatment strategy for asymptomatic pituitary adenoma is still controversial. This case shows that we should always consider the risk of pituitary apoplexy manifesting as ICH which may cause a fatal outcome.

[Case of direct carotid-cavernous fistula presenting with subarachnoid hemorrhage].

We report a case of longstanding asymptomatic direct carotid-cavernous fistula (CCF) which caused fatal subarachnoid hemorrhage (SAH). A 91-year-old female with no history of previous head trauma and optic symptoms presented acute subarachnoid hemorrhage. Angiography revealed a left direct carotid-cavernous fistula draining only into the contralateral cavernous sinus with leptomeningeal venous reflux and small varix on the pontine bridging vein. The affected cavernous sinus was markedly dilated and there was no septum between the left cavernous sinus and the internal carotid artery. The patient underwent transvenous coil embolization for intercavernous sinus and leptomeningeal venous reflux was successfully obliterated and opacification of the varix was diminished. The past history of this patient and angiographical findings strongly suggest long standing asymptomatic CCF caused SAH.

Advanced glycation end products increase permeability of brain microvascular endothelial cells through reactive oxygen species-induced vascular endothelial growth factor expression.

BACKGROUND: Advanced glycation end products (AGEs) have been implicated as important factors in the pathogenesis of diabetic vascular complication. The aim of this study is to reveal the effect of AGEs on permeability of brain microvascular endothelial cells (BMECs) in order to assess its role in diabetic vascular complications. METHODS: Permeability was determined by the flux of fluorescein isothiocyanate (FITC)-labeled dextran (4-kDa molecular weight) through endothelial cell monolayers on a transwell system and was compared between bovine BMECs (BBMECs) and bovine aortic endothelial cells (BAECs). The effect of AGEs on permeability was investigated in terms of the role of vascular endothelial growth factor (VEGF) and reactive oxygen species (ROS). RESULTS: Permeability and VEGF expression were significantly increased by the addition of 100 µg/mL of glycer-AGEs in BBMECs. They also tended to be increased in BAECs, but not enough to make a significant difference. Simultaneous treatment with an anti-VEGF antibody suppressed the AGE-enhanced permeability. Furthermore, simultaneous treatment with a free radical scavenger, edaravone, also suppressed the AGE-enhanced permeability and the increase in VEGF mRNA levels and AGE-induced intracellular ROS overproduction. CONCLUSIONS: These results suggest that BMECs are more susceptible than aortic endothelial cells to AGE-enhanced permeability and that AGE-enhanced permeability is dependent on VEGF expression induced by ROS over production.

[A case report of spinal dural AV fistula which showed drastic recovery].

Spinal dural AVF is the most common type of spinal AVMs. It affects especially old male with slowly progressive paraparesis in most cases. We have experienced a rare case of a middle aged male with spinal dural AVF who showed rapid deterioration in its course. The patient was treated with surgical interruption of AVF after transarterial embolization with NBCA. The patient improved well after the treatment, and intramedullary lesion on MRI disappeared after 4 years. The authors would like to stress the importance of early diagnosis and proper treatment for spinal dural AVFs.

[Surgical treatment for cerebral aneurysm after incomplete Guglielmi detachable coil embolization].

The frequency of surgical treatment for intracranial aneurysms that have been incompletely treated by endovascular coiling will increase in time. The authors describe their experience in the following 3 patients. There was one non-ruptured aneurysm and two ruptured ones. The intervals between coiling and surgery were 1, 5, and 10 months. Surgery was indicated because of partial treatment and/or growth of residual neck. Observation during surgery revealed that coils were exposed to the subarachnoid space at the tip of the aneurysm in the cases of ruptured aneurysms. When the residual neck was large enough for the size of the clip blades, there was no need to remove the coils. The coils in the neck were able to be removed when the interval between coiling and surgery was very short, but could not be removed when the interval was prolonged. Intraoperative angiography and reconstructive bypass surgery may be essential in these complex cases. As pointed out previously, the operative approach should be determined by the need for coil removal and the duration since coiling.