Stem Cell Therapy for Acute/Subacute Ischemic Stroke with a Focus on Intraarterial Stem Cell Transplantation: From Basic Research to Clinical Trials.

Stem cell therapy for ischemic stroke holds great promise for the treatment of neurological impairment and has moved from the laboratory into early clinical trials. The mechanism of action of stem cell therapy includes the bystander effect and cell replacement. The bystander effect plays an important role in the acute to subacute phase, and cell replacement plays an important role in the subacute to chronic phase. Intraarterial (IA) transplantation is less invasive than intraparenchymal transplantation and can provide more cells in the affected brain region than intravenous transplantation. However, transplanted cell migration was reported to be insufficient, and few transplanted cells were retained in the brain for an extended period. Therefore, the bystander effect was considered the main mechanism of action of IA stem cell transplantation. In most clinical trials, IA transplantation was performed during the acute and subacute phases. Although clinical trials of IA transplantation demonstrated safety, they did not demonstrate satisfactory efficacy in improving patient outcomes. To increase efficacy, increased migration of transplanted cells and production of long surviving and effective stem cells would be crucial. Given the lack of knowledge on this subject, we review and summarize the mechanisms of action of transplanted stem cells and recent advancements in preclinical and clinical studies to provide information and guidance for further advancement of acute/subacute phase IA stem cell transplantation therapy for ischemic stroke.

Optogenetic Stimulation Reduces Neuronal Nitric Oxide Synthase Expression After Stroke.

Post-stroke optogenetic stimulation has been shown to enhance neurovascular coupling and functional recovery. Neuronal nitric oxide synthase (nNOS) has been implicated as a key regulator of the neurovascular response in acute stroke; however, its role in subacute recovery remains unclear. We investigated the expression of nNOS in stroke mice undergoing optogenetic stimulation of the contralesional lateral cerebellar nucleus (cLCN). We also examined the effects of nNOS inhibition on functional recovery using a pharmacological inhibitor targeting nNOS. Optogenetically stimulated stroke mice demonstrated significant improvement on the horizontal rotating beam task at post-stroke days 10 and 14. nNOS mRNA and protein expression was significantly and selectively decreased in the contralesional primary motor cortex (cM1) of cLCN-stimulated mice. The nNOS expression in cM1 was negatively correlated with improved recovery. nNOS inhibitor (ARL 17477)-treated stroke mice exhibited a significant functional improvement in speed at post-stroke day 10, when compared to stroke mice receiving vehicle (saline) only. Our results show that optogenetic stimulation of cLCN and systemic nNOS inhibition both produce functional benefits after stroke, and suggest that nNOS may play a maladaptive role in post-stroke recovery.

RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke.

Background and Purpose- Many restorative therapies have been used to study brain repair after stroke. These therapeutic-induced changes have revealed important insights on brain repair and recovery mechanisms; however, the intrinsic changes that occur in spontaneously recovery after stroke is less clear. The goal of this study is to elucidate the intrinsic changes in spontaneous recovery after stroke, by directly investigating the transcriptome of primary motor cortex in mice that naturally recovered after stroke. Methods- Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion. Functional recovery was evaluated using the horizontal rotating beam test. A novel in-depth lesion mapping analysis was used to evaluate infarct size and locations. Ipsilesional and contralesional primary motor cortices (iM1 and cM1) were processed for RNA-sequencing transcriptome analysis. Results- Cluster analysis of the stroke mice behavior performance revealed 2 distinct recovery groups: a spontaneously recovered and a nonrecovered group. Both groups showed similar lesion profile, despite their differential recovery outcome. RNA-sequencing transcriptome analysis revealed distinct biological pathways in the spontaneously recovered stroke mice, in both iM1 and cM1. Correlation analysis revealed that 38 genes in the iM1 were significantly correlated with improved recovery, whereas 74 genes were correlated in the cM1. In particular, ingenuity pathway analysis highlighted the involvement of cAMP signaling in the cM1, with selective reduction of Adora2a (adenosine receptor A2A), Drd2 (dopamine receptor D2), and Pde10a (phosphodiesterase 10A) expression in recovered mice. Interestingly, the expressions of these genes in cM1 were negatively correlated with behavioral recovery. Conclusions- Our RNA-sequencing data revealed a panel of recovery-related genes in the motor cortex of spontaneously recovered stroke mice and highlighted the involvement of contralesional cortex in spontaneous recovery, particularly Adora2a, Drd2, and Pde10a-mediated cAMP signaling pathway. Developing drugs targeting these candidates after stroke may provide beneficial recovery outcome.

Extraforaminal Lumbar Nerve Root Stimulation for Neuropathic Pain: A Case Report.

Electrical stimulation of the spinal cord is commonly used to treat neuropathic pain. However, epidural space adhesion caused by previous surgery may interfere with precise electrical lead placement. We here report a case of successful placement of electrical leads via an extraforaminal approach in the management of recurrent pain after primary spinal cord stimulation. Extraforaminal nerve root stimulation may be an alternative choice for repeated epidural spinal cord stimulation in cases of recurrent neuropathic pain.

Age of donor of human mesenchymal stem cells affects structural and functional recovery after cell therapy following ischaemic stroke.

Cell transplantation therapy offers great potential to improve impairments after stroke. However, the importance of donor age on therapeutic efficacy is unclear. We investigated the regenerative capacity of transplanted cells focusing on donor age (young vs. old) for ischaemic stroke. The quantities of human mesenchymal stem cell (hMSC) secreted brain-derived neurotrophic factor in vitro and of monocyte chemotactic protein-1 at day 7 in vivo were both significantly higher for young hMSC compared with old hMSC. Male Sprague-Dawley rats subjected to transient middle cerebral artery occlusion that received young hMSC (trans-arterially at 24 h after stroke) showed better behavioural recovery with prevention of brain atrophy compared with rats that received old hMSC. Histological analysis of the peri-infarct cortex showed that rats treated with young hMSC had significantly fewer microglia and more vessels covered with pericytes. Interestingly, migration of neural stem/progenitor cells expressing Musashi-1 positively correlated with astrocyte process alignment, which was more pronounced for young hMSC. Aging of hMSC may be a critical factor that affects cell therapy outcomes, and transplantation of young hMSC appears to provide better functional recovery through anti-inflammatory effects, vessel maturation, and neurogenesis potentially by the dominance of trophic factor secretion.

Optogenetic neuronal stimulation of the lateral cerebellar nucleus promotes persistent functional recovery after stroke.

Stroke induces network-wide changes in the brain, affecting the excitability in both nearby and remotely connected regions. Brain stimulation is a promising neurorestorative technique that has been shown to improve stroke recovery by altering neuronal activity of the target area. However, it is unclear whether the beneficial effect of stimulation is a result of neuronal or non-neuronal activation, as existing stimulation techniques nonspecifically activate/inhibit all cell types (neurons, glia, endothelial cells, oligodendrocytes) in the stimulated area. Furthermore, which brain circuit is efficacious for brain stimulation is unknown. Here we use the optogenetics approach to selectively stimulate neurons in the lateral cerebellar nucleus (LCN), a deep cerebellar nucleus that sends major excitatory output to multiple motor and sensory areas in the forebrain. Repeated LCN stimulations resulted in a robust and persistent recovery on the rotating beam test, even after cessation of stimulations for 2 weeks. Furthermore, western blot analysis demonstrated that LCN stimulations significantly increased the axonal growth protein GAP43 in the ipsilesional somatosensory cortex. Our results demonstrate that pan-neuronal stimulations of the LCN is sufficient to promote robust and persistent recovery after stroke, and thus is a promising target for brain stimulation.

Impact of clipping versus coiling on postoperative hemodynamics and pulmonary edema after subarachnoid hemorrhage.

Volume management is critical for assessment of cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). This multicenter prospective cohort study compared the impact of surgical clipping versus endovascular coiling on postoperative hemodynamics and pulmonary edema in patients with SAH. Hemodynamic parameters were measured for 14 days using a transpulmonary thermodilution system. The study included 202 patients, including 160 who underwent clipping and 42 who underwent coiling. There were no differences in global ejection fraction (GEF), cardiac index, systemic vascular resistance index, or global end-diastolic volume index between the clipping and coiling groups in the early period. However, extravascular lung water index (EVLWI) and pulmonary vascular permeability index (PVPI) were significantly higher in the clipping group in the vasospasm period. Postoperative C-reactive protein (CRP) level was higher in the clipping group and was significantly correlated with postoperative brain natriuretic peptide level. Multivariate analysis found that PVPI and GEF were independently associated with high EVLWI in the early period, suggesting cardiogenic edema, and that CRP and PVPI, but not GEF, were independently associated with high EVLWI in the vasospasm period, suggesting noncardiogenic edema. In conclusion, clipping affects postoperative CRP level and may thereby increase noncardiogenic pulmonary edema in the vasospasm period. His trial is registered with University Hospital Medical Information Network UMIN000003794.

Dramatic recovery after severe descending transtentorial herniation-induced Duret haemorrhage: a case report and review of literature.

BACKGROUND: Although Duret haemorrhage of the brainstem caused by descending transtentorial herniation is considered fatal, a few cases have been reported to have good outcome. Moreover, most patients with Duret haemorrhage have severe primary brain injury and the potential outcome of those with mild primary brain injury remains unknown. CASE REPORT: This study reports the case of a patient presenting with Duret haemorrhage caused by an idiopathic subdural haematoma who demonstrated dramatic recovery. The patient presented with a low Glasgow Coma Scale score and bilateral oculomotor palsy on admission. Pre-operative CT revealed a large subdural haematoma and Duret haemorrhage of the mid-brain. The subdural haematoma was immediately evacuated under local anaesthesia and the patient demonstrated dramatic post-operative recovery, with no residual quadriparesis and minimal cognitive dysfunction. Interestingly, only bilateral oculomotor palsy persisted. This indicates that Duret haemorrhage restricted to the central portion of the mid-brain without severe primary brain injury has good prognosis. CONCLUSION: Therefore, patients with Duret haemorrhage of the mid-brain caused by simple subdural haematoma presenting with bilateral oculomotor palsy, including bilateral pupillary dilation, may not always have a poor prognosis.

Intra-arterial cell transplantation provides timing-dependent cell distribution and functional recovery after stroke.

BACKGROUND AND PURPOSE: Intra-arterial cell transplantation offers a novel therapeutic strategy for stroke; however, it remains unclear how the timing of cell administration affects cell distribution, brain repair processes, and functional recovery. Here, we investigate the hypothesis that the timing of cell transplantation changes the behavior of the cell graft and the host environment in a way that affects functional recovery. METHODS: Rats received human mesenchymal stem cells via the internal carotid artery at 1, 4, or 7 days (D1, D4, or D7) after middle cerebral artery occlusion and reperfusion. Animals were euthanized at various time points to assess cell distribution, infiltration of activated microglia, expression of brain-derived neurotrophic factor, reactive astrocytes, angiogenesis, and functional recovery. RESULTS: Human mesenchymal stem cells were widely distributed both in the peri-infarct and core in D1, and dominantly in the peri-infarct in D4. Very few cells were observed on D7. At day 7 poststroke, microglia activation was significantly suppressed in both the peri-infarct and core in D1, and predominantly in the peri-infarct in D4. At day 21 poststroke, brain-derived neurotrophic factor was widely distributed throughout the peri-infarct in D1 and D4, along with many reactive astrocytes and considerable angiogenesis. Motor function improved earlier in D1 and later in D4, but no recovery was obtained in D7. CONCLUSIONS: Our results indicate that intra-arterial cell transplantation provides timing-dependent cell distribution and poststroke functional recovery via a combination of neuroprotection, reactive astrocyte enhancement, and angiogenesis.

Syringomyelia and arachnoid cysts associated with spinal arachnoiditis following subarachnoid hemorrhage.

A 66-year-old woman with primary Sjogren syndrome developed syringomyelia following two episodes of subarachnoid hemorrhage (SAH) due to the rupture of basilar artery aneurysms. Gait disturbance and abnormal sensation with pain over the foot and abdomen appeared 3 years after the last SAH. Magnetic resonance (MR) imaging revealed a syringomyelia throughout the thoracic cord, from the T2 to T11 levels. In addition, the thoracic cord was compressed by multiple arachnoid cysts in the ventral side of spinal cord. Computed tomography myelography revealed complete block of cerebrospinal fluid (CSF) flow at the T7 level. Surgery for microlysis of the adhesions and restoration of the CSF flow pathway was performed. Postoperatively, leg motor function slowly improved and she could walk unaided. However, abdominal paresthesia was persisted. Postoperative MR imaging revealed diminished size of the syrinxes. We should recognize syringomyelia and arachnoid cysts due to adhesive arachnoiditis as a late complication of SAH. Microlysis of the adhesions focusing on the lesion thought to be the cause of the symptoms is one of the choices to treat massive syringomyelia and arachnoid cysts associated with arachnoiditis following SAH.

Assessment of carotid plaque stability based on the dynamic enhancement pattern in plaque components with multidetector CT angiography.

BACKGROUND AND PURPOSE: Recent studies have investigated plaque morphology to determine patients who are at high risk of carotid atherosclerosis. In this study, we investigated whether a difference in dynamic enhancement pattern in plaque components could be useful to assess plaque stability with multidetector CT angiography. METHODS: Fifty-nine lesions with moderate to severe carotid atherosclerosis in 51 patients (33 symptomatic, 18 asymptomatic) were consecutively included. Early- and delayed-phase images were obtained in 3 equivalent axial slices with multidetector CT angiography. Hounsfield units (HU) in the early phase were subtracted from those in the delayed phase in plaques (ΔHU) and compared with clinical features, MRI-based plaque characteristics, and histological findings with 20 surgical specimens acquired from carotid endarterectomy. RESULTS: The ΔHU was significantly higher in asymptomatic than that in symptomatic presentation (P=0.02). With MRI, a higher ΔHU was negatively correlated with signal intensity on T1-weighted imaging (r=-0.56, P<0.0001). Histology confirmed that ΔHU was positively correlated with fibrous tissue (r=0.67, P=0.001) and negatively correlated with a lipid-rich necrotic core with hemorrhage (r=-0.70, P<0.001). Moreover, less neovascularization and inflammation was found in plaques with a higher ΔHU. CONCLUSIONS: Delayed-phase images provide information regarding the dynamic change in contrast media from the early arterial phase. An increase in HU from the early phase on multidetector CT angiography indicates plaque stability with more fibrous tissue and a less lipid-rich necrotic core, intraplaque hemorrhage, and neovascularization.

[Dissecting aneurysm of the anterior cerebral artery with Rubinstein-Taybi syndrome--a case report].

UNLABELLED: The Rubinstein-Taybi syndrome (RTS) is defined congenital anomalies and is characterized by postnatal growth deficiency, microcephaly, specific facial characteristics, broad thumbs and big toes, and mental retardation. RTS displays an autosomal dominant inheritance pattern and is typically caused by cAMP response element-binding (CREB)-binding protein deficiency. Various complications such as eye anomalies and a variety of congenital heart defects are reported in such cases. We treated an RTS patient who had a dissecting aneurysm of the anterior cerebral artery. The patient was a 44-year-old man who was brought to our hospital because of sudden left hemiplegia. Magnetic resonance images showed a cerebral infarction caused by anterior cerebral artery dissection. Coil embolization was performed on enlargement of the dissecting aneurysm, and the procedure was successful. CONCLUSION: RTS may be accompanied by cerebrovascular disease.

[Intracranial granulocytic sarcoma extending from the posterior fossa to the carotid space via the jugular foramen: a case report].

Granulocytic sarcoma consists of neoplastic granulocytic precursors and myeloblasts. It is a focal lesion seen in 2-10.9% of acute myelogenous leukaemia (AML) patients. It usually develops either concurrently with the AML or after a remission. On rare occasions, it may be an initial manifestation of AML. Most common involvement sites are bone, periostium, soft tissue, lymph nodes and skin. Intracranial granulocytic sarcoma rarely occurs in meningeal or parenchymal form. We present an extremely rare case of intracranial granulocytic sarcoma extending from the posterior fossa to the carotid space via the jugular foramen in a 69 year old female. This form of involvement has not been previously reported. On MRI, the lesion appears isointense compared with normal grey matter in T1 and T2 weighted images and shows homogeneous contrast enhancement. With these findings, it is difficult to differentiate the lesion from other extraaxial tumours such as meningioma, paraganglioma, schwannoma, carcinoma, metastatic tumor, malignant lymphoma. However, granulocytic sarcoma, densely increased tumour cells restrict diffusion and reduce the extracellular volume fraction, tends to be markedly hyperintense on diffusion-weighted MR images and exhibits a marked decrease in ADC values. Therefore, DWI may be helpful in differentiating granulocytic sarcoma from other intracranial lesions.

Reversible clinical and magnetic resonance imaging of central pontine myelinolysis following surgery for craniopharyngioma: serial magnetic resonance imaging studies.

An 18-year-old girl presented with central pontine myelinolysis (CPM) following surgery for craniopharyngioma. Postoperatively, the patient developed diabetes insipidus with remarkable fluctuation of serum sodium level, suffered a seizure, and developed mental state changes and quadriparesis. Magnetic resonance (MR) imaging obtained soon after the development of the symptoms showed no significant abnormalities. MR imaging obtained 2 months later demonstrated typical trident or bat-like signal abnormalities in the center of the pons, compatible with CPM. Serial MR imaging obtained at 7 and 10 months showed the lesion had decreased in size or almost completely resolved and the patient almost completely recovered. CPM is well known, but neurosurgeons should consider the possibility following surgery for craniopharyngioma.

[Case of reversible ischemic neurological deficit presented as hemiballism].

Ballism is characterized by continuous, coarse, flinging involuntary movements involving the limbs. Although persistent involuntary movements caused by cerebrovascular diseases mostly in middle-aged patients are well known, transient involuntary movements are an unusual manifestation of cerebrovascular diseases. We describe a rare case of reversible ischemic neurologic deficit (RIND) presented as hemiballism. A 71-year-old man was admitted to our hospital for hemiballism in the right limbs. On magnetic resonance (MR) imagings, there was no evidence of acute ischemic stroke, but MR angiography revealed severe stenosis of left middle cerebral artery. Electroencephalogram showed no epileptic discharge. For hemiballism, chlorpromazine and haloperidol were administered in addition to antiplatelet management for ischemic attack, and the patient completely recovered on the 5 days of hospitalization. Transient ischemic attacks (TIA) or RIND typically present with neurological deficits such as loss of muscle power, reduced sensation, or visual loss. Involuntary movements are not generally regarded to be TIA or RIND. Involuntary movements such as hemiballism, however, can occur as a symptom of TIA or RIND, which should be recognized and differentiated from conditions like partial seizures. Moreover, they may be an indicator of severe carotid stenotic or occlusive diseases, and patients may be at high risk of ischemic events. Early diagnosis and timely treatment are required to prevent ischemic events.

[Efficacy of antimicrobial prophylaxis in neurosurgical operations].

OBJECT: It is reported that antimicrobial prophylaxis (AMP) reduces the incidence of surgical site infection (SSI) in neurological surgery. However, a great deal of variation exists regarding the type of antibiotics, dose, timing and duration. In this study, the authors analyzed the incidence of SSI comparing two different AMP protocols. CLINICAL MATERIALS AND METHODS: Five hundred and fifty patients who had undergone neurosurgeries at our institute between April 2005 and August 2007 were reviewed retrospectively. They were divided into the protocol F (309 patients with two or more days AMP) and the protocol P (241 patients with one-day AMP). RESULTS: Baseline characteristics were not statistically different between two protocols. The overall rate of SSI was 1.5%. Although SSI showed a trend of low SSI incidence in the protocol P (0.8%), this was not statistically significant compared with that in the protocol F (1.9%). CONCLUSIONS: The one-day (< 24 hours) administration of AMP is enough to prevent SSI in neurological surgery.