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Bio

Bio


Dr. Gary Steinberg is the Director of the Stanford Moyamoya Center, the founder and Co-Director of the Stanford Stroke Center, and the former Chair of the Department of Neurosurgery. As a cerebrovascular and skull base neurosurgeon, he specializes in treating brain aneurysms, moyamoya disease, brain and spinal AVMs and other vascular malformations, carotid artery disease, meningiomas, skull base tumors, stroke, and hereditary hemorrhagic telangiectasia.

Dr. Steinberg has practiced neurosurgery at Stanford for more than 31 years. He has pioneered microsurgical techniques to repair intracranial vascular malformations and certain aneurysms that were previously considered untreatable. He has also refined revascularization techniques for patients with cerebrovascular arterial occlusions, as well as moyamoya disease. He is leading novel clinical trials of stem cell therapy for stroke and spinal cord injury.

Clinical Focus


  • Cerebrovascular and Spinal Vascular Surgery
  • Intracranial Aneurysms
  • Intracranial/Intraspinal AVMs, AV fistulas, Cavernous Malformations
  • Moyamoya Disease and Occlusive Cerebrovascular Disease
  • Carotid Endarterectomy
  • Neurological Surgery

Academic Appointments


Administrative Appointments


  • Chair, Stanford University School of Medicine - Neurosurgery (1995 - 2020)
  • Founder and Co-Director, Stanford Stroke Center (1991 - Present)
  • Director, Stanford Moyamoya Center (1991 - Present)

Professional Education


  • Medical Education: Stanford University School of Medicine (1980) CA
  • Residency: Stanford University Neurosurgery Residency (1987) CA
  • Residency: Stanford University General Surgery Residency (1983) CA
  • Residency: Santa Clara Valley Medical Center (1986) CA
  • Board Certification: American Board of Neurological Surgery, Neurological Surgery (1989)
  • Fellowship: Institute Of Neurology (1981) England

Research & Scholarship

Current Research and Scholarly Interests


Our laboratory is interested in elucidating the pathophysiology of acute cerebral ischemia and in developing neuroprotective treatments, as well as methods to restore neurologic function after stroke. Using rodent wild type, knock out and transgenic models of focal and global ischemia, we are investigating the physiologic processes leading from decreased blood flow after arterial occlusion to irreversible brain injury. A major focus of our work concerns the role of oxidative stress, inflammation and gene expression on necrotic and apoptotic mechnisms of ischemic cell death. Alterations in cerebral blood flow, neuronal metabolic activity, electrophysiology, and gene/protein expression are examined in relation to neurologic behavior. We are also studying the brain microenvironment during recovery after stroke and the effects of stem cell transplantation and optogeneticstimulations in promoting recovery of function.

We have been successful in attenuating ischemic cerebral damage by inducing mild brain hypothermia (30-33 degrees C) or overexpression of various genes (glucose transporter, bcl-2, hsp70, calbindin, catalase, glutathione peroxidase, SOD) either before or after stroke. Transplantation of human neural stem cells after experimental stroke results in survival, targeted migration and differentiation into appropriate neuronal and glial cell types, while anti-inflammatory treatment enhances native neurogenesis and gliagenesis following stroke. Additionally, stem cell transplantation and optogenetic stimulation restores motor-sensory behavior after stroke and we are exploring the underlying circuit plasticity and molecular changes that are responsible for recovring neurologic function.
Methodologies utilized in the laboratory include microsurgery, light and confocal microscopy, stereology, molecular biology techniques, FACS, magnetic resonance imaging, electrophysiology, cerebral blood flow measurements, gene transfer therapy, optogenetics, stem cell transplantation and rodent behavioral analysis.


Our clinical research efforts focus on novel approaches for treating intracranial aneurysms, intracranial and spinal vascular malformations, occlusive cerebrovascular disease such as Moyamoya disease and stroke. These include advances in microsurgery, interventional neuroradiology, stereotactic radiosurgery, 3D imaging, surgical navigation, revascularization techniques, the use of mild brain hypothermia and other clinical neuroprotective agents, and stem cell transplantation for stroke and spinal cord injury.

Clinical Trials


  • Carotid Revascularization and Medical Management for Asymptomatic Carotid Stenosis Trial Recruiting

    Carotid revascularization for primary prevention of stroke (CREST-2) is two independent multicenter, randomized controlled trials of carotid revascularization and intensive medical management versus medical management alone in patients with asymptomatic high-grade carotid stenosis. One trial will randomize patients in a 1:1 ratio to endarterectomy versus no endarterectomy and another will randomize patients in a 1:1 ratio to carotid stenting with embolic protection versus no stenting. Medical management will be uniform for all randomized treatment groups and will be centrally directed.

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  • Dose Escalation Study of AST-OPC1 in Spinal Cord Injury Recruiting

    The purpose of this study is to evaluate the safety of cross sequential escalating doses of AST-OPC1 administered among 5 cohorts at a single time-point between 21 and 42 days post injury, inclusively, to subjects with subacute cervical spinal cord injuries (SCI).

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  • A Safety and Tolerability Study of Neural Stem Cells (NR1) in Subjects With Chronic Ischemic Subcortical Stroke (ISS) Not Recruiting

    Evaluation of the safety and tolerability of escalating doses of NR1 administered intracerebrally at a single time-point post-injury to subjects with chronic ISS with or without cortical stroke.

    Stanford is currently not accepting patients for this trial.

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  • A Study of Modified Stem Cells in Stable Ischemic Stroke Not Recruiting

    The primary purpose of the clinical study is to determine the safety of a modified stem cell SB623 when administered to chronic, stable ischemic stroke patients. A second purpose is to determine whether SB623 might improve stroke symptoms. Chronic, stable ischemic stroke patients must be between 6 and 60 months after their stroke, and with only this one prior stroke, and and with no further improvement from physical therapy.

    Stanford is currently not accepting patients for this trial. For more information, please contact Maria Coburn, 650-736-9551.

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  • A Study of Modified Stem Cells in Traumatic Brain Injury (TBI) Not Recruiting

    The primary purpose of the clinical study is to evaluate the clinical efficacy of intracranial administration of SB623 cells on patients with chronic motor deficit from Traumatic Brain Injury. A secondary purpose of the study is 1) to evaluate the effect of intracranial administration of SB623 cells on disability parameters and 2) to evaluate the safety and tolerability of intracranial administration of SB623 cells. Patients with stable, chronic motor deficits secondary to focal traumatic brain injury must be 12 months post TBI.

    Stanford is currently not accepting patients for this trial. For more information, please contact Quiping Qin, 650-736-9551.

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  • Familial Intracranial Aneurysm Study II Not Recruiting

    The purposes of this study are to identify possible genes that may increase the risk of aneurysm development in the brain, and to determine the effect of environmental factors such as cigarette smoking and high blood pressure on the expression of these genes.

    Stanford is currently not accepting patients for this trial. For more information, please contact Maria Coburn, 650-736-9551.

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  • Study of Modified Stem Cells (SB623) in Patients With Chronic Motor Deficit From Ischemic Stroke Not Recruiting

    Controlled study of stereotactic, intracranial injection of SB623 cells in patients with fixed motor deficits from ischemic stroke

    Stanford is currently not accepting patients for this trial.

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Teaching

2020-21 Courses


Stanford Advisees


Graduate and Fellowship Programs


Publications

All Publications


  • Basal ganglia cavernous malformations: case series and systematic review of surgical management and long-term outcomes. Journal of neurosurgery Li, Y. n., Khahera, A. n., Kim, J. n., Mandel, M. n., Han, S. S., Steinberg, G. K. 2021: 1?9

    Abstract

    Reports on basal ganglia cavernous malformations (BGCMs) are rare. Here, the authors report on their experience in resecting these malformations to offer insight into this infrequent disease subtype.The authors retrospectively reviewed a prospectively managed departmental database of all deep-seated cerebral cavernous malformations (CCMs) treated at Stanford between 1987 and 2019 and included for further analysis those with a radiographic diagnosis of BGCM. Moreover, a systematic literature review was undertaken using the PubMed and Web of Science databases.The departmental database search yielded 331 patients with deep-seated CCMs, 44 of whom had a BGCM (13.3%). Headache was the most common presenting sign (53.5%), followed by seizure (32.6%) and hemiparesis (27.9%). Lesion location involved the caudate nucleus in 21.4% of cases compared to 78.6% of cases within the lentiform nucleus. Caudate BGCMs were larger on presentation and were more likely to present to the ependymal surface (p < 0.001) with intraventricular hemorrhage and hydrocephalus (p = 0.005 and 0.007, respectively). Dizziness and diplopia were also more common with lesions involving the caudate. Because of their anatomical location, caudate BGCMs were preferentially treated via an interhemispheric approach and were less likely to be associated with worsening perioperative deficits than lentiform BGCMs (p = 0.006 and 0.045, respectively). Ten patients (25.6%) were clinically worse in the immediate postoperative period, 4 (10.2%) of whom continued to suffer permanent morbidity at the last follow-up. A long-term good outcome (modified Rankin Scale [mRS] score 0-1) was attained in 74.4% of cases compared to the 69.2% of patients who had presented with an mRS score 0-1. Relative to their presenting mRS score, 89.8% of patients had an improved or unchanged status at the last follow-up. The median postoperative follow-up was 11 months (range 1-252 months). Patient outcomes after resection did not differ among surgical approaches; however, patients presenting with hemiparesis and lesions involving the globus pallidus or posterior limb of the internal capsule were more likely to suffer neurological deficits during the immediate perioperative period. Patients who had undergone awake surgeries were more likely to suffer neurological decline at the early as well as the late follow-up. When adjusting for awake craniotomy as a potential confounder of lesion location, a BGCM involving the posterior limb was predictive of developing early postoperative deficits, but this finding did not persist at the long-term follow-up.Surgery is a safe and effective treatment modality for managing BGCMs, with an estimated long-term permanent morbidity rate of around 10%.

    View details for DOI 10.3171/2020.7.JNS2098

    View details for PubMedID 33385997

  • Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke. Stroke Cao, Z. n., Harvey, S. S., Chiang, T. n., Foltz, A. G., Lee, A. G., Cheng, M. Y., Steinberg, G. K. 2021: STROKEAHA120032402

    Abstract

    Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry.Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c+ microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction.Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type. Itgax (CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c+ microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease-associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7.Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c+) with neurodegenerative disease-associated microglia features in the degenerative thalamus after stroke.

    View details for DOI 10.1161/STROKEAHA.120.032402

    View details for PubMedID 33412903

  • Clinical Course of Unilateral Moyamoya Disease. Neurosurgery Church, E. W., Bell-Stephens, T. E., Bigder, M. G., Gummidipundi, S., Han, S. S., Steinberg, G. K. 2020

    Abstract

    BACKGROUND: The natural history of unilateral moyamoya disease (MMD) progressing to bilateral MMD remains an enigma in modern vascular neurosurgery. Few, small series with limited follow-up have reported relatively high rates of contralateral stenosis progression.OBJECTIVE: To review our large series of unilateral MMD patients and evaluate radiographic and surgical progression rates, and identify any factors associated with progression.METHODS: We included all unilateral MMD cases treated from 1991 to 2017 in an observational study. We examined time to contralateral radiographic progression and contralateral progression requiring surgery. Using Cox regression analysis, we evaluated factors potentially associated with contralateral progression.RESULTS: There were 217 patients treated for unilateral MMD. About 71% were female, and the average age at first surgery was 33.8 yr. Average follow-up was 5.8 yr (range 1-22 yr). A total of 18 patients (8.3%) developed contralateral progression. And 8 of these (3.7%) developed progression requiring bypass surgery. Baseline stenosis and hyperlipidemia (HLD) were significantly associated with radiographic progression (hazard ratio [HR] = 9.7, P=.006; HR=4.0, P=.024). Baseline stenosis was associated with surgical progression (HR=44.2, P=.002). Results were similar when controlling for possible confounders using multivariate regression.CONCLUSION: Previous series showed relatively high rates of progression in unilateral MMD (15%-30%), but these studies were small and long-term follow-up was rarely available. Our large series indicates that the rate of progression is lower than previously reported but still warrants yearly noninvasive screening. These data may provide indirect support for statin therapy in MMD.

    View details for DOI 10.1093/neuros/nyaa284

    View details for PubMedID 32710766

  • Treatment of posterior circulation fusiform aneurysms. Journal of neurosurgery Church, E. W., Bigder, M. G., Sussman, E. S., Gummidipundi, S. E., Han, S. S., Heit, J. J., Do, H. M., Dodd, R. L., Marks, M. P., Steinberg, G. K. 2020: 1?7

    Abstract

    OBJECTIVE: Perforator arteries, the absence of an aneurysm discrete neck, and the often-extensive nature of posterior circulation fusiform aneurysms present treatment challenges. There have been advances in microsurgical and endovascular approaches, including flow diversion, and the authors sought to review these treatments in a long-term series at their neurovascular referral center.METHODS: The authors performed a retrospective chart review from 1990 to 2018. Primary outcomes were modified Rankin Scale (mRS) scores and Glasgow Outcome Scale (GOS) scores at follow-up. The authors also examined neurological complication rates. Using regression techniques, they reviewed independent and dependent variables, including presenting features, aneurysm location and size, surgical approach, and pretreatment and posttreatment thrombosis.RESULTS: Eighty-four patients met the inclusion criteria. Their mean age was 53 years, and 49 (58%) were female. Forty-one (49%) patients presented with subarachnoid hemorrhage. Aneurysms were located on the vertebral artery (VA) or posterior inferior cerebellar artery (PICA) in 50 (60%) patients, basilar artery (BA) or vertebrobasilar junction (VBJ) in 22 (26%), and posterior cerebral artery (PCA) in 12 (14%). Thirty-one (37%) patients were treated with microsurgical and 53 (63%) with endovascular approaches. Six aneurysms were treated with endovascular flow diversion. The authors found moderate disability or better (mRS score ? 3) in 85% of the patients at a mean 14-month follow-up. The GOS score was ? 4 in 82% of the patients. The overall neurological complication rate was 12%. In the regression analysis, patients with VA or PICA aneurysms had better functional outcomes than the other groups (p < 0.001). Endovascular strategies were associated with better outcomes for BA-VBJ aneurysms (p < 0.01), but microsurgery was associated with better outcomes for VA-PICA and PCA aneurysms (p < 0.05). There were no other significant associations between patient, aneurysm characteristics, or treatment features and neurological complications (p > 0.05). Patients treated with flow diversion had more complications than those who underwent other endovascular and microsurgical strategies, but the difference was not significant in regression models.CONCLUSIONS: Posterior circulation fusiform aneurysms remain a challenging aneurysm subtype, but an interdisciplinary treatment approach can result in good outcomes. While flow diversion is a useful addition to the armamentarium, traditional endovascular and microsurgical techniques continue to offer effective options.

    View details for DOI 10.3171/2020.4.JNS192838

    View details for PubMedID 32707547

  • Functional Outcomes After Revascularization Procedures in Patients With Hemorrhagic Moyamoya Disease NEUROSURGERY Abhinav, K., Furtado, S., Nielsen, T. H., Iyer, A., Gooderham, P. A., Teo, M., Lee, J., Han, S. S., Steinberg, G. K. 2020; 86 (2): 257?65
  • Incidental De Novo Cerebral Microhemorrhages are Predictive of Future Symptomatic Macrohemorrhages After Surgical Revascularization in Moyamoya Disease. Neurosurgery Li, Y. n., Esene, I. n., Mandel, M. n., Bigder, M. n., Steinberg, G. K. 2020

    Abstract

    Patients with moyamoya disease who develop incidental cerebral microhemorrhages (CMHs) on magnetic resonance imaging (MRI) have higher risk of developing subsequent symptomatic repeat macro hemorrhages.To evaluate the effect of surgical revascularization on development of de novo CMHs and assess its correlation with repeat hemorrhage rates and functional outcome in hemorrhagic onset moyamoya disease (HOMMD).We retrospectively reviewed a prospectively managed departmental database of all patients presenting with HOMMD treated between 1987 and 2019. The search yielded 121 patients with adequate MRI follow-up for inclusion into the study.In total, 42 preoperative CMHs were identified in 18 patients (15%). Patients presenting with preoperative CMH were more likely to develop de novo CMH after surgical revascularization. 7 de novo CHMs were identified in 6 patients (5%) on routine postoperative MRI at distinct locations from previous sites of hemorrhage or CMH. Symptomatic repeat macro hemorrhage was confirmed radiographically in 15 patients (12%). A total 5 (83%) of 6 patients with de novo CMHs later suffered symptomatic repeat macro hemorrhage with 4 of 5 (80%) hemorrhages occurring at sites of previous CMH. On univariate and multivariate analysis, de novo CMHs was the only significant variable predictive for developing repeat symptomatic hemorrhage. Development of delayed repeat symptomatic hemorrhage was prognostic for higher modified Rankin Score and therefore poorer functional status, whereas preoperative functional status was predictive of final outcome.De novo CMHs after surgical revascularization might serve as a radiographic biomarker for refractory disease and suggest patients are at risk for future symptomatic macro hemorrhage.

    View details for DOI 10.1093/neuros/nyaa319

    View details for PubMedID 32717035

  • Direct versus indirect bypass procedure for the treatment of ischemic moyamoya disease: results of an individualized selection strategy. Journal of neurosurgery Nielsen, T. H., Abhinav, K. n., Sussman, E. S., Han, S. S., Weng, Y. n., Bell-Stephens, T. n., Heit, J. J., Steinberg, G. K. 2020: 1?12

    Abstract

    The only effective treatment for ischemic moyamoya disease (iMMD) is cerebral revascularization by an extracranial to intracranial bypass. The preferred revascularization method remains controversial: direct versus indirect bypass. The purpose of this study was to test the hypothesis that method choice should be personalized based on angiographic, hemodynamic, and clinical characteristics to balance the risk of perioperative major stroke against treatment efficacy.Patients with iMMD were identified retrospectively from a prospectively maintained database. Those with mild to moderate internal carotid artery or M1 segment stenosis, preserved cerebrovascular reserve, intraoperative M4 segment anterograde flow ? 8 ml/min, or the absence of frequent and severe transient ischemic attacks (TIAs) or stroke had been assigned to indirect bypass. The criteria for direct bypass were severe ICA or M1 segment stenosis or occlusion, impaired cerebrovascular reserve or steal phenomenon, intraoperative M4 segment retrograde flow or anterograde flow < 8 ml/min, and the presence of frequent and severe TIAs or clinical strokes. The primary study endpoint was MRI-confirmed symptomatic stroke ? 7 days postoperatively resulting in a decline in the modified Rankin Scale (mRS) score from preoperatively to 6 months postoperatively. As a secondary endpoint, the authors assessed 6-month postoperative DSA-demonstrated revascularization, which was classified as < 1/3, 1/3-2/3, or > 2/3 of the middle cerebral artery territory.One hundred thirty-eight patients with iMMD affecting 195 hemispheres revascularized in the period from March 2016 to June 2018 were included in this analysis. One hundred thirty-three hemispheres were revascularized with direct bypass and 62 with indirect bypass. The perioperative stroke rate was 4.7% and 6.8% in the direct and indirect groups, respectively (p = 0.36). Degree of revascularization was higher in the direct bypass group (p = 0.03). The proportion of patients improving to an mRS score 0-1 (from preoperatively to 6 months postoperatively) tended to be higher in the direct bypass group, although the difference between the two bypass groups was not statistically significant (p = 0.27).The selective use of an indirect bypass procedure for iMMD did not decrease the perioperative stroke rate. Direct bypass provided a significantly higher degree of revascularization. The authors conclude that direct bypass is the treatment of choice for iMMD.

    View details for DOI 10.3171/2020.3.JNS192847

    View details for PubMedID 32534489

  • Trans-Lamina Terminalis Approach to Laser-Assisted Resection of Thalamo-mesencephalic Cavernous Malformation. World neurosurgery Bigder, M. G., Li, Y. n., Mandel, M. n., Steinberg, G. n. 2020

    Abstract

    Cavernous malformations of the midbrain require careful consideration of the risks and benefits of intervention, as well as optimal surgical approach for these challenging lesions. Excellent results can be achieved with careful surgical planning and technique.1,2 In this operative video, we demonstrate a contralateral left pterional craniotomy for trans-lamina terminalis approach to CO2 laser-assisted microsurgical resection of a thalamo-mesencephalic cavernoma in a 59 year old female presenting with progressive debilitating diplopia secondary to partial third nerve palsy. We utilized a contralateral left modified pterional craniotomy in which we limit dissection of the temporalis muscle to approximately one third rather than extending the muscle split down to the zygoma. The cavernous malformation was resected without complication and the patient was discharged from hospital on post-operative Day 3. She noted immediate improvement and nearly complete resolution of her symptoms over ensuing weeks. This approach offers a direct route to the lesion with minimal brain transgression while avoiding the critical structures within the interpeduncular cistern including basilar artery and thalamo-mesencephalic perforating arteries, as well as bordering neural structures including cerebral peduncles, oculomotor nerves and mamillary bodies. Use of the CO2 laser, with its 0.55mm tip, offers a low surgical profile and allows for precise cutting thus minimizing thermal damage to surrounding tissues. The trans-lamina terminalis approach, through a pterional craniotomy, offers a safe and potentially less morbid alternative to select thalamo-mesencephalic lesions compared to exposure through the mesencephalic surface which in our experience often necessitates an orbitozygomatic craniotomy.

    View details for DOI 10.1016/j.wneu.2020.04.115

    View details for PubMedID 32360676

  • Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke. Frontiers in aging neuroscience He, J. Q., Sussman, E. S., Steinberg, G. K. 2020; 12: 575990

    Abstract

    Stroke is the leading cause of serious long-term disability, significantly reducing mobility in almost half of the affected patients aged 65 years and older. There are currently no proven neurorestorative treatments for chronic stroke. To address the complex problem of restoring function in ischemic brain tissue, stem cell transplantation-based therapies have emerged as potential restorative therapies. Aligning with the major cell types found within the ischemic brain, stem-cell-based clinical trials for ischemic stroke have fallen under three broad cell lineages: hematopoietic, mesenchymal, and neural. In this review article, we will discuss the scientific rationale for transplanting cells from each of these lineages and provide an overview of published and ongoing trials using this framework.

    View details for DOI 10.3389/fnagi.2020.575990

    View details for PubMedID 33381020

    View details for PubMedCentralID PMC7767918

  • Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow-derived mesenchymal stem cells (SB623): a phase 1/2a study JOURNAL OF NEUROSURGERY Steinberg, G. K., Kondziolka, D., Wechsler, L. R., Lunsford, L., Kim, A. S., Johnson, J. N., Bates, D., Poggio, G., Case, C., McGrogan, M., Yankee, E. W., Schwartz, N. E. 2019; 131 (5): 1462?72
  • Multimodal management of arteriovenous malformations of the basal ganglia and thalamus: factors affecting obliteration and outcome JOURNAL OF NEUROSURGERY Madhugiri, V. S., Teo, M. C., Westbroek, E. M., Chang, S. D., Marks, M. P., Do, H. M., Levy, R. P., Steinberg, G. K. 2019; 131 (2): 410?19
  • Functional Outcomes After Revascularization Procedures in Patients With Hemorrhagic Moyamoya Disease. Neurosurgery Abhinav, K., Furtado, S. V., Nielsen, T. H., Iyer, A., Gooderham, P. A., Teo, M., Lee, J., Han, S. S., Steinberg, G. K. 2019

    Abstract

    BACKGROUND: Poor natural history of hemorrhagic Moyamoya disease (MMD) is related to high rehemorrhage rates between 32% and 61%. Postrevascularization, rehemorrhage rates reportedly decrease to 12% to 17%.OBJECTIVE: To evaluate long-term functional outcomes and rehemorrhage rates of hemorrhagic MMD patients treated with surgical revascularization and examine these in relation to clinical and radiological factors.METHODS: Patients treated surgically for hemorrhagic MMD over a 26-yr period were identified. Modified Rankin scale (mRS) was used to assess clinical status at presentation and functional outcomes. Multivariable regression analyses were performed to evaluate the risk factors associated with rehemorrhage rates and functional outcomes.RESULTS: A total of 104 patients (mean age: 38.04 yr) were identified. The mean mRS score at baseline was 1.3. Of 172 revascularized hemispheres, 157 (91.3%) were direct superficial temporal artery (STA)-middle cerebral artery (MCA) bypasses and the rest indirect. Over the mean follow-up of 61.4 mo, 8 of 104 patients (7.7%) experienced rehemorrhage with rehemorrhage rate per person-years of 1.9%. A total of 4 patients died with 1 related to rehemorrhage. At the last follow-up, mean mRS score improved to 1.1. No significant risk factors were identified in relation to the rehemorrhage rates (P<.05). The patients' initial mRS score was positively associated with mRS scores at the final follow-up (P<.001). STA-MCA direct bypass was associated with better performance status (P=.033).CONCLUSION: Rehemorrhage rate following surgical revascularization of the hemorrhagic MMD patients at 7.7% is lower compared with much higher natural history rates. Surgical revascularization improved patients' performance status. These outcomes support performing revascularization procedure with a preference for direct STA-MCA bypasses.

    View details for PubMedID 30989221

  • Surgical Treatment of Recurrent Previously Coiled and/or Stent-Coiled Intracerebral Aneurysms: A Single-Center Experience in a Series of 75 Patients WORLD NEUROSURGERY Liu, J. J., Nielsen, T. H., Abhinav, K., Lee, J., Han, S. S., Marks, M. P., Do, H. M., Dodd, R. L., Steinberg, G. K. 2019; 124: E649?E658
  • Surgical Treatment of Recurrent Previously Coiled and/or Stent-Coiled Intracerebral Aneurysms: A Single-Center Experience in a Series of 75 Patients. World neurosurgery Liu, J. J., Nielsen, T. H., Abhinav, K., Lee, J., Han, S. S., Marks, M. P., Do, H. M., Dodd, R. L., Steinberg, G. K. 2019

    Abstract

    BACKGROUND: Endovascular treated cerebral aneurysms have a greater recurrence rate compared to microsurgical clip ligation. Despite recent endovascular advances, microsurgical clip ligation might be the treatment of choice for certain previously endovascular treated recurrent aneurysms. We report on our single-center experience with 76 previously coiled and/or stent-coiled aneurysms.OBJECTIVE: To analyse the surgical and radiological outcome after clipping of previous endovascular treated recurrent cerebral aneurysms.METHODS: Patients were retrospectively identified. Demographic data, aneurysm size, location, perioperative coil extraction, occlusion rate and complication rate was recorded. Patients were divided into a previously coiled-only group (COG) and a previously stent-assisted coiled group (SAC).RESULTS: Seventy-five patients with seventy-six aneurysms were included. Sixty-nine patients were included in the COG, seven patients in the SAC. Complete or acceptable near-complete occlusion was obtained in 95% of patients in the COG and 57% in the SAC. Two patients in the COG (2.9%) died postoperatively from a major stroke. One patient died from re-hemorrhage after wrapping of an aneurysm. Minor complications occurred in 8.7%. In the SAC the mortality was 0% with one major stroke (14.2%), 1 (14.2%) minor stroke and 1 (14.2%) cranial nerve palsy. Intraoperative coil extraction and previous stent-assisted coiling were significant predictors of complication rate (p=0.025 and p=0.0036 respectively). Previous stent-assisted coiling was a significant predictor of incomplete occlusion (p=0.036).CONCLUSIONS: Microsurgical clipping of previously endovascular treated recurrent aneurysms is an effective treatment with high obliteration rates. Previously stent-assisted coiling and intraoperative coil extraction are predictors of worse outcome and incomplete occlusion.

    View details for PubMedID 30639494

  • Two-year safety and clinical outcomes in chronic ischemic stroke patients after implantation of modified bone marrow-derived mesenchymal stem cells (SB623): a phase 1/2a study. Journal of neurosurgery Steinberg, G. K., Kondziolka, D., Wechsler, L. R., Lunsford, L. D., Kim, A. S., Johnson, J. N., Bates, D., Poggio, G., Case, C., McGrogan, M., Yankee, E. W., Schwartz, N. E. 2018: 1?11

    Abstract

    OBJECTIVEThe aim of this study was to evaluate the safety and clinical outcomes associated with stereotactic surgical implantation of modified bone marrow-derived mesenchymal stem cells (SB623) in patients with stable chronic ischemic stroke.METHODSThis was a 2-year, open-label, single-arm, phase 1/2a study; the selected patients had chronic motor deficits between 6 and 60 months after nonhemorrhagic stroke. SB623 cells were administered to the target sites surrounding the subcortical stroke region using MRI stereotactic image guidance.RESULTSA total of 18 patients were treated with SB623 cells. All experienced at least 1 treatment-emergent adverse event (TEAE). No patients withdrew due to adverse events, and there were no dose-limiting toxicities or deaths. The most frequent TEAE was headache related to the surgical procedure (88.9%). Seven patients experienced 9 serious adverse events, which resolved without sequelae. In 16 patients who completed 24 months of treatment, statistically significant improvements from baseline (mean) at 24 months were reported for the European Stroke Scale (ESS) score, 5.7 (95% CI 1.4-10.1, p < 0.05); National Institutes of Health Stroke Scale (NIHSS) score, -2.1 (95% CI -3.3 to -1.0, p < 0.01), Fugl-Meyer (F-M) total score, 19.4 (95% CI 9.9-29.0, p < 0.01); and F-M motor scale score, 10.4 (95% CI 4.0-16.7, p < 0.01). Measures of efficacy reached plateau by 12 months with no decline thereafter. There were no statistically significant changes in the modified Rankin Scale score. The size of transient lesions detected by T2-weighted FLAIR imaging in the ipsilateral cortex at weeks 1-2 postimplantation significantly correlated with improvement in ESS (0.619, p < 0.05) and NIHSS (-0.735, p < 0.01) scores at 24 months.CONCLUSIONSIn this completed 2-year phase 1/2a study, implantation of SB623 cells in patients with stable chronic stroke was safe and was accompanied by improvements in clinical outcomes.Clinical trial registration no.: NCT01287936 (clinicaltrials.gov).

    View details for PubMedID 30497166

  • Multimodal management of arteriovenous malformations of the basal ganglia and thalamus: factors affecting obliteration and outcome. Journal of neurosurgery Madhugiri, V. S., Teo, M. K., Westbroek, E. M., Chang, S. D., Marks, M. P., Do, H. M., Levy, R. P., Steinberg, G. K. 2018: 1?10

    Abstract

    OBJECTIVEArteriovenous malformations (AVMs) of the basal ganglia and thalamus are particularly difficult lesions to treat, accounting for 3%-13% of all AVMs in surgical series and 23%-44% of malformations in radiosurgery series. The goal of this study was to report the results of multimodal management of basal ganglia and thalamic AVMs and investigate the factors that influence radiographic cure and good clinical outcomes.METHODSThis study was a retrospective analysis of a prospectively maintained database of all patients treated at the authors' institution. Clinical, radiological, follow-up, and outcome data were analyzed. Univariate and multivariate analyses were conducted to explore the influence of various factors on outcome.RESULTSThe results and data analysis pertaining to 123 patients treated over 32 years are presented. In this cohort, radiographic cure was achieved in 50.9% of the patients. Seventy-five percent of patients had good clinical outcomes (stable or improved performance scores), whereas 25% worsened after treatment. Inclusion of surgery and radiosurgery independently predicted obliteration, whereas nidus diameter and volume predicted clinical outcomes. Nidus volume/diameter and inclusion of surgery predicted the optimal outcome, i.e., good clinical outcomes with lesion obliteration.CONCLUSIONSGood outcomes are possible with multimodal treatment in these complex patients. Increasing size and, by extension, higher Spetzler-Martin grade are associated with worse outcomes. Inclusion of multiple modalities of treatment as indicated could improve the chances of radiographic cure and good outcomes.

    View details for PubMedID 30117771

  • Stem Cell-Based Immunomodulation After Stroke: Effects on Brain Repair Processes STROKE Boshuizen, M. S., Steinberg, G. K. 2018; 49 (6): 1563?70

    View details for PubMedID 29724892

  • Engineered stem cell mimics to enhance stroke recovery. Biomaterials George, P. M., Oh, B. n., Dewi, R. n., Hua, T. n., Cai, L. n., Levinson, A. n., Liang, X. n., Krajina, B. A., Bliss, T. M., Heilshorn, S. C., Steinberg, G. K. 2018; 178: 63?72

    Abstract

    Currently, no medical therapies exist to augment stroke recovery. Stem cells are an intriguing treatment option being evaluated, but cell-based therapies have several challenges including developing a stable cell product with long term reproducibility. Since much of the improvement observed from cellular therapeutics is believed to result from trophic factors the stem cells release over time, biomaterials are well-positioned to deliver these important molecules in a similar fashion. Here we show that essential trophic factors secreted from stem cells can be effectively released from a multi-component hydrogel system into the post-stroke environment. Using our polymeric system to deliver VEGF-A and MMP-9, we improved recovery after stroke to an equivalent degree as observed with traditional stem cell treatment in a rodent model. While VEGF-A and MMP-9 have many unique mechanisms of action, connective tissue growth factor (CTGF) interacts with both VEGF-A and MMP-9. With our hydrogel system as well as with stem cell delivery, the CTGF pathway is shown to be downregulated with improved stroke recovery.

    View details for PubMedID 29909038

  • Long-Term Effectiveness of Gross-Total Resection for Symptomatic Spinal Cord Cavernous Malformations. Neurosurgery Azad, T. D., Veeravagu, A. n., Li, A. n., Zhang, M. n., Madhugiri, V. n., Steinberg, G. K. 2018

    Abstract

    Intramedullary spinal cord cavernous malformations (CMs) account for 5% of all CMs in the central nervous system and 5% to 12% of all spinal cord vascular lesions, yet their optimal management is controversial.To identify factors associated with the clinical progression of spinal cord CMs and quantify the range of surgical outcomes.Retrospective observational cohort study of 32 patients who underwent open surgical resection for spinal CMs, the majority of which presented to a dorsal or lateral pial surface, from 1996 to 2017 at a single institution. We evaluated outcomes as clinically improved, worsened, or unchanged against preoperative baseline; Frankel and Aminoff-Logue disability grades were also calculated.Mean age at presentation was 44.2 (range, 0.5-77 yr). Symptoms included sensory deficits (n = 26, 81%), loss of strength/coordination (n = 16, 50%), pain (n = 16, 50%), and bladder/bowel dysfunction (n = 6, 19%). Thoracic (n = 16, 50%) and cervical CMs (n = 16, 50%) were equally common, with overall mean size of 7.1 mm (range, 1-20 mm). Functional outcomes at last follow-up, compared to preoperative status for patients with >6 mo of follow-up, were improved in 6 (23%), unchanged in 19 (73%), and worsened in 1 (4%) patients. Preoperative Frankel grade and improved Frankel grade immediately following resection were strongly associated with improvement from baseline at long-term followup (P < .01).Gross total resection of symptomatic spinal cord CMs can prevent further neurological decline. Our experience suggests excellent long-term outcomes and minimal surgical morbidity following resection.

    View details for PubMedID 29425323

  • Strategies for and Outcome of Repeat Revascularization Surgery for Moyamoya Disease: An American Institutional Series NEUROSURGERY Teo, M., Johnson, J., Steinberg, G. K. 2017; 81 (5): 852?59

    Abstract

    Revascularization for moyamoya disease (MMD) effectively prevents future ischemic events. However, small subsets of patients with persistent or new symptoms due to inadequate collateralization require repeat revascularizations.To investigate the clinical and radiological outcome of repeat revascularization in MMD patients with previous indirect or direct bypasses.Single institution, retrospective analysis of a prospective MMD database.From 1991 to 2014, this institution performed 1244 revascularization bypasses (1107 direct, 137 indirect) in 765 patients, of whom 57 were repeat revascularizations (38 indirect, 19 direct bypass). When initially performed at the institution, the repeat revascularization rate was 4% for indirect and 1% for direct bypasses (P = .03). Cohorts with previous indirect vs direct bypass were slightly younger (mean age 23 vs 30 yr), with fewer females (61% vs 84%, P = .08), and a similar mean duration between initial bypass and repeat revascularization (49 vs 47 mo). Both groups had similar repeat revascularization due to transient ischemic attacks (66% vs 63%). One acute graft occlusion in the previous direct bypass group was revised within 1 wk postoperatively. Over 50% of the repeat revascularizations in both groups were direct bypasses; the major difference being that the repeat bypass in the direct group was to augment another vascular territory. At nearly 5 yr mean follow-up, over 80% of patients in both groups are well, free from stroke/transient ischemic attack symptoms, with excellent radiological results.Repeat revascularization can safely and effectively prevent future ischemic events. Indirect bypass has a higher rate of repeat revascularization than direct bypass.

    View details for PubMedID 28605467

  • Brainstem arteriovenous malformations: lesion characteristics and treatment outcomes. Journal of neurosurgery Madhugiri, V. S., Teo, M. K., Vavao, J., Bell-Stephens, T., Steinberg, G. K. 2017: 1-11

    Abstract

    OBJECTIVE Brainstem arteriovenous malformations (AVMs) are rare lesions that are difficult to diagnose and treat. They are often more aggressive in their behavior when compared with their supratentorial counterparts. The consequence of a brainstem hemorrhage is often devastating, and many patients are in poor neurological status at presentation. The authors examine the factors associated with angiographically confirmed cure and those affecting management outcomes for these complex lesions. METHODS This was a retrospective analysis of data gathered from the prospectively maintained Stanford AVM database. Lesions were grouped based on their location in the brainstem (medulla, pons, or midbrain) and the quadrant they occupied. Angiographic cure was dichotomized as completely obliterated or not, and functional outcome was dichotomized as either independent or not independent at last follow-up. RESULTS Over a 23-year period, 39 lesions were treated. Of these, 3 were located in the medulla, 14 in the pons, and 22 in the midbrain. At presentation, 92% of the patients had hemorrhage, and only 43.6% were functionally independent. Surgery resulted in the best radiographic cure rates, with a morbidity rate of 12.5%. In all, 53% of patients either improved or remained stable after surgery. Absence of residual nidus and female sex correlated with better outcomes. CONCLUSIONS Brainstem AVMs usually present with hemorrhage. Surgery offers the best chance of cure, either in isolation or in combination with other modalities as appropriate.

    View details for DOI 10.3171/2016.9.JNS16943

    View details for PubMedID 28298018

  • Electrical preconditioning of stem cells with a conductive polymer scaffold enhances stroke recovery. Biomaterials George, P. M., Bliss, T. M., Hua, T. n., Lee, A. n., Oh, B. n., Levinson, A. n., Mehta, S. n., Sun, G. n., Steinberg, G. K. 2017; 142: 31?40

    Abstract

    Exogenous human neural progenitor cells (hNPCs) are promising stroke therapeutics, but optimal delivery conditions and exact recovery mechanisms remain elusive. To further elucidate repair processes and improve stroke outcomes, we developed an electrically conductive, polymer scaffold for hNPC delivery. Electrical stimulation of hNPCs alters their transcriptome including changes to the VEGF-A pathway and genes involved in cell survival, inflammatory response, and synaptic remodeling. In our experiments, exogenous hNPCs were electrically stimulated (electrically preconditioned) via the scaffold 1 day prior to implantation. After in vitro stimulation, hNPCs on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. Electrically preconditioned hNPCs improved functional outcomes compared to unstimulated hNPCs or hNPCs where VEGF-A was blocked during in vitro electrical preconditioning. The ability to manipulate hNPCs via a conductive scaffold creates a new approach to optimize stem cell-based therapy and determine which factors (such as VEGF-A) are essential for stroke recovery.

    View details for PubMedID 28719819

  • Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke A Phase 1/2a Study STROKE Steinberg, G. K., Kondziolka, D., Wechsler, L. R., Lunsford, L. D., Coburn, M. L., Billigen, J. B., Kim, A. S., Johnson, J. N., Bates, D., King, B., Case, C., McGrogan, M., Yankee, E. W., Schwartz, N. E. 2016; 47 (7): 1817-1824

    Abstract

    Preclinical data suggest that cell-based therapies have the potential to improve stroke outcomes.Eighteen patients with stable, chronic stroke were enrolled in a 2-year, open-label, single-arm study to evaluate the safety and clinical outcomes of surgical transplantation of modified bone marrow-derived mesenchymal stem cells (SB623).All patients in the safety population (N=18) experienced at least 1 treatment-emergent adverse event. Six patients experienced 6 serious treatment-emergent adverse events; 2 were probably or definitely related to surgical procedure; none were related to cell treatment. All serious treatment-emergent adverse events resolved without sequelae. There were no dose-limiting toxicities or deaths. Sixteen patients completed 12 months of follow-up at the time of this analysis. Significant improvement from baseline (mean) was reported for: (1) European Stroke Scale: mean increase 6.88 (95% confidence interval, 3.5-10.3; P<0.001), (2) National Institutes of Health Stroke Scale: mean decrease 2.00 (95% confidence interval, -2.7 to -1.3; P<0.001), (3) Fugl-Meyer total score: mean increase 19.20 (95% confidence interval, 11.4-27.0; P<0.001), and (4) Fugl-Meyer motor function total score: mean increase 11.40 (95% confidence interval, 4.6-18.2; P<0.001). No changes were observed in modified Rankin Scale. The area of magnetic resonance T2 fluid-attenuated inversion recovery signal change in the ipsilateral cortex 1 week after implantation significantly correlated with clinical improvement at 12 months (P<0.001 for European Stroke Scale).In this interim report, SB623 cells were safe and associated with improvement in clinical outcome end points at 12 months.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01287936.

    View details for DOI 10.1161/STROKEAHA.116.012995

    View details for Web of Science ID 000379844900035

    View details for PubMedID 27256670

  • Optogenetic Approaches to Target Specific Neural Circuits in Post-stroke Recovery NEUROTHERAPEUTICS Cheng, M. Y., Aswendt, M., Steinberg, G. K. 2016; 13 (2): 325-340

    Abstract

    Stroke is a leading cause of death and disability in the USA, yet treatment options are very limited. Functional recovery can occur after stroke and is attributed, in part, to rewiring of neural connections in areas adjacent to or remotely connected to the infarct. A better understanding of neural circuit rewiring is thus an important step toward developing future therapeutic strategies for stroke recovery. Because stroke disrupts functional connections in peri-infarct and remotely connected regions, it is important to investigate brain-wide network dynamics during post-stroke recovery. Optogenetics is a revolutionary neuroscience tool that uses bioengineered light-sensitive proteins to selectively activate or inhibit specific cell types and neural circuits within milliseconds, allowing greater specificity and temporal precision for dissecting neural circuit mechanisms in diseases. In this review, we discuss the current view of post-stroke remapping and recovery, including recent studies that use optogenetics to investigate neural circuit remapping after stroke, as well as optogenetic stimulation to enhance stroke recovery. Multimodal approaches employing optogenetics in conjunction with other readouts (e.g., in vivo neuroimaging techniques, behavior assays, and next-generation sequencing) will advance our understanding of neural circuit reorganization during post-stroke recovery, as well as provide important insights into which brain circuits to target when designing brain stimulation strategies for future clinical studies.

    View details for DOI 10.1007/s13311-015-0411-5

    View details for Web of Science ID 000373642100006

    View details for PubMedID 26701667

  • Enhanced phasic GABA inhibition during the repair phase of stroke: a novel therapeutic target BRAIN Hiu, T., Farzampour, Z., Paz, J. T., Wang, E. H., Badgely, C., Olson, A., Micheva, K. D., Wang, G., Lemmens, R., Tran, K. V., Nishiyama, Y., Liang, X., Hamilton, S. A., O'Rourke, N., Smith, S. J., Huguenard, J. R., Bliss, T. M., Steinberg, G. K. 2016; 139: 468-480

    Abstract

    Ischaemic stroke is the leading cause of severe long-term disability yet lacks drug therapies that promote the repair phase of recovery. This repair phase of stroke occurs days to months after stroke onset and involves brain remapping and plasticity within the peri-infarct zone. Elucidating mechanisms that promote this plasticity is critical for the development of new therapeutics with a broad treatment window. Inhibiting tonic (extrasynaptic) GABA signalling during the repair phase was reported to enhance functional recovery in mice suggesting that GABA plays an important function in modulating brain repair. While tonic GABA appears to suppress brain repair after stroke, less is known about the role of phasic (synaptic) GABA during the repair phase. We observed an increase in postsynaptic phasic GABA signalling in mice within the peri-infarct cortex specific to layer 5; we found increased numbers of ?1 receptor subunit-containing GABAergic synapses detected using array tomography, and an associated increased efficacy of spontaneous and miniature inhibitory postsynaptic currents in pyramidal neurons. Furthermore, we demonstrate that enhancing phasic GABA signalling using zolpidem, a Food and Drug Administration (FDA)-approved GABA-positive allosteric modulator, during the repair phase improved behavioural recovery. These data identify potentiation of phasic GABA signalling as a novel therapeutic strategy, indicate zolpidem's potential to improve recovery, and underscore the necessity to distinguish the role of tonic and phasic GABA signalling in stroke recovery.

    View details for DOI 10.1093/brain/awv360

    View details for Web of Science ID 000370205100025

    View details for PubMedID 26685158

    View details for PubMedCentralID PMC4805083

  • Novel Stroke Therapeutics: Unraveling Stroke Pathophysiology and Its Impact on Clinical Treatments. Neuron George, P. M., Steinberg, G. K. 2015; 87 (2): 297-309

    Abstract

    Stroke remains a leading cause of death and disability in the world. Over the past few decades our understanding of the pathophysiology of stroke has increased, but greater insight is required to advance the field of stroke recovery. Clinical treatments have improved in the acute time window, but long-term therapeutics remain limited. Complex neural circuits damaged by ischemia make restoration of function after stroke difficult. New therapeutic approaches, including cell transplantation or stimulation, focus on reestablishing these circuits through multiple mechanisms to improve circuit plasticity and remodeling. Other research targets intact networks to compensate for damaged regions. This review highlights several important mechanisms of stroke injury and describes emerging therapies aimed at improving clinical outcomes.

    View details for DOI 10.1016/j.neuron.2015.05.041

    View details for PubMedID 26182415

  • Is local hypoperfusion the reason for transient neurological deficits after STA-MCA bypass for moyamoya disease? JOURNAL OF NEUROSURGERY Mukerji, N., Cook, D. J., Steinberg, G. K. 2015; 122 (1): 90-94

    Abstract

    Hyperperfusion is believed to be the cause of transient neurological events (TNEs) in patients with moyamoya disease (MMD) who have undergone an extracranial-to-intracranial (EC-IC) bypass between the superficial temporal artery (STA) and the middle cerebral artery (MCA). The objective of this study was to evaluate this possibility by analyzing cerebral blood flow (CBF) data obtained with thermal diffusion probes used at the authors' center.The authors examined postoperative cerebral perfusion in 31 patients with MMD who underwent a direct EC-IC STA-MCA bypass. A Hemedex Q500 flow probe was placed in the frontal lobe adjacent to the bypass and connected to a Bowman cerebral perfusion monitor, and CBF data were statistically analyzed using JMP 8.0.2 software. Seven patients experienced a TNE after surgery in the left hemisphere (that is, after left-sided surgery), manifesting as dysphasia approximately 24 hours postoperatively and which had improved by 48 hours. No TNEs were observed after right-sided surgeries. Operative and postoperative CBFs in the left side with the TNE were compared with those in the left side with no TNE and on the right side.A detailed analysis of 64,980 minute-by-minute flow observations showed that the initial postbypass CBF was higher on the left side where the TNEs occurred. This CBF increase was followed by a widely fluctuating pattern and a statistically significant and sharp drop in perfusion (p < 0.001, mean difference of CBF between groups, paired t-test) associated with a TNE not observed in the other 2 groups.On the basis of the authors' initial observations, an early-onset altered pattern of CBF was identified. These findings suggest local hypoperfusion as the cause of the TNEs. This hypoperfusion may originate from competing blood flows resulting from impaired cerebral autoregulation and a fluctuating flow in cerebral microcirculation.

    View details for DOI 10.3171/2014.8.JNS132413

    View details for Web of Science ID 000346947600011

    View details for PubMedID 25343178

  • Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing. G3 (Bethesda, Md.) Shoemaker, L. D., Clark, M. J., Patwardhan, A., Chandratillake, G., Garcia, S., Chen, R., Morgan, A. A., Leng, N., Kirk, S., Chen, R., Cook, D. J., Snyder, M., Steinberg, G. K. 2015; 6 (1): 41-49

    Abstract

    Moyamoya disease (MMD) is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10-12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K) in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K) in Asian cases (P = 6.01×10(-5)) that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52×10(-4)) and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93×10(-4)) and non-RNF213 founder mutation (P = 1.51×10(-3)) cases was ZXDC (p.P562L), a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07×10(-4)) and non-RNF213 founder mutation cases (P = 5.31×10(-5)). These findings further support the East Asian origins of the RNF213 (p.R4810K) variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis.

    View details for DOI 10.1534/g3.115.020321

    View details for PubMedID 26530418

  • Optogenetic neuronal stimulation promotes functional recovery after stroke PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cheng, M. Y., Wang, E. H., Woodson, W. J., Wang, S., Sun, G., Lee, A. G., Arac, A., Fenno, L. E., Deisseroth, K., Steinberg, G. K. 2014; 111 (35): 12913-12918

    Abstract

    Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.

    View details for DOI 10.1073/pnas.1404109111

    View details for Web of Science ID 000341230800084

    View details for PubMedCentralID PMC4156770

  • Flexible Omnidirectional Carbon Dioxide Laser as an Effective Tool for Resection of Brainstem, Supratentorial, and Intramedullary Cavernous Malformations NEUROSURGERY Choudhri, O., Karamchandani, J., Gooderham, P., Steinberg, G. K. 2014; 10 (1): 34-44

    Abstract

    Lasers have a long history in neurosurgery, yet bulky designs and difficult ergonomics limit their use. With its ease of manipulation and multiple applications, the OmniGuide CO2 laser has reintroduced laser technology to the microsurgical resection of brain and spine lesions. This laser, delivered through a hollow-core fiber lined with a unidirectional mirror, minimizes energy loss and allows precise targeting.To analyze resections performed by the senior author from April 2009 to March 2013 of 58 cavernous malformations (CMs) in the brain and spine with the use of the OmniGuide CO2 laser, to reflect on lessons learned from laser use in eloquent areas, and to share data on comparisons of laser power calibration and histopathology.Data were collected from electronic medical records, radiology reports, operative room records, OmniGuide CO2 laser case logs, and pathology records.Of 58 CMs, approximately 50% were in the brainstem (30) and the rest were in supratentorial (26) and intramedullary spinal locations (2). Fifty-seven, ranging from 5 to 45 mm, were resected, with a subtotal resection in 1. Laser power ranged from 2 to 10 W. Pathology specimens showed minimal thermal damage compared with traditionally resected specimens with bipolar coagulation.The OmniGuide CO2 laser is safe and has excellent precision for the resection of supratentorial, brainstem, and spinal intramedullary CMs. No laser-associated complications occurred, and very low energy was used to dissect malformations from their surrounding hemosiderin-stained parenchymas. The authors recommend its use for deep-seated and critically located CMs, along with traditional tools.

    View details for DOI 10.1227/NEU.0000000000000212

    View details for PubMedID 24141477

  • Less invasive pedicled omental-cranial transposition in pediatric patients with moyamoya disease and failed prior revascularization. Neurosurgery Navarro, R., Chao, K., Gooderham, P. A., Bruzoni, M., Dutta, S., Steinberg, G. K. 2014; 10: 1-14

    Abstract

    Patients with moyamoya disease and progressive neurologic deterioration despite previous revascularization pose a major treatment challenge. Many have exhausted typical sources for bypass or have ischemia in areas that are difficult to reach with an indirect pedicled flap. Omental-cranial transposition has been an effective, but sparingly used technique because of its associated morbidity.We have refined a laparoscopic method of harvesting an omental flap that preserves its gastroepiploic arterial supply.The pedicled omentum can be lengthened as needed by dividing it between the vascular arcades. It is transposed to the brain via skip incisions. The flap can be trimmed or stretched to cover ischemic areas of the brain. The cranial exposure is performed in parallel with pediatric surgeons. We performed this technique in 3 pediatric moyamoya patients (aged 5 to 12 years) with prior STA-MCA bypasses and progressive ischemic symptoms. In 1 patient, we transposed omentum to both hemispheres.Blood loss ranged from 75 to 250 ml. After surgery, patients immediately tolerated a diet and were discharged in 3 to 5 days. All 3 children's ischemic symptoms resolved within 3 months postoperatively. MRI at 1 year showed improved perfusion and no new infarcts. Angiography showed excellent revascularization of targeted areas and patency of the donor gastroepiploic artery.Laparoscopic omental harvest for cranial-omental transposition can be performed efficiently and safely. Moyamoya patients appear to tolerate this technique much better than laparotomy. With this method we can achieve excellent angiographic revascularization and resolution of ischemic symptoms.

    View details for DOI 10.1227/NEU.0000000000000119

    View details for PubMedID 23921707

  • Cavernous malformation of brainstem, thalamus, and basal ganglia: a series of 176 patients. Neurosurgery Pandey, P., Westbroek, E. M., Gooderham, P. A., Steinberg, G. K. 2013; 72 (4): 573-589

    Abstract

    Cavernous malformations (CMs) in deep locations account for 9% to 35% of brain malformations and are surgically challenging.To study the clinical features and outcomes following surgery for deep CMs and the complication of hypertrophic olivary degeneration (HOD).Clinical records, radiological findings, operative details, and complications of 176 patients with deep CMs were reviewed retrospectively.Of 176 patients with 179 CMs, 136 CMs were in the brainstem, 27 in the basal ganglia, and 16 in the thalamus. Cranial nerve deficits (51.1%), hemiparesis (40.9%), numbness (34.7%), and cerebellar symptoms (38.6%) presented most commonly. Hemorrhage presented in 172 patients (70 single, 102 multiple). The annual retrospective hemorrhage rate was 5.1% (assuming CMs are congenital with uniform hemorrhage risk throughout life); the rebleed rate was 31.5%/patient per year. Surgical approach depended on the proximity of the CM to the pial or ependymal surface. Postoperatively, 121 patients (68.8%) had no new neurological deficits. Follow-up occurred in 170 patients. Delayed postoperative HOD developed in 9/134 (6.7%) patients with brainstem CMs. HOD occurred predominantly following surgery for pontine CMs (9/10 patients). Three patients with HOD had palatal myoclonus, nystagmus, and oscillopsia, whereas 1 patient each had limb tremor and hemiballismus. At follow-up, 105 patients (61.8%) improved, 44 (25.9%) were unchanged, and 19 (11.2%) worsened neurologically. Good preoperative modified Rankin Score (98.2% vs 54.5%, P = .001) and single hemorrhage (89% vs 77.3%, P < .05) were predictive of good long-term outcome.Symptomatic deep CMs can be resected with acceptable morbidity and outcomes. Good preoperative modified Rankin Score and single hemorrhage are predictors of good long-term outcome.

    View details for DOI 10.1227/NEU.0b013e318283c9c2

    View details for PubMedID 23262564

  • Multimodality management of Spetzler-Martin Grade III arteriovenous malformations JOURNAL OF NEUROSURGERY Pandey, P., Marks, M. P., Harraher, C. D., Westbroek, E. M., Chang, S. D., Do, H. M., Levy, R. P., Dodd, R. L., Steinberg, G. K. 2012; 116 (6): 1279-1288

    Abstract

    Grade III arteriovenous malformations (AVMs) are diverse because of their variations in size (S), location in eloquent cortex (E), and presence of central venous drainage (V). Because they may have implications for management and outcome, the authors evaluated these variations in the present study.Between 1984 and 2010, 100 patients with Grade III AVMs were treated. The AVMs were categorized by Spetzler-Martin characteristics as follows: Type 1 = S1E1V1, Type 2 = S2E1V0, Type 3 = S2E0V1, and Type 4 = S3E0V0. The occurrence of a new neurological deficit, functional status (based on modified Rankin Scale [mRS] score) at discharge and follow-up, and radiological obliteration were correlated with demographic and morphological characteristics.One hundred patients (49 female and 51 male; age range 5-68 years, mean 35.8 years) were evaluated. The size of AVMs was less than 3 cm in 28 patients, 3-6 cm in 71, and greater than 6 cm in 1; 86 AVMs were located in eloquent cortex and 38 had central drainage. The AVMs were Type 1 in 28 cases, Type 2 in 60, Type 3 in 11, and Type 4 in 1. The authors performed embolization in 77 patients (175 procedures), surgery in 64 patients (74 surgeries), and radiosurgery in 49 patients (44 primary and 5 postoperative). The mortality rate following the management of these AVMs was 1%. Fourteen patients (14%) had new neurological deficits, with 5 (5%) being disabling (mRS score > 2) and 9 (9%) being nondisabling (mRS score ? 2) events. Patients with Type 1 AVMs (small size) had the best outcome, with 1 (3.6%) in 28 having a new neurological deficit, compared with 72 patients with larger AVMs, of whom 13 (18.1%) had a new neurological deficit (p < 0.002). Older age (> 40 years), malformation size > 3 cm, and nonhemorrhagic presentation predicted the occurrence of new deficits (p < 0.002). Sex, eloquent cortex, and venous drainage did not confer any benefit. In 89 cases follow-up was adequate for data to be included in the obliteration analysis. The AVM was obliterated in 78 patients (87.6%), 69 of them (88.5%) demonstrated on angiography and 9 on MRI /MR angiography. There was no difference between obliteration rates between different types of AVMs, size, eloquence, and drainage. Age, sex, and clinical presentation also did not predict obliteration.Multimodality management of Grade III AVMs results in a high rate of obliteration, which was not influenced by size, venous drainage, or eloquent location. However, the development of new neurological deficits did correlate with size, whereas eloquence and venous drainage did not affect the neurological complication rate. The authors propose subclassifying the Grade III AVMs according to their size (< 3 and ? 3 cm) to account for treatment risk.

    View details for DOI 10.3171/2012.3.JNS111575

    View details for PubMedID 22482792

  • Arterial Spin-Labeling MRI Can Identify the Presence and Intensity of Collateral Perfusion in Patients With Moyamoya Disease STROKE Zaharchuk, G., Do, H. M., Marks, M. P., Rosenberg, J., Moseley, M. E., Steinberg, G. K. 2011; 42 (9): 2485-U183

    Abstract

    Determining the presence and adequacy of collateral blood flow is important in cerebrovascular disease. Therefore, we explored whether a noninvasive imaging modality, arterial spin labeling (ASL) MRI, could be used to detect the presence and intensity of collateral flow using digital subtraction angiography (DSA) and stable xenon CT cerebral blood flow as gold standards for collaterals and cerebral blood flow, respectively.ASL and DSA were obtained within 4 days of each other in 18 patients with Moyamoya disease. Two neurointerventionalists scored DSA images using a collateral grading scale in regions of interest corresponding to ASPECTS methodology. Two neuroradiologists similarly scored ASL images based on the presence of arterial transit artifact. Agreement of ASL and DSA consensus scores was determined, including kappa statistics. In 15 patients, additional quantitative xenon CT cerebral blood flow measurements were performed and compared with collateral grades.The agreement between ASL and DSA consensus readings was moderate to strong, with a weighted kappa value of 0.58 (95% confidence interval, 0.52-0.64), but there was better agreement between readers for ASL compared with DSA. Sensitivity and specificity for identifying collaterals with ASL were 0.83 (95% confidence interval, 0.77-0.88) and 0.82 (95% confidence interval, 0.76-0.87), respectively. Xenon CT cerebral blood flow increased with increasing DSA and ASL collateral grade (P<0.05).ASL can noninvasively predict the presence and intensity of collateral flow in patients with Moyamoya disease using DSA as a gold standard. Further study of other cerebrovascular diseases, including acute ischemic stroke, is warranted.

    View details for DOI 10.1161/STROKEAHA.111.61646

    View details for PubMedID 21799169

  • Management of Pediatric Intracranial Arteriovenous Malformations: Experience With Multimodality Therapy NEUROSURGERY Darsaut, T. E., Guzman, R., Marcellus, M. L., Edwards, M. S., Tian, L., Do, H. M., Chang, S. D., Levy, R. P., Adler, J. R., Marks, M. P., Steinberg, G. K. 2011; 69 (3): 540-556

    Abstract

    Successful management of pediatric arteriovenous malformations (AVMs) often requires a balanced application of embolization, surgery, and radiosurgery.To describe our experience treating pediatric AVMs.We analyzed 120 pediatric patients (< 18 years of age) with AVMs treated with various combinations of radiosurgery, surgery, and endovascular techniques.Between 1985 and 2009, 76 children with low Spetzler-Martin grade (1-3) and 44 with high-grade (4-5) AVMs were treated. Annual risk of hemorrhage from presentation to initial treatment was 4.0%, decreasing to 3.2% after treatment initiation until confirmed obliteration. Results for AVM obliteration were available in 101 patients. Initial single-modality therapy led to AVM obliteration in 51 of 67 low-grade (76%) and 3 of 34 high-grade (9%) AVMs, improving to 58 of 67 (87%) and 9 of 34 (26%), respectively, with further treatment. Mean time to obliteration was 1.8 years for low-grade and 6.4 years for high-grade AVMs. Disabling neurological complications occurred in 4 of 77 low-grade (5%) and 12 of 43 high-grade (28%) AVMs. At the final clinical follow-up (mean, 9.2 years), 48 of 67 patients (72%) with low-grade lesions had a modified Rankin Scale score (mRS) of 0 to 1 compared with 12 of 34 patients (35%) with high-grade AVMs. On multivariate analysis, significant risk factors for poor final clinical outcome (mRS ? 2) included baseline mRS ? 2 (odds ratio, 9.51; 95% confidence interval, 3.31-27.37; P < .01), left-sided location (odds ratio, 3.03; 95% confidence interval, 1.11-8.33; P = .03), and high AVM grade (odds ratio, 4.35; 95% confidence interval, 1.28-14.28; P = .02).Treatment of pediatric AVMs with multimodality therapy can substantially improve obliteration rates and may decrease AVM hemorrhage rates. The poor natural history and risks of intervention must be carefully considered when deciding to treat high-grade pediatric AVMs.

    View details for DOI 10.1227/NEU.0b013e3182181c00

    View details for PubMedID 21430584

  • Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain BRAIN Andres, R. H., Horie, N., Slikker, W., Keren-Gill, H., Zhan, K., Sun, G., Manley, N. C., Pereira, M. P., Sheikh, L. A., McMillan, E. L., Schaar, B. T., Svendsen, C. N., Bliss, T. M., Steinberg, G. K. 2011; 134: 1777-1789

    Abstract

    Stem cell transplantation promises new hope for the treatment of stroke although significant questions remain about how the grafted cells elicit their effects. One hypothesis is that transplanted stem cells enhance endogenous repair mechanisms activated after cerebral ischaemia. Recognizing that bilateral reorganization of surviving circuits is associated with recovery after stroke, we investigated the ability of transplanted human neural progenitor cells to enhance this structural plasticity. Our results show the first evidence that human neural progenitor cell treatment can significantly increase dendritic plasticity in both the ipsi- and contralesional cortex and this coincides with stem cell-induced functional recovery. Moreover, stem cell-grafted rats demonstrated increased corticocortical, corticostriatal, corticothalamic and corticospinal axonal rewiring from the contralesional side; with the transcallosal and corticospinal axonal sprouting correlating with functional recovery. Furthermore, we demonstrate that axonal transport, which is critical for both proper axonal function and axonal sprouting, is inhibited by stroke and that this is rescued by the stem cell treatment, thus identifying another novel potential mechanism of action of transplanted cells. Finally, we established in vitro co-culture assays in which these stem cells mimicked the effects observed in vivo. Through immunodepletion studies, we identified vascular endothelial growth factor, thrombospondins 1 and 2, and slit as mediators partially responsible for stem cell-induced effects on dendritic sprouting, axonal plasticity and axonal transport in vitro. Thus, we postulate that human neural progenitor cells aid recovery after stroke through secretion of factors that enhance brain repair and plasticity.

    View details for DOI 10.1093/brain/awr094

    View details for Web of Science ID 000291063900018

    View details for PubMedID 21616972

    View details for PubMedCentralID PMC3102243

  • Predictors of Clinical and Angiographic Outcome After Surgical or Endovascular Therapy of Very Large and Giant Intracranial Aneurysms NEUROSURGERY Darsaut, T. E., Darsaut, N. M., Chang, S. D., Silverberg, G. D., Shuer, L. M., Tian, L., Dodd, R. L., Do, H. M., Marks, M. P., Steinberg, G. K. 2011; 68 (4): 903-915

    Abstract

    Risk factors for poor outcome in the treatment of very large (?20-24 mm) and giant (?25 mm) intracranial aneurysms remain incompletely defined.To present an aggregate clinical series detailing a 24-year experience with very large and giant aneurysms to identify and assess the relative importance of various patient, aneurysm, and treatment-specific characteristics associated with clinical and angiographic outcomes.The authors retrospectively identified 184 aneurysms measuring 20 mm or larger (85 very large, 99 giant) treated at Stanford University Medical Center between 1984 and 2008. Clinical data including age, presentation, and modified Rankin Scale (mRS) score were recorded, along with aneurysm size, location, and morphology. Type of treatment was noted and clinical outcome measured using the mRS score at final follow-up. Angiographic outcomes were completely occluded, occluded with residual neck, partly obliterated, or patent with modified flow.After multivariate analysis, risk factors for poor clinical outcome included a baseline mRS score of 2 or higher (odds ratio [OR], 0.23; 95% confidence interval [CI]: 0.08-0.66; P = .01), aneurysm size of 25 mm or larger (OR, 3.32; 95% CI: 1.51-7.28; P < .01), and posterior circulation location (OR, 0.18; 95% CI: 0.07-0.43; P < .01). Risk factors for incomplete angiographic obliteration included fusiform morphology (OR, 0.25; 95% CI: 0.10-0.66; P < .01), posterior circulation location (OR, 0.33; 95% CI: 0.13-0.83; P = .02), and endovascular treatment (OR, 0.14; 95% CI: 0.06-0.32; P < .01). Patients with incompletely occluded aneurysms experienced higher rates of posttreatment subarachnoid hemorrhage and had increased mortality compared with those with completely obliterated aneurysms.Our results suggest that patients with poor baseline functional status, giant aneurysms, and aneurysms in the posterior circulation had a significantly higher proportion of poor outcomes at final follow-up. Fusiform morphology, posterior circulation location, and endovascular treatment were risk factors for incompletely obliterated aneurysms.

    View details for DOI 10.1227/NEU.0b013e3182098ad0

    View details for PubMedID 21221025

  • Intraoperative blood flow analysis of direct revascularization procedures in patients with moyamoya disease JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Lee, M., Guzman, R., Bell-Stephens, T., Steinberg, G. K. 2011; 31 (1): 262-274

    Abstract

    Moyamoya disease is characterized by the progressive stenosis and often occlusion of the terminal internal carotid arteries, which leads to ischemic and hemorrhagic injuries. The etiology is unknown and surgical revascularization remains the mainstay treatment. We analyzed various hemodynamic factors in 292 patients with moyamoya disease, representing 496 revascularization procedures, including vessel dimension and intraoperative blood flow, using a perivascular ultrasonic flowprobe. Mean middle cerebral artery (MCA) flow rate was 4.4 ± 0.26 mL/min. After superficial temporal artery (STA)-MCA bypass surgery, flows at the microanastomosis were increased fivefold to a mean of 22.2 ± 0.8 mL/min. The MCA flows were significantly lower in the pediatric (16.2 ± 1.3 mL/min) compared with the adult (23.9 ± 1.0 mL/min; P<0.0001) population. Increased local flow rates were associated with clinical improvement. Permanent postoperative complications were low (<5%), but very high postanastomosis MCA flow was associated with postoperative stroke (31.2 ± 6.8 mL/min; P=0.045), hemorrhage (32.1 ± 10.2 mL/min; P=0.045), and transient neurologic deficits (28.6 ± 5.6 mL/min; P=0.047) compared with controls. Other flow and vessel dimension data are presented to elucidate the hemodynamic changes related to the vasculopathy and subsequent to surgical intervention.

    View details for DOI 10.1038/jcbfm.2010.85

    View details for Web of Science ID 000285870700028

    View details for PubMedID 20588321

    View details for PubMedCentralID PMC3049490

  • Transplanted Stem Cell-Secreted VEGF Effects Post-Stroke Recovery, Inflammation, and Vascular Repair. Stem cells (Dayton, Ohio) Horie, N. n., Pereira, M. P., Niizuma, K. n., Sun, G. n., Keren-Gill, H. n., Encarnacion, A. n., Shamloo, M. n., Hamilton, S. A., Jiang, K. n., Huhn, S. n., Palmer, T. D., Bliss, T. M., Steinberg, G. K. 2011

    Abstract

    Cell transplantation offers a novel therapeutic strategy for stroke; however, how transplanted cells function in vivo is poorly understood. We show for the first time that after sub-acute transplantation into the ischemic brain of human central nervous system stem cells grown as neurospheres (hCNS-SCns), the stem cell-secreted factor, human VEGF (hVEGF), is necessary for cell-induced functional recovery. We correlate this functional recovery to hVEGF-induced effects on the host brain including multiple facets of vascular repair, and its unexpected suppression of the inflammatory response. We found that transplanted hCNS-SCns affected multiple parameters in the brain with different kinetics: early improvement in blood-brain barrier (BBB) integrity and suppression of inflammation was followed by a delayed spatio-temporal regulated increase in neovascularization. These events coincided with a bi-modal pattern of functional recovery: an early recovery independent of neovascularization, and a delayed hVEGF-dependent recovery coincident with neovascularization. Therefore, cell transplantation therapy offers an exciting multi-modal strategy for brain repair in stroke and potentially other disorders with a vascular or inflammatory component.

    View details for DOI 10.1002/stem.584

    View details for PubMedID 21240943

    View details for PubMedCentralID PMC3524414

  • Long-term monitoring of transplanted human neural stem cells in developmental and pathological contexts with MRI PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Guzman, R., Uchida, N., Bliss, T. M., He, D., Christopherson, K. K., Stellwagen, D., Capela, A., Greve, J., Malenka, R. C., Moseley, M. E., Palmer, T. D., Steinberg, G. K. 2007; 104 (24): 10211-10216

    Abstract

    Noninvasive monitoring of stem cells, using high-resolution molecular imaging, will be instrumental to improve clinical neural transplantation strategies. We show that labeling of human central nervous system stem cells grown as neurospheres with magnetic nanoparticles does not adversely affect survival, migration, and differentiation or alter neuronal electrophysiological characteristics. Using MRI, we show that human central nervous system stem cells transplanted either to the neonatal, the adult, or the injured rodent brain respond to cues characteristic for the ambient microenvironment resulting in distinct migration patterns. Nanoparticle-labeled human central nervous system stem cells survive long-term and differentiate in a site-specific manner identical to that seen for transplants of unlabeled cells. We also demonstrate the impact of graft location on cell migration and describe magnetic resonance characteristics of graft cell death and subsequent clearance. Knowledge of migration patterns and implementation of noninvasive stem cell tracking might help to improve the design of future clinical neural stem cell transplantation.

    View details for DOI 10.1073/pnas.0608519104

    View details for Web of Science ID 000247363000053

    View details for PubMedID 17553967

    View details for PubMedCentralID PMC1891235

  • Establishing a Data Science Unit in an Academic Medical Center: An Illustrative Model. Academic medicine : journal of the Association of American Medical Colleges Desai, M., Boulos, M., Pomann, G. M., Steinberg, G. K., Longo, F. M., Leonard, M., Montine, T., Blomkalns, A. L., Harrington, R. A. 2021

    Abstract

    The field of data science has great potential to address critical questions relevant for academic medical centers. Data science initiatives are consequently being established within academic medicine. At the cornerstone of such initiatives are scientists who practice data science. These scientists include biostatisticians, clinical informaticians, database and software developers, computational scientists, and computational biologists. Too often, however, those involved in the practice of data science are viewed by academic leadership as providing a noncomplex service to facilitate research and further the careers of other academic faculty. The authors contend that the success of data science initiatives relies heavily on the understanding that the practice of data science is a critical intellectual contribution to the overall science conducted at an academic medical center. Further, careful thought by academic leadership is needed for allocation of resources devoted to the practice of data science. At the Stanford University School of Medicine, the authors have developed an innovative model for a data science collaboratory based on 4 fundamental elements: an emphasis on collaboration over consultation; a subscription-based funding mechanism that reflects commitment by key partners; an investment in the career development of faculty who practice data science; and a strong educational component for data science members in team science and for clinical and translational investigators in data science. As data science becomes increasingly essential to learning health systems, centers that specialize in the practice of data science are a critical component of the research infrastructure and intellectual environment of academic medical centers.

    View details for DOI 10.1097/ACM.0000000000004079

    View details for PubMedID 33769342

  • Cell Therapy for Chronic TBI: Interim Analysis of the Randomized Controlled STEMTRA Trial. Neurology Kawabori, M., Weintraub, A. H., Imai, H., Zinkevych, L., McAllister, P., Steinberg, G. K., Frishberg, B. M., Yasuhara, T., Chen, J. W., Cramer, S. C., Achrol, A. S., Schwartz, N. E., Suenaga, J., Lu, D. C., Semeniv, I., Nakamura, H., Kondziolka, D., Chida, D., Kaneko, T., Karasawa, Y., Paadre, S., Nejadnik, B., Bates, D., Stonehouse, A. H., Richardson, R. M., Okonkwo, D. O. 2021

    Abstract

    OBJECTIVE: To determine if chronic motor deficits secondary to traumatic brain injury (TBI) can be improved by implantation of allogeneic modified bone marrow-derived mesenchymal stromal/stem cells (SB623).METHODS: This 6-month interim analysis of the 1-year double-blind, randomized, surgical sham-controlled, phase 2 STEMTRA trial (NCT02416492) evaluated safety and efficacy of the stereotactic intracranial implantation of SB623 in patients with stable chronic motor deficits secondary to TBI. Patients in this multi-center trial (N = 63) underwent randomization in a 1:1:1:1 ratio to 2.5 * 106, 5.0 * 106, 10 * 106 SB623 cells or control. Safety was assessed in patients who underwent surgery (N = 61), and efficacy in the modified intent-to-treat population of randomized patients who underwent surgery (N = 61; SB623 = 46, control = 15).RESULTS: The primary efficacy endpoint of significant improvement from baseline of Fugl-Meyer Motor Scale score at 6 months for SB623-treated patients was achieved. SB623-treated patients improved by (LS mean [SE]) +8.3 (1.4) vs +2.3 (2.5) for control at 6 months, the LS mean difference was 6.0 (95% CI: 0.3-11.8); p = 0.040. Secondary efficacy endpoints improved from baseline, but were not statistically significant vs control at 6 months. There were no dose-limiting toxicities or deaths, and 100% of SB623-treated patients experienced treatment-emergent adverse events vs 93.3% of control patients (p = 0.25).CONCLUSIONS: SB623 cell implantation appeared to be safe and well tolerated, and patients implanted with SB623 experienced significant improvement from baseline motor status at 6 months compared to controls.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that implantation of SB623 was well tolerated and associated with improvement in motor status.

    View details for DOI 10.1212/WNL.0000000000011450

    View details for PubMedID 33397772

  • Comparison of diffusion MRI and CLARITY fiber orientation estimates in both gray and white matter regions of human and primate brain. NeuroImage Leuze, C., Goubran, M., Barakovic, M., Aswendt, M., Tian, Q., Hsueh, B., Crow, A., Weber, E. M., Steinberg, G. K., Zeineh, M., Plowey, E. D., Daducci, A., Innocenti, G., Thiran, J., Deisseroth, K., McNab, J. A. 2020; 228: 117692

    Abstract

    Diffusion MRI (dMRI) represents one of the few methods for mapping brain fiber orientations non-invasively. Unfortunately, dMRI fiber mapping is an indirect method that relies on inference from measured diffusion patterns. Comparing dMRI results with other modalities is a way to improve the interpretation of dMRI data and help advance dMRI technologies. Here, we present methods for comparing dMRI fiber orientation estimates with optical imaging of fluorescently labeled neurofilaments and vasculature in 3D human and primate brain tissue cuboids cleared using CLARITY. The recent advancements in tissue clearing provide a new opportunity to histologically map fibers projecting in 3D, which represents a captivating complement to dMRI measurements. In this work, we demonstrate the capability to directly compare dMRI and CLARITY in the same human brain tissue and assess multiple approaches for extracting fiber orientation estimates from CLARITY data. We estimate the three-dimensional neuronal fiber and vasculature orientations from neurofilament and vasculature stained CLARITY images by calculating the tertiary eigenvector of structure tensors. We then extend CLARITY orientation estimates to an orientation distribution function (ODF) formalism by summing multiple sub-voxel structure tensor orientation estimates. In a sample containing part of the human thalamus, there is a mean angular difference of 19o±15o between the primary eigenvectors of the dMRI tensors and the tertiary eigenvectors from the CLARITY neurofilament stain. We also demonstrate evidence that vascular compartments do not affect the dMRI orientation estimates by showing an apparent lack of correspondence (mean angular difference=49o±23o) between the orientation of the dMRI tensors and the structure tensors in the vasculature stained CLARITY images. In a macaque brain dataset, we examine how the CLARITY feature extraction depends on the chosen feature extraction parameters. By varying the volume of tissue over which the structure tensor estimates are derived, we show that orientation estimates are noisier with more spurious ODF peaks for sub-voxels below 30m3 and that, for our data, the optimal gray matter sub-voxel size is between 62.5m3 and 125m3. The example experiments presented here represent an important advancement towards robust multi-modal MRI-CLARITY comparisons.

    View details for DOI 10.1016/j.neuroimage.2020.117692

    View details for PubMedID 33385546

  • Staged Surgical Resection of Brain Arteriovenous Malformations. World neurosurgery Sussman, E. S., Gummidipundi, S. E., Pendharkar, A. V., Church, E. W., Ho, A. L., Han, S. S., Steinberg, G. K. 2020

    Abstract

    BACKGROUND AND OBJECTIVE: Staged treatment of brain AVMs is sometimes necessary to minimize risks associated with sudden changes in cerebral hemodynamics. With the increasing availability and optimization of endovascular techniques, multiple surgical resections are rarely necessary, however due to specific anatomic circumstances, some AVMs still require staged surgery. Here, we describe the largest reported series of staged surgical resections of brain AVMs.METHODS: This is a retrospective review of surgically resected AVMs at a single institution from 1998-2018. Patients who underwent ?2 resections within one year were reviewed. Only those in whom initial resection was terminated with intention for further resection were included in analysis.RESULTS: Twenty patients underwent deliberately staged resection from 1998-2018. Average age at treatment was 36.2 years (SD=16.5). Eleven patients (55%) were female, and 12 (60%) had left-sided AVMs. Median Spetzler-Martin grade was 4 (IQR3-4). Average AVM nidus diameter was 5.0cm (SD=1.7). Seven patients (35%) presented with AVM rupture, and 12 (60%) presented with focal neurologic deficits without hemorrhage. Seventeen patients (85%) underwent pre-operative embolization, median number of embolizations was 3 (IQR2-4). Three patients (15%) underwent pre-operative radiosurgery. Median number of days between surgeries was 28 (IQR8-41). Peri-operative course was complicated by hemorrhage in three patients (15%); one required decompressive hemicraniectomy prior to the second stage of surgery. Good functional outcome (defined as mRS?2) was achieved in 14 patients (70%).CONCLUSIONS: Staged surgical resection of large and complex AVMs can be performed with good outcomes in carefully selected patients.

    View details for DOI 10.1016/j.wneu.2020.11.036

    View details for PubMedID 33212272

  • Efficacy and safety of embolization of dural arteriovenous fistulas via the ophthalmic artery. Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences Mayercik, V. A., Sussman, E. S., Pulli, B., Dodd, R. L., Do, H. M., Telischak, N. A., Marks, M. P., Steinberg, G. K., Chang, S. D., Heit, J. J. 2020: 1591019920969270

    Abstract

    INTRODUCTION: Dural arteriovenous fistulae (DAVF) are vascular lesions with arteriovenous shunting that may be treated with surgical obliteration or endovascular embolization. Some DAVF, such as anterior cranial fossa DAVF (AC-DAVF) derive their arterial supply from ophthalmic artery branches in nearly all cases, and trans-arterial embolization carries a risk of vision loss. We determined the efficacy and safety of trans-ophthalmic artery embolization of DAVF.MATERIALS AND METHODS: We performed a retrospective cohort study of all patients with DAVF treated by trans-ophthalmic artery embolization from 2012 to 2020. Primary outcome was angiographic cure of the DAVF. Secondary outcomes included vision loss, visual impairment, orbital cranial nerve injury, stroke, modified Rankin Scale at 90-days, and mortality.RESULTS: 12 patients met inclusion criteria (9 males; 3 females). 10 patients had AC-DAVF. Patient age was 59.7±9.5 (mean±SD) years. Patients presented with intracranial hemorrhage (4 patients), headache (4 patients), amaurosis fugax (1 patients), or were incidentally discovered (2 patients). DAVF Cognard grades were: II (1 patient), III (6 patients), and IV (5 patients). DAVF were embolized with Onyx (10 patients), nBCA glue (1 patient), and a combination of coils and Onyx (1 patient). DAVF cure was achieved in 11 patients (92%). No patients experienced vision loss, death, or permanent disability. One patient experienced a minor complication of blurry vision attributed to posterior ischemic optic neuropathy. 90-day mRS was 0 (10 patients) and 1 (2 patients).CONCLUSIONS: Trans-ophthalmic artery embolization is an effective and safe treatment for DAVF.

    View details for DOI 10.1177/1591019920969270

    View details for PubMedID 33106085

  • Predicting PET Cerebrovascular Reserve with Deep Learning by Using Baseline MRI: A Pilot Investigation of a Drug-Free Brain Stress Test. Radiology Chen, D. Y., Ishii, Y., Fan, A. P., Guo, J., Zhao, M. Y., Steinberg, G. K., Zaharchuk, G. 2020: 192793

    Abstract

    Background Cerebrovascular reserve (CVR) may be measured by using an acetazolamide test to clinically evaluate patients with cerebrovascular disease. However, acetazolamide use may be contraindicated and/or undesirable in certain clinical settings. Purpose To predict CVR images generated from acetazolamide vasodilation with a deep learning network by using only images before acetazolamide administration. Materials and Methods Simultaneous oxygen 15 (15O)-labeled water PET/MRI before and after acetazolamide injection were retrospectively analyzed for patients with Moyamoya disease and healthy control participants from April 2017 to May 2019. Inputs to deep learning models were perfusion-based images (arterial spin labeling [ASL]), structural scans (T2 fluid-attenuated inversion-recovery, T1), and brain location. Two models, that is, 15O-labeled water PET cerebral blood flow (CBF) and MRI (PET-plus-MRI model) before acetazolamide administration and only MRI (MRI-only model) before acetazolamide administration, were trained and tested with sixfold cross-validation. The models learned to predict a voxelwise relative CBF change (rDeltaCBF) map by using rDeltaCBF measured with PET due to acetazolamide as ground truth. Quantitative analysis included image quality metrics (peak signal-to-noise ratio, root mean square error, and structural similarity index), as well as comparison between the various methods by using correlation and Bland-Altman analyses. Identification of vascular territories with impaired rDeltaCBF was evaluated by using receiver operating characteristic metrics. Results Thirty-six participants were included: 24 patients with Moyamoya disease (mean age ± standard deviation, 41 years ± 12; 17 women) and 12 age-matched healthy control participants (mean age, 39 years ± 16; nine women). The rDeltaCBF maps predicted by both deep learning models demonstrated better image quality metrics than did ASL (all P < .001 in patients) and higher correlation coefficient with PET than with ASL (PET-plus-MRI model, 0.704; MRI-only model, 0.690 vs ASL, 0.432; both P < .001 in patients). Both models also achieved high diagnostic performance in identifying territories with impaired rDeltaCBF (area under receiver operating characteristic curve, 0.95 for PET-plus-MRI model [95% confidence interval: 0.90, 0.99] and 0.95 for MRI-only model [95% confidence interval: 0.91, 0.98]). Conclusion By using only images before acetazolamide administration, PET-plus-MRI and MRI-only deep learning models predicted cerebrovascular reserve images without the need for vasodilator injection. © RSNA, 2020 Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.2020192793

    View details for PubMedID 32662761

  • Optogenetic Stimulation Reduces Neuronal Nitric Oxide Synthase Expression After Stroke. Translational stroke research Pendharkar, A. V., Smerin, D., Gonzalez, L., Wang, E. H., Levy, S., Wang, S., Ishizaka, S., Ito, M., Uchino, H., Chiang, T., Cheng, M. Y., Steinberg, G. K. 2020

    Abstract

    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.

    View details for DOI 10.1007/s12975-020-00831-y

    View details for PubMedID 32661768

  • In Reply: Early Diffusion Magnetic Resonance Imaging Changes in Normal-Appearing Brain in Pediatric Moyamoya Disease. Neurosurgery Quon, J. L., Kim, L. H., MacEachern, S. J., Maleki, M., Steinberg, G. K., Madhugiri, V., Edwards, M. S., Grant, G. A., Yeom, K. W., Forkert, N. D. 2020

    View details for DOI 10.1093/neuros/nyaa265

    View details for PubMedID 32585687

  • Minimally invasive foramen magnum durectomy and obexostomy for treatment of craniocervical junction-related syringomyelia in adults: case series and midterm follow-up. Journal of neurosurgery. Spine Mandel, M., Ferreira da Silva, I. A., Paiva, W., Li, Y., Steinberg, G. K., Teixeira, M. J. 2020: 1?10

    Abstract

    OBJECTIVE: Craniocervical junction-related syringomyelia (CCJS) is the most common form of syringomyelia. Approximately 30% of patients treated with foramen magnum decompression (FMD) will show persistence, recurrence, or progression of the syrinx. The authors present a pilot study with a new minimally invasive surgery technique targeting the pathophysiology of CCJS in adult patients.METHODS: The authors retrospectively analyzed the clinical and radiological features of a consecutive series of patients treated for CCJS. An FMD and FM durectomy were performed through a 1.5- to 2-cm skin incision. Then arachnoid adhesions were cleared, creating a permanent communication from the fourth ventricle to the new paraspinal extradural cavity (obexostomy) and with the spinal subarachnoid space. The hypothesis was that the new CSF pouch acts like a pressure leak, interrupting the CCJS pathogenesis.RESULTS: Twenty-four patients (13 female, 21-61 years old) were treated between 2014 and 2018. The etiology of CCJS was Chiari malformation type I (CM-I) in 20 patients (83.3%), Chiari malformation type 0 (CM-0) in 2 patients (8.3%), and CCJ arachnoiditis in 2 patients (8.3%). Two patients underwent reoperations after failed FMD for CM-I at other institutions. No major surgical complication occurred. One patient had postoperative meningitis with no CSF fistula. On postoperative MRI, shrinkage of the syrinx was seen in all patients. No patients experienced recurrence of the CCJS. No patient required a subsequent operation. The mean duration of surgery was 72 ± 11 minutes (mean ± SD), and blood loss was 35-80 ml (mean 51 ml). Follow-up ranged from 12 to 58 months. The average overall improvement in modified Japanese Orthopaedic Association scores was 10% (p < 0.001). The Odom scale showed that 19 patients (79.1%) were satisfied, 4 (16.7%) remained the same, and 1 (4.2%) reported a poor outcome. All patients experienced postoperative improvement in perception of quality of life (p < 0.001).CONCLUSIONS: Minimally invasive FM durectomy and obexostomy is a safe and effective treatment for CCJS and for patients who have not responded to other treatment.

    View details for DOI 10.3171/2020.2.SPINE2032

    View details for PubMedID 32302978

  • Investigating the Pathogenesis of Moyamoya Disease Using Patient Derived Induced Pluripotent Stem Cells Rao, S., Zhang, Q., Uchino, H., Pendharkar, A., Cheng, M., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Arterial-spin labeling MRI identifies residual cerebral arteriovenous malformation following stereotactic radiosurgery treatment JOURNAL OF NEURORADIOLOGY Heit, J. J., Thakur, N. H., Iv, M., Fischbein, N. J., Wintermark, M., Dodd, R. L., Steinberg, G. K., Chang, S. D., Kapadia, K. B., Zaharchuk, G. 2020; 47 (1): 13?19
  • Validation and Application for the Berlin Grading System of Moyamoya Disease in Adult Patients NEUROSURGERY Teo, M., Furtado, S., Kaneko, O. F., Azad, T. D., Madhugiri, V., Do, H. M., Steinberg, G. K. 2020; 86 (2): 203?11
  • Automated Assessment of Behavioral Function After Experimental Stroke Chiang, T., Harvey, S., Pendharkar, A. V., Cheng, M. Y., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2020
  • Microsurgical Resection of an Orbital Arteriovenous Malformation With Intraoperative Digital Subtraction Angiography. Ophthalmic plastic and reconstructive surgery Rosenblatt, T. R., Myung, D. n., Fischbein, N. J., Steinberg, G. K., Kossler, A. L. 2020

    View details for DOI 10.1097/IOP.0000000000001815

    View details for PubMedID 32976328

  • Inflammatory Responses in the Secondary Thalamic Injury After Cortical Ischemic Stroke. Frontiers in neurology Cao, Z., Harvey, S. S., Bliss, T. M., Cheng, M. Y., Steinberg, G. K. 2020; 11: 236

    Abstract

    Stroke is one of the major causes of chronic disability worldwide and increasing efforts have focused on studying brain repair and recovery after stroke. Following stroke, the primary injury site can disrupt functional connections in nearby and remotely connected brain regions, resulting in the development of secondary injuries that may impede long-term functional recovery. In particular, secondary degenerative injury occurs in the connected ipsilesional thalamus following a cortical stroke. Although secondary thalamic injury was first described decades ago, the underlying mechanisms still remain unclear. We performed a systematic literature review using the NCBI PubMed database for studies that focused on the secondary thalamic degeneration after cortical ischemic stroke. In this review, we discussed emerging studies that characterized the pathological changes in the secondary degenerative thalamus after stroke; these included excitotoxicity, apoptosis, amyloid beta protein accumulation, blood-brain-barrier breakdown, and inflammatory responses. In particular, we highlighted key findings of the dynamic inflammatory responses in the secondary thalamic injury and discussed the involvement of several cell types in this process. We also discussed studies that investigated the effects of blocking secondary thalamic injury on inflammatory responses and stroke outcome. Targeting secondary injuries after stroke may alleviate network-wide deficits, and ultimately promote stroke recovery.

    View details for DOI 10.3389/fneur.2020.00236

    View details for PubMedID 32318016

  • Initial experience with the Scepter Mini dual-lumen balloon for transophthalmic artery embolization of anterior cranial fossa dural arteriovenous fistulae. Journal of neurointerventional surgery Pulli, B. n., Sussman, E. S., Mayercik, V. n., Steinberg, G. K., Do, H. M., Heit, J. J. 2020

    Abstract

    Precise delivery of liquid embolic agents (LEAs) remains a challenge in the endovascular treatment of dural arteriovenous fistulae (dAVFs) and cerebral arteriovenous malformations (cAVMs). Despite significant advances in the past decade, LEA reflux and catheter navigability remain shortcomings of current endovascular technology, particularly in small and tortuous arteries. The Scepter Mini dual-lumen balloon microcatheter aims to address these issues by decreasing the distal catheter profile (1.6 French) while allowing for a small (2.2 mm diameter) balloon at its tip.We report our initial experience with the Scepter Mini in two patients with anterior cranial fossa dAVFs that were treated with transophthalmic artery embolization.In both patients, the Scepter Mini catheter was able to be safely advanced into the distal ophthalmic artery close to the fistula site, and several centimeters past the origins of the central retinal and posterior ciliary arteries. A single Onyx injection without any reflux resulted in angiographic cure of the dAVF in both cases, and neither patient suffered any vision loss.These initial experiences suggest that the Scepter Mini represents a significant advance in the endovascular treatment of dAVFs and cAVMs and will allow for safer and more efficacious delivery of LEAs into smaller and more distal arteries while diminishing the risk of LEA reflux.

    View details for DOI 10.1136/neurintsurg-2020-016013

    View details for PubMedID 32434799

  • Contralateral Vasospasm in an Uncomplicated Elective Anterior Communicating Artery Aneurysm Clipping. World neurosurgery Knight, J. A., Bigder, M. G., Brigido, M. M., Li, Y. n., Steinberg, G. K. 2020

    Abstract

    Cerebral vasospasm (CVS) following clipping of an unruptured aneurysm is a rare phenomenon. When it does occur, CVS usually occurs on the side ipsilateral to the surgical intervention.Here, we report the case of a 68-year-old male who underwent right-sided pterional craniotomy for clipping of an unruptured, anterior communicating artery aneurysm and experienced contralateral vasospasm five days later.We further discuss the pathophysiology underlying vasospasm after uncomplicated craniotomy and non-hemorrhagic aneurysm clipping.

    View details for DOI 10.1016/j.wneu.2020.02.136

    View details for PubMedID 32145422

  • Simultaneous Phase-Contrast MRI and PET for Noninvasive Quantification of Cerebral Blood Flow and Reactivity in Healthy Subjects and Patients With Cerebrovascular Disease JOURNAL OF MAGNETIC RESONANCE IMAGING Ishii, Y., Thamm, T., Guo, J., Khalighi, M., Wardak, M., Holley, D., Gandhi, H., Park, J., Shen, B., Steinberg, G. K., Chin, F. T., Zaharchuk, G., Fan, A. 2020; 51 (1): 183?94

    View details for DOI 10.1002/jmri.26773

    View details for Web of Science ID 000530627200018

  • In Reply: Validation and Application for the Berlin Grading System of Moyamoya Disease in Adult Patients. Neurosurgery Teo, M. n., Steinberg, G. K. 2020

    View details for DOI 10.1093/neuros/nyaa137

    View details for PubMedID 32365181

  • Recurrence of cavernous malformations after surgery in childhood. Journal of neurosurgery. Pediatrics Prolo, L. M., Jin, M. C., Loven, T. n., Vogel, H. n., Edwards, M. S., Steinberg, G. K., Grant, G. A. 2020: 1?10

    Abstract

    Cavernous malformations (CMs) are commonly treated cerebrovascular anomalies in the pediatric population; however, the data on radiographic recurrence of pediatric CMs after surgery are limited. The authors aimed to study the clinical presentation, outcomes, and recurrence rate following surgery for a large cohort of CMs in children.Pediatric patients (? 18 years old) who had a CM resected at a single institution were identified and retrospectively reviewed. Fisher's exact test of independence was used to assess differences in categorical variables. Survival curves were evaluated using the Mantel-Cox method.Fifty-three patients aged 3 months to 18 years underwent resection of 74 symptomatic CMs between 1996 and 2018 at a single institution. The median length of follow-up was 5.65 years. Patients most commonly presented with seizures (45.3%, n = 24) and the majority of CMs were cortical (58.0%, n = 43). Acute radiographic hemorrhage was common at presentation (64.2%, n = 34). Forty-two percent (n = 22) of patients presented with multiple CMs, and they were more likely to develop de novo lesions (71%) compared to patients presenting with a single CM (3.4%). Both radiographic hemorrhage and multiple CMs were independently prognostic for a higher risk of the patient requiring subsequent surgery. Fifty percent (n = 6) of the 12 patients with both risk factors required additional surgery within 2.5 years of initial surgery compared to none of the patients with neither risk factor (n = 9).Patients with either acute radiographic hemorrhage or multiple CMs are at higher risk for subsequent surgery and require long-term MRI surveillance. In contrast, patients with a single CM are unlikely to require additional surgery and may require less frequent routine imaging.

    View details for DOI 10.3171/2020.2.PEDS19543

    View details for PubMedID 32357336

  • In Reply to the Letter to the Editor Regarding "Contralateral Vasospasm in an Uncomplicated Elective Anterior Communicating Artery Aneurysm Clipping". World neurosurgery Bigder, M. G., Steinberg, G. K. 2020; 142: 540

    View details for DOI 10.1016/j.wneu.2020.07.193

    View details for PubMedID 32987589

  • Contralateral acute vascular occlusion following revascularization surgery for moyamoya disease JOURNAL OF NEUROSURGERY Sussman, E. S., Madhugiri, V., Teo, M., Nielsen, T. H., Furtado, S., Pendharkar, A., Ho, A. L., Esparza, R., Azad, T. D., Zhang, M., Steinberg, G. K. 2019; 131 (6): 1702?8

    Abstract

    OBJECTIVERevascularization surgery is a safe and effective surgical treatment for symptomatic moyamoya disease (MMD) and has been shown to reduce the frequency of future ischemic events and improve quality of life in affected patients. The authors sought to investigate the occurrence of acute perioperative occlusion of the contralateral internal carotid artery (ICA) with contralateral stroke following revascularization surgery, a rare complication that has not been previously reported.METHODSThis study is a retrospective review of a prospective database of a single surgeon's series of revascularization operations in patients with MMD. From 1991 to 2016, 1446 bypasses were performed in 905 patients, 89.6% of which involved direct anastomosis of the superficial temporal artery (STA) to a distal branch of the middle cerebral artery (MCA). Demographic, surgical, and radiographic data were collected prospectively in all treated patients.RESULTSSymptomatic contralateral hemispheric infarcts occurred during the postoperative period in 34 cases (2.4%). Digital subtraction angiography (DSA) was performed in each of these patients. In 8 cases (0.6%), DSA during the immediate postoperative period revealed associated new occlusion of the contralateral ICA. In each of these cases, revascularization surgery involved direct anastomosis of the STA to an M4 branch of the MCA. Preoperative DSA revealed moderate (n = 1) or severe (n = 3) stenosis or occlusion (n = 4) of the ipsilateral ICA and mild (n = 2), moderate (n = 4), or severe (n = 2) stenosis of the contralateral ICA. The baseline Suzuki stage was 4 (n = 7) or 5 (n = 1). The collateral supply originated exclusively from the intracranial circulation in 4/8 patients (50%), and from both the intracranial and extracranial circulation in the remaining 50% of patients. Seven (88%) of 8 patients improved symptomatically during the acute postoperative period with induced hypertension. The modified Rankin Scale (mRS) score at discharge was worse than baseline in 7/8 patients (88%), whereas 1 patient had only minor deficits that did not affect the mRS score. At the 3-year follow-up, 3/8 patients (38%) were at their baseline mRS score or better, 1 patient had significant disability compared with preoperatively, 2 patients had died, and 1 patient was lost to follow-up. Three-year follow-up is not yet available in 1 patient.CONCLUSIONSAcute occlusion of the ICA on the contralateral side from an STA-MCA bypass is a rare, but potentially serious, complication of revascularization surgery for MMD. It highlights the importance of the hemodynamic interrelationships that exist between the two hemispheres, a concept that has been previously underappreciated. Induced hypertension during the acute period may provide adequate cerebral blood flow via developing collateral vessels, and good outcomes may be achieved with aggressive supportive management and expedited contralateral revascularization.

    View details for DOI 10.3171/2018.8.JNS18951

    View details for Web of Science ID 000500253800003

    View details for PubMedID 30554188

  • Seven-Year Experience with Laparoscopic Pedicled Omental Flap for Cerebral Revascularization in Patients with Moyamoya Disease Wood, L. Y., Jones, R. E., Chandler, J. M., Taylor, J., Dutta, S., Steinberg, G., Bruzoni, M. ELSEVIER SCIENCE INC. 2019: E126?E127
  • Arterial spin labeling underestimates cerebral blood flow in regions with fast arrival times: a simultaneous [O-15] PET/MRI study with acetazolamide challenge Ishii, Y., Thamn, T., Guo, J., Khalighi, M. M., Wardak, M., Park, J. H., Steinberg, G. K., Chin, F. T., Zaharchuk, G., Fan, A. P. SAGE PUBLICATIONS INC. 2019: 54?55
  • Immunopanning purification of primary human astrocytes and comparison with mouse astrocytes Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Edwards, M. S., Li, G., Duncan, J. A., Steinberg, G. K., Cheshier, S. H., Shuer, L. M., Chang, E. F., Grant, G. A., Gephart, M., Barres, B. A. WILEY. 2019: E86?E87
  • Early Diffusion Magnetic Resonance Imaging Changes in Normal-Appearing Brain in Pediatric Moyamoya Disease. Neurosurgery Quon, J. L., Kim, L. H., MacEachern, S. J., Maleki, M., Steinberg, G. K., Madhugiri, V., Edwards, M. S., Grant, G. A., Yeom, K. W., Forkert, N. D. 2019

    Abstract

    BACKGROUND: Moyamoya disease often leads to ischemic strokes visible on diffusion-weighted imaging (DWI) and T2-weighted magnetic resonance imaging (MRI) with subsequent cognitive impairment. In adults with moyamoya, apparent diffusion coefficient (ADC) is correlated with regions of steal phenomenon and executive dysfunction prior to white matter changes.OBJECTIVE: To investigate quantitative global diffusion changes in pediatric moyamoya patients prior to explicit structural ischemic damage.METHODS: We retrospectively reviewed children (<20 yr old) with moyamoya disease and syndrome who underwent bypass surgery at our institution. We identified 29 children with normal structural preoperative MRI and without findings of cortical infarction or chronic white matter ischemic changes. DWI datasets were used to calculate ADC maps for each subject as well as for 60 age-matched healthy controls. Using an atlas-based approach, the cerebral white matter, cerebral cortex, thalamus, caudate, putamen, pallidum, hippocampus, amygdala, nucleus accumbens, and brainstem were segmented in each DWI dataset and used to calculate regional volumes and ADC values.RESULTS: Multivariate analysis of covariance using the regional ADC and volume values as dependent variables and age and gender as covariates revealed a significant difference between the groups (P<.001). Post hoc analysis demonstrated significantly elevated ADC values for children with moyamoya in the cerebral cortex, white matter, caudate, putamen, and nucleus accumbens. No significant volume differences were found.CONCLUSION: Prior to having bypass surgery, and in the absence of imaging evidence of ischemic stroke, children with moyamoya exhibit cerebral diffusion changes. These findings could reflect microstructural changes stemming from exhaustion of cerebrovascular reserve.

    View details for DOI 10.1093/neuros/nyz230

    View details for PubMedID 31245817

  • Cerebrovascular events after surgery versus conservative therapy for moyamoya disease: a meta-analysis. Acta neurologica Belgica Wouters, A., Smets, I., Van den Noortgate, W., Steinberg, G. K., Lemmens, R. 2019

    Abstract

    The background of this article is to determine the effect of a neurosurgical intervention in patients with moyamoya disease (MMD) on the risk of cerebrovascular events. We included studies with at least ten MMD patients in either intervention or control group which investigated cerebrovascular events during a minimal follow-up period of 1 year after neurosurgical intervention vs. conservative therapy. The primary outcome was all strokes; secondary outcome events were mortality, hemorrhagic, and ischemic stroke. Effects were evaluated for three prespecified subpopulations: adult, ischemic, and hemorrhagic moyamoya patients. We performed random-effects meta-analyses on odds ratios (ORs). We included 2,484 patients from 10 studies. The rate of all stroke was 14.1% in surgical treated compared to 30.0% in non-surgical-treated patients [pooled OR 0.38, 95%; confidence interval (CI) 0.23-0.64]. In subgroup analyses, we identified an association between surgery and all stroke in patients presenting with hemorrhagic, but not in patients with ischemic MMD. Hemorrhagic stroke during follow-up was less frequent in patients who underwent a surgical intervention, 4.6% compared to 18.6% of the conservatively treated patients (pooled OR 0.27, 95% CI 0.14-0.53). In addition, we observed a difference in mortality, 0.6% vs. 2.9% (pooled OR 0.32, 95% CI 0.13-0.77), but did not identify an association between surgical treatment and ischemic stroke (pooled OR 0.71, 95% CI 0.46-1.09). Surgical intervention in MMD is associated with a decreased risk of stroke most striking in patients presenting with hemorrhagic MMD. The relationship was present between surgical treatment and the outcome of hemorrhagic, but not ischemic stroke.

    View details for DOI 10.1007/s13760-019-01165-9

    View details for PubMedID 31215004

  • Stability of Blood Biomarkers of Traumatic Brain Injury JOURNAL OF NEUROTRAUMA Rezaii, P., Grant, G., Zeineh, M., Richardson, K., Coburn, M., Bet, A., Weber, A., Jiang, B., Li, Y., Ubungen, K., Routh, G., Wheatcroft, A., Paulino, A., Hayes, R., Steinberg, G., Wintermark, M. 2019: 1?10
  • STAIR X. Stroke Demchuk, A. M., Albers, G. W., Nogueira, R. G., STAIR X Consortium *, STAIR X (Stroke Treatment Academic Industry Roundtable) writing contributors, Alexandrov, A. V., Arbe-Barnes, S., Baron, J., Boltze, J., Broderick, J. P., Broschat, K., Campbell, B. C., Derdeyn, C. P., Elkind, M. S., Emberson, J. R., En'Wezoh, D., Furlan, A. J., Gorelick, P. B., Hancock, A. M., Hill, M. D., Holt, B., Khatri, P., Kim, W., Kjos, D., Kleindorfer, D., Lansberg, M. G., Liberman, M., Liebeskind, D. S., Luby, M., Lyden, P., Lynch, J. K., Mocco, J., Palesch, Y. Y., Pereira, V. M., Sanossian, N., Savitz, S. I., Schwamm, L. H., Selim, M., Sheth, K. N., Simpkins, A. N., Singhal, A., Solberg, Y., Steinberg, G. K., Tymianski, M., Warach, S., Wechsler, L. R., Wright, C., Yoo, A. J., Zaidat, O. O. 2019: STROKEAHA119024337

    View details for DOI 10.1161/STROKEAHA.119.024337

    View details for PubMedID 31112484

  • Stability of Blood Biomarkers of Traumatic Brain Injury. Journal of neurotrauma Rezaii, P., Grant, G., Zeineh, M., Richardson, K. J., Coburn, M. L., Bet, A. M., Weber, A., Jiang, B., Li, Y., Ubungen, K., Routh, G., Wheatcroft, A. M., Paulino, A., Hayes, R. L., Steinberg, G. K., Wintermark, M. 2019

    Abstract

    Blood biomarker tests were recently approved for clinical diagnosis of traumatic brain injury (TBI), yet there are still fundamental questions which need attention. One such question is the stability of putative biomarkers in blood over the course of several days after injury if the sample is unable to be processed into serum or plasma and stored at low temperatures. Blood may not be able to be stored at ultra-low temperatures in austere combat or sports environments. In this prospective study of 20 adult patients with positive head computed tomography imaging findings, the stability of three biomarkers (glial fibrillary acidic protein [GFAP], ubiquitin C-terminal hydrolase-L1 [UCH-L1], and S100B) in whole blood and in serum stored at 4-5°C was evaluated over the course of 72 hours after blood collection. The amount of time whole blood and serum were refrigerated had no significant effect on GFAP concentration in plasma obtained from whole blood and in serum (p=0.6256 and p=0.3687, respectively), UCH-L1 concentration in plasma obtained from whole blood and in serum (p=0.0611 and p=0.5189, respectively), and S100B concentration in serum (p=0.4663). Concentration levels of GFAP, UCH-L1, and S100B in blood collected from patients with TBI were found to be stable at 4-5°C for at least 3 days after blood draw. This study suggests that the levels of the three diagnostic markers above are still valid for diagnostic TBI tests if the sample is stored in 4-5°C refrigerated conditions.

    View details for PubMedID 30968744

  • Meningeal Mast Cells as Key Effectors of Stroke Pathology FRONTIERS IN CELLULAR NEUROSCIENCE Arac, A., Grimbaldeston, M. A., Galli, S. J., Bliss, T. M., Steinberg, G. K. 2019; 13
  • Arterial spin-labeling cerebral perfusion changes after revascularization surgery in pediatric moyamoya disease and syndrome JOURNAL OF NEUROSURGERY-PEDIATRICS Quon, J. L., Kim, L. H., Lober, R. M., Maleki, M., Steinberg, G. K., Yeom, K. W. 2019; 23 (4): 486?92
  • Validation and Application for the Berlin Grading System of Moyamoya Disease in Adult Patients. Neurosurgery Teo, M., Furtado, S., Kaneko, O. F., Azad, T. D., Madhugiri, V., Do, H. M., Steinberg, G. K. 2019

    Abstract

    BACKGROUND: Traditional moyamoya disease (MMD) classification relies on morphological digital subtraction angiography (DSA) assessment, which do not reflect hemodynamic status, clinical symptoms, or surgical treatment outcome.OBJECTIVE: To (1) validate the new Berlin MMD preoperative symptomatology grading system and (2) determine the clinical application of the grading system in predicting radiological and clinical outcomes after surgical revascularization.METHODS: Ninety-six MMD patients (192 hemispheres) with all 3 investigations (DSA, magnetic resonance imaging [MRI], Xenon-CT) performed preoperatively at our institution (2007-2013) were included. Two clinicians independently graded the imaging findings according to the proposed criteria. Patients' modified Rankin Score (mRS) scores (preoperative, postoperative, last follow-up), postoperative infarct (radiological, clinical) were collected and statistical correlations performed.RESULTS: One hundred fifty-seven direct superficial temporal artery-middle cerebral artery bypasses were performed on 96 patients (66 female, mean age 41 yr, mean follow-up 4.3 yr). DSA, MRI, and cerebrovascular reserve capacity were independent factors associated hemispheric symptomatology (when analyzed individually or in the combined grading system). Mild (grade I), moderate (grade II), severe (grade III) were graded in 45, 71, and 76 hemispheres respectively; of which, clinical symptoms were found in 33% of grade I, 92% of grade II, 100% of grade III hemispheres (P<.0001). Two percent of grade I, 11% of grade II, 20% of grade III hemispheres showed postoperative radiological diffusion weighted image-positive ischemic changes or hemorrhage on MRI (P=.018). Clinical postoperative stroke was observed in 1.4% of grade II, 6.6% of grade III hemispheres (P=.077). The grading system also correlated well to dichotomized mRS postoperative outcome.CONCLUSION: The Berlin MMD grading system is able to stratify preoperative hemispheric symptomatology. Furthermore, it correlated with postoperative new ischemic changes on MRI, and showed a strong trend in predicting clinical postoperative stroke.

    View details for PubMedID 30864668

  • Long-term follow up data on difficult to treat intracranial arteriovenous malformations treated with the CyberKnife JOURNAL OF CLINICAL NEUROSCIENCE Gupta, R., Moore, J. M., Amorin, A., Appelboom, G., Chaudhary, N., Iyer, A., Soltys, S. G., Gibbs, I. C., Steinberg, G. K., Chang, S. D. 2019; 61: 120?23
  • Pathogenesis of aneurysms on major vessels in moyamoya disease and management outcome JOURNAL OF CLINICAL NEUROSCIENCE Furtado, S. V., Medress, Z. A., Teo, M., Steinberg, G. K. 2019; 61: 219?24
  • Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [O-15]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database STROKE Fan, A. P., Khalighi, M. M., Guo, J., Ishii, Y., Rosenberg, J., Wardak, M., Park, J., Shen, B., Holley, D., Gandhi, H., Haywood, T., Singh, P., Steinberg, G. K., Chin, F. T., Zaharchuk, G. 2019; 50 (2): 373?80
  • Grafted Human Neural Stem Cell-Secreted Matrilin-2 Improves Functional Recovery in Ischemic-Stroke Rats Azevedo-Pereira, R. L., Vu, J., Du, F., Bliss, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Optogenetic Stimulation of Excitatory Motor Cortex Neurons Promotes Functional Recovery After Stroke Pendharkar, A., Harvey, S. S., Chiang, T., Cheng, M. Y., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Cellular and Molecular Characterization of Microglia in Secondary Thalamic Injury After Ischemic Stroke Cao Zhijuan, Harvey, S., Chiang, T., Foltz, A., Cheng, M., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • Post-Ischemic Cortical Excitability and Gene Expression are Modulated by Transplanted Human Neural Stem Cells Azevedo-Pereira, R. L., Weerakkody, T., Vu, J., Du, F., Liang Xibin, Huguenard, J., Bliss, T. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2019
  • A Review of Magnetic Particle Imaging and Perspectives on Neuroimaging AMERICAN JOURNAL OF NEURORADIOLOGY Wu, L. C., Zhang, Y., Steinberg, G., Qu, H., Huang, S., Cheng, M., Bliss, T., Du, F., Rao, J., Song, G., Pisani, L., Doyle, T., Conolly, S., Krishnan, K., Grant, G., Wintermark, M. 2019; 40 (2): 206?12

    View details for DOI 10.3174/ajnr.A5896

    View details for Web of Science ID 000458569700006

  • A Review of Magnetic Particle Imaging and Perspectives on Neuroimaging. AJNR. American journal of neuroradiology Wu, L. C., Zhang, Y., Steinberg, G., Qu, H., Huang, S., Cheng, M., Bliss, T., Du, F., Rao, J., Song, G., Pisani, L., Doyle, T., Conolly, S., Krishnan, K., Grant, G., Wintermark, M. 2019

    Abstract

    Magnetic particle imaging is an emerging tomographic technique with the potential for simultaneous high-resolution, high-sensitivity, and real-time imaging. Magnetic particle imaging is based on the unique behavior of superparamagnetic iron oxide nanoparticles modeled by the Langevin theory, with the ability to track and quantify nanoparticle concentrations without tissue background noise. It is a promising new imaging technique for multiple applications, including vascular and perfusion imaging, oncology imaging, cell tracking, inflammation imaging, and trauma imaging. In particular, many neuroimaging applications may be enabled and enhanced with magnetic particle imaging. In this review, we will provide an overview of magnetic particle imaging principles and implementation, current applications, promising neuroimaging applications, and practical considerations.

    View details for PubMedID 30655254

  • Identifying Hypoperfusion in Moyamoya Disease With Arterial Spin Labeling and an [15O]-Water Positron Emission Tomography/Magnetic Resonance Imaging Normative Database. Stroke Fan, A. P., Khalighi, M. M., Guo, J., Ishii, Y., Rosenberg, J., Wardak, M., Park, J. H., Shen, B., Holley, D., Gandhi, H., Haywood, T., Singh, P., Steinberg, G. K., Chin, F. T., Zaharchuk, G. 2019: STROKEAHA118023426

    Abstract

    Background and Purpose- Noninvasive imaging of brain perfusion has the potential to elucidate pathophysiological mechanisms underlying Moyamoya disease and enable clinical imaging of cerebral blood flow (CBF) to select revascularization therapies for patients. We used hybrid positron emission tomography (PET)/magnetic resonance imaging (MRI) technology to characterize the distribution of hypoperfusion in Moyamoya disease and its relationship to vessel stenosis severity, through comparisons with a normative perfusion database of healthy controls. Methods- To image CBF, we acquired [15O]-water PET as a reference and simultaneously acquired arterial spin labeling (ASL) MRI scans in 20 Moyamoya patients and 15 age-matched, healthy controls on a PET/MRI scanner. The ASL MRI scans included a standard single-delay ASL scan with postlabel delay of 2.0 s and a multidelay scan with 5 postlabel delays (0.7-3.0s) to estimate and account for arterial transit time in CBF quantification. The percent volume of hypoperfusion in patients (determined as the fifth percentile of CBF values in the healthy control database) was the outcome measure in a logistic regression model that included stenosis grade and location. Results- Logistic regression showed that anterior ( P<0.0001) and middle cerebral artery territory regions ( P=0.003) in Moyamoya patients were susceptible to hypoperfusion, whereas posterior regions were not. Cortical regions supplied by arteries with stenosis on MR angiography showed more hypoperfusion than normal arteries ( P=0.001), but the extent of hypoperfusion was not different between mild-moderate versus severe stenosis. Multidelay ASL did not perform differently from [15O]-water PET in detecting perfusion abnormalities, but standard ASL overestimated the extent of hypoperfusion in patients ( P=0.003). Conclusions- This simultaneous PET/MRI study supports the use of multidelay ASL MRI in clinical evaluation of Moyamoya disease in settings where nuclear medicine imaging is not available and application of a normative perfusion database to automatically identify abnormal CBF in patients.

    View details for PubMedID 30636572

  • Multimodal image registration and connectivity analysis for integration of connectomic data from microscopy to MRI. Nature communications Goubran, M. n., Leuze, C. n., Hsueh, B. n., Aswendt, M. n., Ye, L. n., Tian, Q. n., Cheng, M. Y., Crow, A. n., Steinberg, G. K., McNab, J. A., Deisseroth, K. n., Zeineh, M. n. 2019; 10 (1): 5504

    Abstract

    3D histology, slice-based connectivity atlases, and diffusion MRI are common techniques to map brain wiring. While there are many modality-specific tools to process these data, there is a lack of integration across modalities. We develop an automated resource that combines histologically cleared volumes with connectivity atlases and MRI, enabling the analysis of histological features across multiple fiber tracts and networks, and their correlation with in-vivo biomarkers. We apply our pipeline in a murine stroke model, demonstrating not only strong correspondence between MRI abnormalities and CLARITY-tissue staining, but also uncovering acute cellular effects in areas connected to the ischemic core. We provide improved maps of connectivity by quantifying projection terminals from CLARITY viral injections, and integrate diffusion MRI with CLARITY viral tracing to compare connectivity maps across scales. Finally, we demonstrate tract-level histological changes of stroke through this multimodal integration. This resource can propel investigations of network alterations underlying neurological disorders.

    View details for DOI 10.1038/s41467-019-13374-0

    View details for PubMedID 31796741

  • Spatial Gradient Based Segmentation of Vessels and Quantitative Measurement of the Inner Diameter and Wall Thickness from ICG Fluorescence Angiographies Naber, A., Berwanger, D., Steinberg, G. K., Nahm, W., MahadevanJansen, A. SPIE-INT SOC OPTICAL ENGINEERING. 2019

    View details for DOI 10.1117/12.2542521

    View details for Web of Science ID 000565688100010

  • Milestones in stereotactic radiosurgery for the central nervous system JOURNAL OF CLINICAL NEUROSCIENCE Mitrasinovic, S., Zhang, M., Appelboom, G., Sussman, E., Moore, J. M., Hancock, S. L., Adler, J. R., Kondziolka, D., Steinberg, G. K., Chang, S. D. 2019; 59: 12?19
  • Pregnancy after direct cerebral bypass for moyamoya disease. Journal of neurosurgery Church, E. W., Qaiser, R. n., Bell-Stephens, T. E., Bigder, M. G., Chow, E. K., Han, S. S., El-Sayed, Y. Y., Steinberg, G. K. 2019: 1?7

    Abstract

    Moyamoya disease (MMD) disproportionately affects young to middle-aged women. The main treatment for this challenging disease is cerebral bypass surgery. Vascular neurosurgeons often need to counsel women regarding pregnancy following bypass for MMD, but there is a paucity of data. The authors set out to examine neurological and obstetric outcomes in an extensive cohort of MMD patients who had pregnancies following cerebral revascularization at the Stanford Medical Center.The authors identified all patients at their institution who underwent cerebral bypass for MMD from 1990 through 2018 and who later became pregnant. Some of these patients also had pregnancies prior to undergoing bypass surgery, and the authors examined these pregnancies as well. They performed a chart review and brief telephone survey to identify obstetric complications, transient ischemic attacks (TIAs), and strokes. Neurological and obstetric outcomes were compared to published rates. They also compared pre- and post-bypass pregnancy complication rates using logistic regression techniques.There were 71 pregnancies among 56 women whose mean age was 30.5 years. Among 59 post-bypass pregnancies, there were 5 (8%) perinatal TIAs. There were no MRI-confirmed strokes or strokes with residual deficits. Among 12 pre-bypass pregnancies, there were 3 (25%) TIAs and 2 (17%) MRI-confirmed strokes. There were no hemorrhagic complications in either group. In the generalized estimating equations analysis, performing cerebral revascularization prior to pregnancy versus after pregnancy was associated with lower odds of perinatal stroke or TIA (OR 0.15, p = 0.0061). Nine pregnancies (13%) were complicated by preeclampsia, and there was one (1%) instance of eclampsia. The overall rate of cesarean delivery was 39%. There were 2 miscarriages, both occurring in the first trimester. There were no maternal deaths.The authors present neurological and obstetric outcomes data in a large cohort of MMD patients. These data indicate that post-bypass pregnancy is accompanied by low complication rates. There were no ischemic or hemorrhagic strokes among post-bypass pregnant MMD patients. The rate of obstetric complications was low overall. The authors recommend close collaboration between the vascular neurosurgeon and the obstetrician regarding medical management, including blood pressure goals and continuation of low-dose aspirin.

    View details for DOI 10.3171/2019.8.JNS191372

    View details for PubMedID 31731267

  • Milestones in stereotactic radiosurgery for the central nervous system. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Mitrasinovic, S., Zhang, M., Appelboom, G., Sussman, E., Moore, J. M., Hancock, S. L., Adler, J. R., Kondziolka, D., Steinberg, G. K., Chang, S. D. 2019; 59: 12?19

    Abstract

    INTRODUCTION: Since Lars Leksell developed the first stereotactic radiosurgery (SRS) device in 1951, there has been growth in the technologies available and clinical indications for SRS. This expansion has been reflected in the medical literature, which is built upon key articles and institutions that have significantly impacted SRS applications. Our aim was to identify these prominent works and provide an educational tool for training and further inquiry.METHOD: A list of search phrases relating to central nervous system applications of stereotactic radiosurgery was compiled. A topic search was performed using PubMed and Scopus databases. The journal, year of publication, authors, treatment technology, clinical subject, study design and level of evidence for each article were documented. Influence was proposed by citation count and rate.RESULTS: Our search identified a total of 10,211 articles with the top 10 publications overall on the study of SRS spanning 443-1313 total citations. Four articles reported on randomized controlled trials, all of which evaluated intracranial metastases. The most prominent subtopics included SRS for arteriovenous malformation, glioblastoma, and acoustic neuroma. Greatest representation by treatment modality included Gamma Knife, LINAC, and TomoTherapy.CONCLUSIONS: This systematic reporting of the influential literature on SRS for intracranial and spinal pathologies underscores the technology's rapid and wide reaching clinical applications. Moreover the findings provide an academic guide to future health practitioners and engineers in their study of SRS for neurosurgery.

    View details for PubMedID 30595165

  • Arterial-Spin Labeling MRI Identifies Residual Cerebral Arteriovenous Malformation Following Stereotactic Radiosurgery Treatment. Journal of neuroradiology. Journal de neuroradiologie Heit, J. J., Thakur, N. H., Iv, M. n., Fischbein, N. J., Wintermark, M. n., Dodd, R. L., Steinberg, G. K., Chang, S. D., Kapadia, K. B., Zaharchuk, G. n. 2019

    Abstract

    Brain arteriovenous malformation (AVM) treatment by stereotactic radiosurgery (SRS) is effective, but AVM obliteration following SRS may take two years or longer. MRI with arterial spin labeling (ASL) may detect brain AVMs with high sensitivity. We determined whether brain MRI with ASL may accurately detect residual AVM following SRS treatment.We performed a retrospective cohort study of patients who underwent brain AVM evaluation by DSA between June 2010 and June 2015. Inclusion criteria were: (1) AVM treatment by SRS, (2) follow?-?up MRI with ASL at least 30 months after SRS, (3) DSA within 3 months of the follow-up MRI with ASL, and (4) no intervening AVM treatment between the MRI and DSA. Four neuroradiologists blindly and independently reviewed follow-up MRIs. Primary outcome measure was residual AVM indicated by abnormal venous ASL signal.15 patients (12 females, mean age 29 years) met inclusion criteria. There were three posterior fossa AVMs and 12 supratentorial AVMs. Spetzler-Martin (SM) Grades were: SM1 (8%), SM2 (33%), SM3 (17%), SM4 (25%), and SM5 (17%). DSA demonstrated residual AVM in 10 patients. The pooled sensitivity, specificity, positive predictive value, and negative predictive value of venous ASL signal for predicting residual AVM were 100% (95% CI: 0.9-1.0), 95% (95% CI: 0.7-1.0), 98% (95% CI: 0.9-1.0), and 100% (95% CI: 0.8-1.0), respectively. High inter-reader agreement as found by Fleiss' Kappa analysis (k?=?0.92; 95% CI: 0.8-1.0; p?

    View details for PubMedID 30658138

  • Arterial spin-labeling cerebral perfusion changes after revascularization surgery in pediatric moyamoya disease and syndrome. Journal of neurosurgery. Pediatrics Quon, J. L., Kim, L. H., Lober, R. M., Maleki, M. n., Steinberg, G. K., Yeom, K. W. 2019: 1?7

    Abstract

    OBJECTIVEMoyamoya disease is a dynamic cerebrovascular condition that often requires vascular surveillance. Arterial spin labeling (ASL) is an MR perfusion method that is increasingly used for stroke and other various neurovascular pathologies. Unlike perfusion-weighted MRI, ASL uses endogenous water molecules for signal and therefore obviates gadolinium use; and provides direct, not relative, quantitative cerebral blood flow (CBF) measures. Presently, the potential role of ASL for evaluating postoperative pediatric moyamoya patients is relatively unexplored. This study investigated the role for ASL in evaluating cerebral hemodynamic changes in children who underwent revascularization surgery.METHODSThis retrospective study examined 15 consecutive pediatric patients with moyamoya disease (n = 7) or moyamoya syndrome (n = 8) presenting between 2010 and 2014 who underwent revascularization and in whom 3T ASL was performed pre- and postoperatively. Postoperative MRI at least 3 months after revascularization procedure was used for analysis. Quantitative CBF in various vascular territories was interrogated: anterior, middle, and posterior cerebral arteries, and basal ganglia supplied by the lenticulostriate collaterals, resulting in evaluation of 20 brain regions.RESULTSAfter revascularization, CBF in the high middle cerebral artery territory significantly increased (p = 0.0059), accompanied by a decrease in CBF to the ipsilateral lenticulostriate-supplied basal ganglia (p = 0.0053). No perfusion changes occurred in the remaining cerebral vascular territories after surgery.CONCLUSIONSASL-based quantitative CBF showed improved cerebral perfusion to the middle cerebral artery territory after revascularization in children with both moyamoya syndrome and disease. Reduced perfusion to the basal ganglia might reflect pruning of the lenticulostriate collaterals, potentially from effects of revascularization. ASL can quantitatively evaluate hemodynamic changes in children with moyamoya after revascularization, and it may be a useful adjunct to routine clinical MRI surveillance.

    View details for PubMedID 30738390

  • Consensus Paper: Experimental Neurostimulation of the Cerebellum. Cerebellum (London, England) Miterko, L. N., Baker, K. B., Beckinghausen, J. n., Bradnam, L. V., Cheng, M. Y., Cooperrider, J. n., DeLong, M. R., Gornati, S. V., Hallett, M. n., Heck, D. H., Hoebeek, F. E., Kouzani, A. Z., Kuo, S. H., Louis, E. D., Machado, A. n., Manto, M. n., McCambridge, A. B., Nitsche, M. A., Taib, N. O., Popa, T. n., Tanaka, M. n., Timmann, D. n., Steinberg, G. K., Wang, E. H., Wichmann, T. n., Xie, T. n., Sillitoe, R. V. 2019

    Abstract

    The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

    View details for DOI 10.1007/s12311-019-01041-5

    View details for PubMedID 31165428

  • Utility of a Quantitative Approach Using Diffusion Tensor Imaging for Prognostication Regarding Motor and Functional Outcomes in Patients With Surgically Resected Deep Intracranial Cavernous Malformations. Neurosurgery Abhinav, K. n., Nielsen, T. H., Singh, R. n., Weng, Y. n., Han, S. S., Iv, M. n., Steinberg, G. K. 2019

    Abstract

    Resection of deep intracranial cavernous malformations (CMs) is associated with a higher risk of neurological deterioration and uncertainty regarding clinical outcomes.To examine diffusion tractography imaging (DTI) data evaluating the corticospinal tract (CST) in relation to motor and functional outcomes in patients with surgically resected deep CMs.Perilesional CST was characterized as disrupted, displaced, or normal. Mean fractional anisotropy (FA) values were obtained for whole ipsilateral CST and in 3 regions: subcortical (proximal), perilesional, and distally. Mean FA values in anatomically equivalent regions in the contralateral CST were obtained. Clinical and radiological data were collected independently. Multivariable regression analysis was used for statistical analysis.A total of 18 patients [brainstem (15) and thalamus/basal ganglia (3); median follow-up: 270 d] were identified over 2 yr. The CST was identified preoperatively as disrupted (6), displaced (8), and normal (4). Five of 6 patients with disruption had weakness. Higher preoperative mean FA values for distal ipsilateral CST segment were associated with better preoperative lower (P < .001), upper limb (P = .004), postoperative lower (P = .005), and upper limb (P < .001) motor examination. Preoperative mean FA values for distal ipsilateral CST segment (P = .001) and contralateral perilesional CST segment (P < .001) were negatively associated with postoperative modified Rankin scale scores.Lower preoperative mean FA values for overall and defined CST segments corresponded to worse patient pre- and postoperative motor examination and/or functional status. FA value for the distal ipsilateral CST segment has prognostic potential with respect to clinical outcomes.

    View details for DOI 10.1093/neuros/nyz259

    View details for PubMedID 31360998

  • Simultaneous phase-contrast MRI and PET for noninvasive quantification of cerebral blood flow and reactivity in healthy subjects and patients with cerebrovascular disease. Journal of magnetic resonance imaging : JMRI Ishii, Y. n., Thamm, T. n., Guo, J. n., Khalighi, M. M., Wardak, M. n., Holley, D. n., Gandhi, H. n., Park, J. H., Shen, B. n., Steinberg, G. K., Chin, F. T., Zaharchuk, G. n., Fan, A. P. 2019

    Abstract

    H215 O-positron emission tomography (PET) is considered the reference standard for absolute cerebral blood flow (CBF). However, this technique requires an arterial input function measured through continuous sampling of arterial blood, which is invasive and has limitations with tracer delay and dispersion.To demonstrate a new noninvasive method to quantify absolute CBF with a PET/MRI hybrid scanner. This blood-free approach, called PC-PET, takes the spatial CBF distribution from a static H215 O-PET scan, and scales it to the whole-brain average CBF value measured by simultaneous phase-contrast MRI.Observational.Twelve healthy controls (HC) and 13 patients with Moyamoya disease (MM) as a model of chronic ischemic disease.3T/2D cardiac-gated phase-contrast MRI and H215 O-PET.PC-PET CBF values from whole brain (WB), gray matter (GM), and white matter (WM) in HCs were compared with literature values since 2000. CBF and cerebrovascular reactivity (CVR), which is defined as the percent CBF change between baseline and post-acetazolamide (vasodilator) scans, were measured by PC-PET in MM patients and HCs within cortical regions corresponding to major vascular territories. Statistical Tests: Linear, mixed effects models were created to compare CBF and CVR, respectively, between patients and controls, and between different degrees of stenosis.The mean CBF values in WB, GM, and WM in HC were 42 ± 7 ml/100 g/min, 50 ± 7 ml/100 g/min, and 23 ± 3 ml/100 g/min, respectively, which agree well with literature values. Compared with normal regions (57 ± 23%), patients showed significantly decreased CVR in areas with mild/moderate stenosis (47 ± 17%, P = 0.011) and in severe/occluded areas (40 ± 16%, P = 0.016). Data Conclusion: PC-PET identifies differences in cerebrovascular reactivity between healthy controls and cerebrovascular patients. PC-PET is suitable for CBF measurement when arterial blood sampling is not accessible, and warrants comparison to fully quantitative H215 O-PET in future studies.3 Technical Efficacy Stage: 2 J. Magn. Reson. Imaging 2019.

    View details for PubMedID 31044459

  • Meningeal Mast Cells as Key Effectors of Stroke Pathology. Frontiers in cellular neuroscience Arac, A. n., Grimbaldeston, M. A., Galli, S. J., Bliss, T. M., Steinberg, G. K. 2019; 13: 126

    Abstract

    Stroke is the leading cause of adult disability in the United States. Because post-stroke inflammation is a critical determinant of damage and recovery after stroke, understanding the interplay between the immune system and the brain after stroke holds much promise for therapeutic intervention. An understudied, but important aspect of this interplay is the role of meninges that surround the brain. All blood vessels travel through the meningeal space before entering the brain parenchyma, making the meninges ideally located to act as an immune gatekeeper for the underlying parenchyma. Emerging evidence suggests that the actions of immune cells resident in the meninges are essential for executing this gatekeeper function. Mast cells (MCs), best known as proinflammatory effector cells, are one of the long-term resident immune cells in the meninges. Here, we discuss recent findings in the literature regarding the role of MCs located in the meningeal space and stroke pathology. We review the latest advances in mouse models to investigate the roles of MCs and MC-derived products in vivo, and the importance of using these mouse models. We examine the concept of the meninges playing a critical role in brain and immune interactions, reevaluate the perspectives on the key effectors of stroke pathology, and discuss the opportunities and challenges for therapeutic development.

    View details for PubMedID 31001088

  • Long-term follow up data on difficult to treat intracranial arteriovenous malformations treated with the CyberKnife. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Gupta, R., Moore, J. M., Amorin, A., Appelboom, G., Chaudhary, N., Iyer, A., Steinberg, G. K., Chang, S. D., Soltys, S., Gibbs, I. 2018

    Abstract

    INTRODUCTION: The CyberKnife, a frameless, robotic, stereotactic device, has been developed to radiosurgically treat arteriovenous malformations (AVMs). While most AVMs are obliterated within two-to-three years, a subset remain recalcitrant; long-term data on these difficult to treat AVMs are limited in the neurosurgical literature.MATERIALS AND METHODS: A retrospective analysis of all patients who underwent CyberKnife treatment for intracranial AVMs at a single U.S. institution between 2002 and 2012, whose AVMs had failed to obliterate within 48?months or longer from the treatment start date, were eligible for inclusion.RESULTS: Eleven patients (9 AVMs; 7 males, 2 females) were followed for an average of 85.2?months (range 56.2-119.4). The median lesion size was 3.5?cm (range: 2.8-8.0?cm) and median Spetzler-Martin grade was 3 (range: 2-5). All AVMs were treated with one radiation dose (median prescribed dose was 18.0?Gy; median Dmax: 23.7?Gy). Six (66.7%) were obliterated in a median time of 84?months (range: 52-94?months), while 3 (33.3%) remained active after a median of 90.8?months (range 69.7-119.4). Transient, post-radiosurgery adverse radiation effects occurred in 5 (55.6%) cases. One (11.1%) patient had an acute hemorrhage from the AVM after radiosurgery. Four (44.4%) patients underwent repeat radiosurgery and/or embolization. Three of these lesions eventually obliterated, while 1 did not.CONCLUSION: The median time to obliteration was 84?months. Two-thirds of AVMs which persisted for over 4?years following initial radiosurgery treatment eventually obliterated. Transient post-radiosurgery adverse effects were common; delayed hemorrhages were rare in our case series.

    View details for PubMedID 30587419

  • Long-Term Effectiveness of Gross-Total Resection for Symptomatic Spinal Cord Cavernous Malformations NEUROSURGERY Azad, T. D., Veeravagu, A., Li, A., Zhang, M., Madhugiri, V., Steinberg, G. K. 2018; 83 (6): 1201?8
  • Pathogenesis of aneurysms on major vessels in moyamoya disease and management outcome. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Furtado, S. V., Medress, Z. A., Teo, M., Steinberg, G. K. 2018

    Abstract

    Patients with moyamoya disease develop intracranial aneurysms at a higher rate than the general population. The authors aimed to test the hypothesis for development of aneurysms on large arteries in such patients using quantitative vessel imaging. Twenty-six patients representing 3.7% of moyamoya disease patients in our database were retrospectively analyzed with respect to aneurysm characteristics, management modalities, and outcome. Quantitative arterial flow data in patients with and without aneurysms were obtained using noninvasive quantitative vessel imaging technology and microflow-probe in moyamoya. Kruskal-Wallis one-way analysis of variance was used for case-control comparison. Twelve aneurysms were managed surgically, seven using the endovascular route, and eight were observed on follow-up to the primary revascularization procedure. The mean modified Rankin score after aneurysm and disease management was 1.29 at follow-up. The mean quantitative blood flow (ml/min) in the posterior cerebral artery was 98.4 and 133.5 (p?=?0.04) in moyamoya disease patients with and without aneurysms. In moyamoya disease, aneurysm development can potentially occur in the anterior circulation due to robust blood flow across communicating arteries from the posterior circulation.

    View details for PubMedID 30389363

  • Blood Pressure Elevation and Risk of Moyamoya Syndrome in Patients With Trisomy 21 PEDIATRICS Santoro, J. D., Lee, S., Mlynash, M., Thuy Nguyen, Lazzareschi, D. V., Kraler, L. D., Mayne, E. W., Steinberg, G. K. 2018; 142 (4)
  • Blood Pressure Elevation and Risk of Moyamoya Syndrome in Patients With Trisomy 21. Pediatrics Santoro, J. D., Lee, S., Mlynash, M., Nguyen, T., Lazzareschi, D. V., Kraler, L. D., Mayne, E. W., Steinberg, G. K. 2018

    Abstract

    OBJECTIVES: Individuals with Down syndrome (DS) are at risk for the development of moyamoya syndrome (MMS); MMS is often recognized only after a resulting stroke has occurred. Our goal with this study was to determine if elevations in blood pressure (BP) precede acute presentation of MMS in individuals with DS.METHODS: A single-center, retrospective case-control study was performed. Thirty patients with MMS and DS and 116 patients with DS only were identified retrospectively. Three BP recordings were evaluated at set intervals (18-24 months, 12-18 months, and 6-12 months before diagnosis of MMS). These were then compared against control averages from patients with DS only. To assess changes over the time, we used general linear model repeated measures analysis of variance. To identify independent predictors of MMS and DS, we used a multivariable analysis using generalized estimating equations accounting for repeated measures of BP.RESULTS: BP in patients with MMS and DS rose significantly over the 24-month period preceding presentation (34th, 42nd, and 70th percentiles at the 18-24-month, 12-18-month, and 6-12-month periods, respectively). BPs in the patients with both MMS and DS were significantly higher than in the DS-only controls in the 6 to 12 (P < .001) and 12 to 18 months before presentation (P = .016). Higher Suzuki scores, bilateral disease, and posterior circulation involvement were also predictive of BP elevation before presentation.CONCLUSIONS: Elevations in BP may foreshadow presentation of MMS in individuals with DS. This simple, low-cost screening measure may lead to early identification of at-risk patients in the medical home and prevent irreversible neurologic injury.

    View details for PubMedID 30190347

  • RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke STROKE Ito, M., Aswendt, M., Lee, A. G., Ishizaka, S., Cao, Z., Wang, E. H., Levy, S. L., Smerin, D. L., McNab, J. A., Zeineh, M., Leuze, C., Goubran, M., Cheng, M. Y., Steinberg, G. K. 2018; 49 (9): 2191?99
  • Engineered stem cell mimics to enhance stroke recovery BIOMATERIALS George, P. M., Oh, B., Dewi, R., Hua, T., Cai, L., Levinson, A., Liang, X., Krajina, B. A., Bliss, T. M., Heilshorn, S. C., Steinberg, G. K. 2018; 178: 63?72
  • Embolization before stereotactic radiosurgery for the treatment of brain arteriovenous malformations JOURNAL OF NEUROSURGICAL SCIENCES Iyer, A., D'Souza, M., Steinberg, G. K. 2018; 62 (4): 514?18
  • Nurse Telephonic Triage Service for After-hour Patient Calls in Neurosurgery. Annals of surgery Escobedo-Wu, E. L., Dhebar, F., Harsh, G., Steinberg, G., Vyas, A., Katznelson, L., Ho, A. L., Pendharkar, A. V., Sussman, E. S., Rohatgi, N. 2018; 267 (4): e67?e68

    Abstract

    OBJECTIVE: The aim of this study was to report the utilization and experience of the nurse telephonic triage service for after-hour patient calls in Neurosurgery.BACKGROUND: It is challenging for patients to reach their clinicians after-hours in a timely manner. This may result in worse health outcomes for the patients, or inappropriate utilization of emergency rooms and urgent care facilities. Physicians continue to remain overwhelmed with frequent after-hours calls in addition to other clinical responsibilities while on-call.METHODS: In August 2015, our institution launched the Clinical Advice Service (CAS) to provide a patient-centric, nurse-run telephone triage service for after-hour calls from Neurosurgery patients. Clinical protocols were created for use by CAS staff by Neurosurgery clinicians.RESULTS: Between July 2016 and June 2017, CAS has accepted 1021 after-hours calls from Neurosurgery patients. A total of 71.4% of these calls were clinical, and the remaining nonclinical (directions, appointments, general information). CAS escalated 37.3% of the calls to the on-call Neurosurgery physician; 4.8% Neurosurgery patients were triaged to the emergency room by CAS.CONCLUSION: CAS has been able to provide well-coordinated care to Neurosurgery patients while reducing physician workload.

    View details for PubMedID 29064895

  • Nurse Telephonic Triage Service for After-hour Patient Calls in Neurosurgery ANNALS OF SURGERY Escobedo-Wu, E. G., Dhebar, F., Harsh, G., Steinberg, G., Vyas, A., Katznelson, L., Ho, A. L., Pendharkar, A., Sussman, E. S., Rohatgi, N. 2018; 267 (4): E67?E68
  • Embolization before stereotactic radiosurgery for the treatment of brain arteriovenous malformations. Journal of neurosurgical sciences Iyer, A., D'Souza, M., Steinberg, G. K. 2018

    Abstract

    INTRODUCTION: Embolization is commonly used for the treatment of brain arteriovenous malformations (AVM) prior to stereotactic radiosurgery (SRS). Due to mixed outcomes, however, its use remains controversial. This article is a review of recent studies assessing the efficacy of pre-radiosurgical embolization for brain AVMs.EVIDENCE ACQUISITION: Articles published between 1990 and 2017 on the subject of pre- radiosurgical AVM embolization were retrieved from PubMed.EVIDENCE SYNTHESIS: A literature review was performed on the selected studies to compare obliteration, hemorrhage, and complication rates from groups treated with embolization prior to radiosurgery to those treated without embolization.CONCLUSIONS: Overall, the studies reviewed demonstrate mixed results on the efficacy of pre-radiosurgical AVM embolization. For large, complex AVMs, embolization prior to radiosurgery may have a role in carefully selected patients performed by experienced practitioners.

    View details for PubMedID 29582980

  • The Utility of Collaterals as a Biomarker in Pediatric Unilateral Intracranial Arteriopathy PEDIATRIC NEUROLOGY Elbers, J., Armstrong, D., Benseler, S. M., Dlamini, N., Steinberg, G. K., Yeom, K. W. 2018; 78: 27?34

    Abstract

    Intracranial arteriopathies are frequent causes of pediatric stroke and important risk factors for stroke recurrence. Without tissue diagnosis, vascular imaging is relied upon to identify the underlying etiology and prognosis. We hypothesized that children with unilateral intracranial arteriopathy with lenticulostriate collaterals would demonstrate distinct vascular outcomes compared with children without collaterals.We retrospectively identified children with unilateral intracranial arteriopathy from two institutions. Two blinded raters from each institution reviewed magnetic resonance or digital subtraction angiography at baseline and ?12 months. Patients were grouped according to presence or absence of lenticulostriate collaterals. Clinical features and vascular imaging outcomes were compared using univariate analysis and multivariate logistic regression.Forty-four children were included: 22 males, median age 8.2 years (range two to 16.9 years), and further stratified into the collateral group (n = 20) and non-collateral group (n = 24), with median follow-up of 25.5 months and 23 months, respectively. Both groups demonstrated similar rates of progression on vascular imaging at ?12 months, 50% in the collateral group versus 37.5% in the non-collateral group (P > 0.05). The collateral group was associated with asymptomatic clinical presentation, normal brain MRI, border zone infarcts, and either vascular stabilization or new contralateral disease. The non-collateral group demonstrated either vascular improvement or discordant progression (combination of improved and progressive lesions). Using a multivariate model, collaterals continued to be an independent predictor of vascular outcome.This study suggests that lenticulostriate collaterals in children with unilateral intracranial arteriopathy may serve as a useful neuroimaging biomarker that helps to stratify patients with distinct clinical features and patterns of vascular evolution.

    View details for PubMedID 29174857

  • Brain Arteriovenous Malformations and Arteriovenous Fistulas Foreword BRAIN ARTERIOVENOUS MALFORMATIONS AND ARTERIOVENOUS FISTULAS Steinberg, G. K., Dumont, A., Lanzino, G., Sheehan, J. 2018: IX
  • Surgery of Basal Ganglia, Thalamic, and Brainstem Arteriovenous Malformations BRAIN ARTERIOVENOUS MALFORMATIONS AND ARTERIOVENOUS FISTULAS Madhugiri, V. S., Teo, M., Steinberg, G. K., Dumont, A., Lanzino, G., Sheehan, J. 2018: 143?53
  • RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke. Stroke Ito, M. n., Aswendt, M. n., Lee, A. G., Ishizaka, S. n., Cao, Z. n., Wang, E. H., Levy, S. L., Smerin, D. L., McNab, J. A., Zeineh, M. n., Leuze, C. n., Goubran, M. n., Cheng, M. Y., Steinberg, G. K. 2018; 49 (9): 2191?99

    Abstract

    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.

    View details for PubMedID 30354987

  • How Can We Reduce The Risks Of STA-MCA Bypasses? Teo, M., Abhinav, K., Bell-Stephens, T., Madhugiri, Sussman, E., Azad, T. D., Zhang, M., Steinberg, G. K., Kandasamy, R. EDITOGRAFICA S R L. 2018: 120?31
  • Reduced Intravoxel Incoherent Motion Microvascular Perfusion Predicts Delayed Cerebral Ischemia and Vasospasm After Aneurysm Rupture. Stroke Heit, J. J., Wintermark, M. n., Martin, B. W., Zhu, G. n., Marks, M. P., Zaharchuk, G. n., Dodd, R. L., Do, H. M., Steinberg, G. K., Lansberg, M. G., Albers, G. W., Federau, C. n. 2018

    Abstract

    Proximal artery vasospasm and delayed cerebral ischemia (DCI) after cerebral aneurysm rupture result in reduced cerebral perfusion and microperfusion and significant morbidity and mortality. Intravoxel incoherent motion (IVIM) magnetic resonance imaging extracts microvascular perfusion information from a multi-b value diffusion-weighted sequence. We determined whether decreased IVIM perfusion may identify patients with proximal artery vasospasm and DCI.We performed a pilot retrospective cohort study of patients with ruptured cerebral aneurysms. Consecutive patients who underwent a brain magnetic resonance imaging with IVIM after ruptured aneurysm treatment were included. Patient demographic, treatment, imaging, and outcome data were determined by electronic medical record review. Primary outcome was DCI development with proximal artery vasospasm that required endovascular treatment. Secondary outcomes included mortality and clinical outcomes at 6 months.Sixteen patients (11 females, 69%;P=0.9) were included. There were no differences in age, neurological status, or comorbidities between patients who subsequently underwent endovascular treatment of DCI (10 patients; DCI+ group) and those who did not (6 patients; DCI- group). Compared with DCI- patients, DCI+ patients had decreased IVIM perfusion fractionf(0.09±0.03 versus 0.13±0.01;P=0.03), reduced diffusion coefficientD(0.82±0.05 versus 0.92±0.07×10-3mm2/s;P=0.003), and reduced blood flow-related parameterfD* (1.18±0.40 versus 1.83±0.40×10-3mm2/s;P=0.009). IVIM pseudodiffusion coefficientD* did not differ between DCI- (0.011±0.002) and DCI+ (0.013±0.005 mm2/s;P=0.4) patients. No differences in mortality or clinical outcome were identified.Decreased IVIM perfusion fractionfand blood flow-related parameterfD* correlate with DCI and proximal artery vasospasm development after cerebral aneurysm rupture.

    View details for DOI 10.1161/STROKEAHA.117.020395

    View details for PubMedID 29439196

  • Management of Arteriovenous Malformations Associated with Developmental Venous Anomalies: A Literature Review and Report of 2 Cases WORLD NEUROSURGERY Zhang, M., Connolly, I. D., Teo, M. K., Yang, G., Dodd, R., Marks, M., Zuccarello, M., Steinberg, G. K. 2017; 106: 563?69

    Abstract

    Classification of cerebrovascular malformations has revealed intermediary lesions that warrant further review owing to their unusual presentation and management. We present 2 cases of arteriovenous malformation (AVM) associated with a developmental venous anomaly (DVA), and discuss the efficacy of previously published management strategies.Two cases of AVMs associated with DVA were identified, and a literature search for published cases between 1980 and 2016 was conducted. Patient demographic data and clinical features were documented.In case 1, a 29-year-old female presenting with parenchymal hemorrhage and left homonymous hemianopia was found to have a right parieto-occipital AVM fed from the anterior cerebral, middle cerebral, and posterior cerebral arteries, with major venous drainage to the superior sagittal sinus. In case 2, imaging in a 34-year-old female evaluated for night tremors and incontinence revealed a left parietal AVM with venous drainage to the superior sagittal sinus. Including our 2 cases, 22 cases of coexisting AVMs and DVAs have been reported in the literature. At presentation, 68% had radiographic evidence of hemorrhage. Stereotactic radiosurgery was performed in 7 cases, embolization in 6 cases, surgical resection in 4 cases, and multimodal therapy in 5 cases. Radiography at follow-up demonstrated successful AVM obliteration in 67% of cases (12 of 18).Patients with coexisting AVMs and DVAs tend to have a hemorrhagic presentation. Contrary to traditional AVM management, in these cases it is important to preserve the draining vein via the DVA to ensure a safe, sustained circulatory outflow of the associated brain parenchyma while achieving safe AVM obliteration.

    View details for PubMedID 28735125

  • A Focused Review of Clinical and Preclinical Studies of Cell-Based Therapies in Stroke. Neurosurgery Sussman, E. S., Steinberg, G. K. 2017; 64 (CN_suppl_1): 92?96

    View details for PubMedID 28899062

  • A Focused Review of Clinical and Preclinical Studies of Cell-Based Therapies in Stroke Sussman, E. S., Steinberg, G. K. OXFORD UNIV PRESS INC. 2017: 92?96
  • Translational Stroke Research Vision and Opportunities STROKE Bosetti, F., Koenig, J. I., Ayata, C., Back, S. A., Becker, K., Broderick, J. P., Carmichael, S., Cho, S., Cipolla, M. J., Corbett, D., Corriveau, R. A., Cramer, S. C., Ferguson, A. R., Finklestein, S. P., Ford, B. D., Furie, K. L., Hemmen, T. M., Iadecola, C., Jakeman, L. B., Janis, S., Jauch, E. C., Johnston, K. C., Kochanek, P. M., Kohn, H., Lo, E. H., Lyden, P. D., Mallard, C., McCullough, L. D., McGavern, L. M., Meschia, J. F., Moy, C. S., Perez-Pinzon, M. A., Ramadan, I., Savitz, S. I., Schwamm, L. H., Steinberg, G. K., Stenzel-Poore, M. P., Tymianski, M., Warach, S., Wechsler, L. R., Zhang, J. H., Koroshetz, W. 2017; 48 (9): 2632?37

    View details for PubMedID 28751554

    View details for PubMedCentralID PMC5599159

  • Direct Versus Indirect Bypass for Moyamoya Disease NEUROSURGERY CLINICS OF NORTH AMERICA Liu, J. J., Steinberg, G. K. 2017; 28 (3): 361-+

    Abstract

    Moyamoya disease is a progressive occlusive vasculopathy that involves the supraclinoid internal carotid arteries and Circle of Willis, and results in the formation of collateral vessels at the skull base. The progressive nature of this disease leads to cerebral ischemia and sometimes intracerebral hemorrhage. The treatment of moyamoya disease is mainly surgical revascularization, using revascularization techniques that include direct, indirect, and combined strategies. Here we discuss the available options for revascularization as well as our opinions regarding the surgical management of patients with moyamoya disease.

    View details for PubMedID 28600011

  • Neurocognitive Performance After Cerebral Revascularization in Adult Moyamoya Disease. Stroke Zeifert, P. D., Karzmark, P., Bell-Stephens, T. E., Steinberg, G. K., Dorfman, L. J. 2017; 48 (6): 1514-1517

    Abstract

    Cerebral revascularization using EC-IC bypass is widely used to treat moyamoya disease, but the effects of surgery on cognition are unknown. We compared performance on formal neurocognitive testing in adults with moyamoya disease before and after undergoing direct EC-IC bypass.We performed a structured battery of 13 neurocognitive tests on 84 adults with moyamoya disease before and 6 months after EC-IC bypass. The results were analyzed using reliable change indices for each test, to minimize test-retest variability and practice effects.Twelve patients (14%) showed significant decline postoperatively, 9 patients (11%) improved, and 63 patients (75%) were unchanged. Similar results were obtained when the analysis was confined to those who underwent unilateral (33) or bilateral (51) revascularization.The majority of patients showed neither significant decline nor improvement in neurocognitive performance after EC-IC bypass surgery. Uncomplicated EC-IC bypass seems not to be a risk factor for cognitive decline in this patient population.

    View details for DOI 10.1161/STROKEAHA.116.016028

    View details for PubMedID 28487332

  • Optogenetic neuronal stimulation of the lateral cerebellar nucleus promotes persistent functional recovery after stroke. Scientific reports Shah, A. M., Ishizaka, S., Cheng, M. Y., Wang, E. H., Bautista, A. R., Levy, S., Smerin, D., Sun, G., Steinberg, G. K. 2017; 7: 46612-?

    Abstract

    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.

    View details for DOI 10.1038/srep46612

    View details for PubMedID 28569261

  • Ipsilateral Pupillary Dilation Following Carotid Endarterectomy: A Temporary and Benign Phenomenon. Neurosurgery Steinberg, J. A., Carter, B. S., Lee, M. B., Steinberg, G. K. 2017; 80 (5): E239-E244

    Abstract

    Cases of post carotid endarterectomy (CEA) Horner's syndrome have been reported, with symptoms attributed to manipulation of the sympathetic plexus situated along the carotid artery; however, these patients presented with the typical constricted pupil. We report the first 3 cases to our knowledge of mydriasis following CEA.We present 3 cases of CEA followed by immediate postoperative development of ipsilateral mydriasis. The patients were otherwise at their neurologic baseline and the mydriasis resolved over the ensuing few days.We suggest that these cases are secondary to an ischemic phenomenon, specifically to parasympathetic structures such as the ciliary ganglion and/or oculomotor nerve, resulting in autonomic dysfunction manifested by pupillary dilation. A similar finding of mydriasis occurring subsequent to other carotid pathology has been reported, with ischemia to parasympathetic structures also proposed as the underlying etiology. Although pupillary dilation often represents a worrisome neurosurgical sign indicating herniation, it should be recognized that after CEA this finding may be a transient, benign occurrence.

    View details for DOI 10.1093/neuros/nyx051

    View details for PubMedID 28387821

  • Safety and Efficacy of Human Embryonic Stem Cell Derived Oligodendrocyte Progenitor Cells (AST-OPC1) in Patients with Subacute Cervical Spinal Cord Injury Lebkowski, J. S., Fessler, R., Leslie, D., Steinberg, G., Kurpad, S., Liu, C., Wirth, E. CELL PRESS. 2017: 229?30
  • The separate effects of lipids and proteins on brain MRI contrast revealed through tissue clearing. NeuroImage Leuze, C., Aswendt, M., Ferenczi, E., Liu, C. W., Hsueh, B., Goubran, M., Tian, Q., Steinberg, G., Zeineh, M. M., Deisseroth, K., McNab, J. A. 2017

    Abstract

    Despite the widespread use of magnetic resonance imaging (MRI) of the brain, the relative contribution of different biological components (e.g. lipids and proteins) to structural MRI contrasts (e.g., T1, T2, T2*, proton density, diffusion) remains incompletely understood. This limitation can undermine the interpretation of clinical MRI and hinder the development of new contrast mechanisms. Here, we determine the respective contribution of lipids and proteins to MRI contrast by removing lipids and preserving proteins in mouse brains using CLARITY. We monitor the temporal dynamics of tissue clearance via NMR spectroscopy, protein assays and optical emission spectroscopy. MRI of cleared brain tissue showed: 1) minimal contrast on standard MRI sequences; 2) increased relaxation times; and 3) diffusion rates close to free water. We conclude that lipids, present in myelin and membranes, are a dominant source of MRI contrast in brain tissue.

    View details for DOI 10.1016/j.neuroimage.2017.04.021

    View details for PubMedID 28411157

  • Disrupting the CD47-SIRP alpha anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors SCIENCE TRANSLATIONAL MEDICINE Gholamin, S., Mitra, S. S., Feroze, A. H., Liu, J., Kahn, S. A., Zhang, M., Esparza, R., Richard, C., Ramaswamy, V., Remke, M., Volkmer, A. K., Willingham, S., Ponnuswami, A., McCarty, A., Lovelace, P., Storm, T. A., Schubert, S., Hutter, G., Narayanan, C., Chu, P., Raabe, E. H., Harsh, G., Taylor, M. D., Monje, M., Cho, Y., Majeti, R., Volkmer, J. P., Fisher, P. G., Grant, G., Steinberg, G. K., Vogel, H., Edwards, M., Weissman, I. L., Cheshier, S. H. 2017; 9 (381)

    Abstract

    Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRP? interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

    View details for DOI 10.1126/scitranslmed.aaf2968

    View details for PubMedID 28298418

  • Interventional therapy for brain arteriovenous malformations before and after ARUBA JOURNAL OF CLINICAL NEUROSCIENCE Sussman, E. S., Iyer, A. K., Teo, M., Pendharkar, A. V., Ho, A. L., Steinberg, G. K. 2017; 37: 54-56

    Abstract

    The ARUBA trial (2014) concluded that medical management alone is superior to medical management plus interventional therapy for the treatment of unruptured brain arteriovenous malformations (bAVMs). This sparked considerable controversy among involved healthcare providers. Here, we evaluated the impact of ARUBA on the volume, type, and treatment modality of bAVMs referred to a large tertiary care center. This was achieved by conducting a retrospective review of a prospectively maintained database of all bAVMs treated at Stanford Health Care and Stanford Children's Health from January 2012 through July 2015. The case volume of bAVMs treated at Stanford has been relatively unchanged in the period of time leading up to and after ARUBA. Furthermore, there has been no significant change in the proportion of unruptured AVMs treated. Although differences existed in types of interventions administered, these differences are best explained by variations in the SM grades of AVMs treated during each study period, rather than by underlying changes in treatment strategy. Additional research is warranted to more thoroughly characterize the impact of ARUBA on the treatment patterns of bAVMS.

    View details for DOI 10.1016/j.jocn.2016.10.036

    View details for Web of Science ID 000394396400015

  • Embolization Followed by Radiosurgery for the Treatment of Brain Arteriovenous Malformations (AVMs) WORLD NEUROSURGERY Marks, M. P., Marcellus, M. L., Santarelli, J., Dodd, R. L., Do, H. M., Chang, S. D., Adler, J. R., Mlynash, M., Steinberg, G. K. 2017; 99: 471-476

    Abstract

    Embolization has been proposed to reduce the size of the arteriovenous malformation (AVM) nidus in advance of radiosurgical treatment. Embolization followed by radiosurgery for brain AVMs, however, is controversial.We assessed the impact of embolization on nidal size before radiosurgical treatment and evaluated cure rates and complications by using embolization followed by radiosurgery.A retrospective review of our institutional AVM database identified 91 patients treated from 1995 to 2009 with embolization followed by radiosurgery. Pre- and postembolization AVM volumes were measured with angiography, and the modified radiation-based AVM scores (RBAS) also were calculated pre- and postembolization. RBAS determined from pre-embolization volumes were correlated with postradiosurgical obliteration.Median AVM volume declined from 18.8 mL (interquartile range, 10.2-32.2 mL) to 9.9 mL (3.1-19.2 mL) after embolization, P < 0.00003. Median RBAS scores decreased from 2.6 mL (1.8-3.9 mL) to 1.8 mL (1.0-2.8 mL), P < 0.00003. Two of 91 (2.2%) had new fixed deficits after embolization; however, no patient had new disabling deficits (modified Rankin Scale score >2). A total of 71 of 91 (79%) have had >3 years' follow-up, and 40 (56%) had complete obliteration, with 38 (53%) having excellent outcomes (complete obliteration without neurologic decline). Excellent outcome was seen in 90% of patients with modified RBAS score <1, 66% of patients with score 1-1.5, 50% patients with score 1.5-2, and 43% of patients with score >2.These data suggest that embolization of brain AVMs can safely and effectively reduce the treatment volume before radiosurgery. Combined therapy with embolization and radiosurgery does not appear to adversely affect rates of excellent outcome.

    View details for DOI 10.1016/j.wneu.2016.12.059

    View details for Web of Science ID 000397190100066

  • Measuring Cerebral Blood Flow in Moyamoya Angiopathy by Quantitative Magnetic Resonance Angiography Noninvasive Optimal Vessel Analysis. Neurosurgery Khan, N., Lober, R. M., Ostergren, L., Petralia, J., Bell-Stephens, T., Navarro, R., Feroze, A., Steinberg, G. K. 2017

    Abstract

    Moyamoya disease causes progressive occlusion of the supraclinoidal internal carotid artery, and middle, anterior, and less frequently the posterior cerebral arteries, carrying the risk of stroke. Blood flow is often partially reconstituted by compensatory moyamoya collaterals and sometimes the posterior circulation. Cerebral revascularization can further augment blood flow. These changes to blood flow within the cerebral vessels, however, are not well characterized.To evaluate blood flow changes resulting from the disease process and revascularization surgery using quantitative magnetic resonance angiography with noninvasive optimal vessel analysis (NOVA).We retrospectively analyzed 190 preoperative and postoperative imaging scans in 66 moyamoya patients after revascularization surgery. Images were analyzed for blood flow using NOVA and compared with preoperative angiographic staging and postoperative blood flow. Blood flow rates within superficial temporal artery grafts were compared based on angiographic evidence of patency.Diseased vessels had lower blood flow, correlating with angiographic staging. Flow in posterior cererbal and basilar arteries increased with disease severity, particularly when both the anterior and middle cerebral arteries were occluded. Basilar artery flow and ipsilateral internal carotid artery flow decreased after surgery. Flow rates were different between angiographically robust and poor direct bypass grafts, as well as between robust and patent grafts.Preoperative changes in cerebral vessel flow as measured by NOVA correlated with angiographic disease progression. NOVA demonstrated that preoperative augmentation of the posterior circulation decreased after surgery. This report is the first to quantify the shift in collateral supply from the posterior circulation to the bypass graft.

    View details for DOI 10.1093/neuros/nyw122

    View details for PubMedID 28204602

  • Comparison of porcine and bovine collagen dural substitutes in posterior fossa decompression for Chiari I malformation in adults. World neurosurgery Lee, C. K., Mokhtari, T. n., Connolly, I. D., Li, G. n., Shuer, L. M., Chang, S. D., Steinberg, G. K., Gephart, M. H. 2017

    Abstract

    Posterior fossa decompression surgeries for Chiari malformations are susceptible to post-operative complications such as pseudomeningocele, external cerebrospinal fluid (CSF) leak, and meningitis. Various dural substitutes have been employed to improve surgical outcomes.This study examined whether the collagen matrix dural substitute type correlated with the incidence of post-operative complications following posterior fossa decompression in adult patients with Chiari I malformations.A retrospective cohort study was conducted on 81 adult patients who underwent an elective decompressive surgery for treatment of symptomatic Chiari I malformations, with duraplasty involving a dural substitute derived from either bovine or porcine collagen matrix. Demographics and treatment characteristics were correlated with surgical outcomes.A total of 81 patients were included in the study. Compared to bovine dural substitute, porcine dural substitute was associated with a significantly higher risk of pseudomeningocele occurrence (OR 5.78, 95% CI 1.65-27.15; P = .01) and a higher overall complication rate (OR 3.70, 95% CI 1.23-12.71; P = .03) by univariate analysis. There was no significant difference in the rate of meningitis, repeat operations, or overall complication rate between the two dural substitutes. In addition, estimated blood loss was a significant risk factor for meningitis (P = .03). Multivariate analyses again demonstrated that porcine dural substitute was associated with pseudomeningocele occurrence, though the association with higher overall complication rate did not reach significance.Dural substitutes generated from porcine collagen, compared to those from bovine collagen, were associated with a higher likelihood of pseudomeningocele development in adult patients undergoing Chiari I malformation decompression and duraplasty.

    View details for PubMedID 28838875

  • The separate effects of lipids and proteins on brain MRI contrast revealed through tissue clearing. NeuroImage Leuze, C. n., Aswendt, M. n., Ferenczi, E. n., Liu, C. W., Hsueh, B. n., Goubran, M. n., Tian, Q. n., Steinberg, G. n., Zeineh, M. M., Deisseroth, K. n., McNab, J. A. 2017

    Abstract

    Despite the widespread use of magnetic resonance imaging (MRI) of the brain, the relative contribution of different biological components (e.g. lipids and proteins) to structural MRI contrasts (e.g., T1, T2, T2*, proton density, diffusion) remains incompletely understood. This limitation can undermine the interpretation of clinical MRI and hinder the development of new contrast mechanisms. Here, we determine the respective contribution of lipids and proteins to MRI contrast by removing lipids and preserving proteins in mouse brains using CLARITY. We monitor the temporal dynamics of tissue clearance via NMR spectroscopy, protein assays and optical emission spectroscopy. MRI of cleared brain tissue showed: 1) minimal contrast on standard MRI sequences; 2) increased relaxation times; and 3) diffusion rates close to free water. We conclude that lipids, present in myelin and membranes, are a dominant source of MRI contrast in brain tissue.

    View details for PubMedID 28411157

  • Long-Delay Arterial Spin Labeling Provides More Accurate Cerebral Blood Flow Measurements in Moyamoya Patients: A Simultaneous Positron Emission Tomography/MRI Study. Stroke Fan, A. P., Guo, J. n., Khalighi, M. M., Gulaka, P. K., Shen, B. n., Park, J. H., Gandhi, H. n., Holley, D. n., Rutledge, O. n., Singh, P. n., Haywood, T. n., Steinberg, G. K., Chin, F. T., Zaharchuk, G. n. 2017; 48 (9): 2441?49

    Abstract

    Arterial spin labeling (ASL) MRI is a promising, noninvasive technique to image cerebral blood flow (CBF) but is difficult to use in cerebrovascular patients with abnormal, long arterial transit times through collateral pathways. To be clinically adopted, ASL must first be optimized and validated against a reference standard in these challenging patient cases.We compared standard-delay ASL (post-label delay=2.025 seconds), multidelay ASL (post-label delay=0.7-3.0 seconds), and long-label long-delay ASL acquisitions (post-label delay=4.0 seconds) against simultaneous [15O]-positron emission tomography (PET) CBF maps in 15 Moyamoya patients on a hybrid PET/MRI scanner. Dynamic susceptibility contrast was performed in each patient to identify areas of mild, moderate, and severe time-to-maximum (Tmax) delays. Relative CBF measurements by each ASL scan in 20 cortical regions were compared with the PET reference standard, and correlations were calculated for areas with moderate and severe Tmax delays.Standard-delay ASL underestimated relative CBF by 20% in areas of severe Tmax delays, particularly in anterior and middle territories commonly affected by Moyamoya disease (P<0.001). Arterial transit times correction by multidelay acquisitions led to improved consistency with PET, but still underestimated CBF in the presence of long transit delays (P=0.02). Long-label long-delay ASL scans showed the strongest correlation relative to PET, and there was no difference in mean relative CBF between the modalities, even in areas of severe delays.Post-label delay times of ?4 seconds are needed and may be combined with multidelay strategies for robust ASL assessment of CBF in Moyamoya disease.

    View details for PubMedID 28765286

  • Pipeline embolization device retraction and foreshortening after internal carotid artery blister aneurysm treatment. Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences Heit, J. J., Telischak, N. A., Do, H. M., Dodd, R. L., Steinberg, G. K., Marks, M. P. 2017; 23 (6): 614?19

    Abstract

    Background Subarachnoid hemorrhage (SAH) secondary to rupture of a blister aneurysm (BA) results in high morbidity and mortality. Endovascular treatment with the pipeline embolization device (PED) has been described as a new treatment strategy for these lesions. We present the first reported case of PED retraction and foreshortening after treatment of a ruptured internal carotid artery (ICA) BA. Case description A middle-aged patient presented with SAH secondary to ICA BA rupture. The patient was treated with telescoping PED placement across the BA. After 5 days from treatment, the patient developed a new SAH due to re-rupture of the BA. Digital subtraction angiography revealed an increase in caliber of the supraclinoid ICA with associated retraction and foreshortening of the PED that resulted in aneurysm uncovering and growth. Conclusions PED should be oversized during ruptured BA treatment to prevent device retraction and aneurysm regrowth. Frequent imaging follow up after BA treatment with PED is warranted to ensure aneurysm occlusion.

    View details for PubMedID 28758549

  • Patient Outcomes and Cerebral Infarction after Ruptured Anterior Communicating Artery Aneurysm Treatment. AJNR. American journal of neuroradiology Heit, J. J., Ball, R. L., Telischak, N. A., Do, H. M., Dodd, R. L., Steinberg, G. K., Chang, S. D., Wintermark, M. n., Marks, M. P. 2017; 38 (11): 2119?25

    Abstract

    Anterior communicating artery aneurysm rupture and treatment is associated with high rates of dependency, which are more severe after clipping compared with coiling. To determine whether ischemic injury might account for these differences, we characterized cerebral infarction burden, infarction patterns, and patient outcomes after surgical or endovascular treatment of ruptured anterior communicating artery aneurysms.We performed a retrospective cohort study of consecutive patients with ruptured anterior communicating artery aneurysms. Patient data and neuroimaging studies were reviewed. A propensity score for outcome measures was calculated to account for the nonrandom assignment to treatment. Primary outcome was the frequency of frontal lobe and striatum ischemic injury. Secondary outcomes were patient mortality and clinical outcome at discharge and at 3 months.Coiled patients were older (median, 55 versus 50 years;P= .03), presented with a worse clinical status (60% with Hunt and Hess Score >2 versus 34% in clipped patients;P= .02), had a higher modified Fisher grade (P= .01), and were more likely to present with intraventricular hemorrhage (78% versus 56%;P= .03). Ischemic frontal lobe infarction (OR, 2.9; 95% CI, 1.1-8.4;P= .03) and recurrent artery of Heubner infarction (OR, 20.9; 95% CI, 3.5-403.7;P< .001) were more common in clipped patients. Clipped patients were more likely to be functionally dependent at discharge (OR, 3.2;P= .05) compared with coiled patients. Mortality and clinical outcome at 3 months were similar between coiled and clipped patients.Frontal lobe and recurrent artery of Heubner infarctions are more common after surgical clipping of ruptured anterior communicating artery aneurysms, and are associated with poorer clinical outcomes at discharge.

    View details for PubMedID 28882863

  • Clinical and Arterial Spin Labeling Brain MRI Features of Transitional Venous Anomalies. Journal of neuroimaging : official journal of the American Society of Neuroimaging Zhang, M. n., Telischak, N. A., Fischbein, N. J., Steinberg, G. K., Marks, M. n., Zaharchuk, G. n., Heit, J. J., Iv, M. n. 2017

    Abstract

    Transitional venous anomalies (TVAs) are rare cerebrovascular lesions that resemble developmental venous anomalies (DVAs), but demonstrate early arteriovenous shunting on digital subtraction angiography (DSA) without the parenchymal nidus of arteriovenous malformations (AVMs). We investigate whether arterial spin labeling (ASL) magnetic resonance imaging (MRI) can distinguish brain TVAs from DVAs and guide their clinical management.We conducted a single-center retrospective review of patients with brain parenchymal DVA-like lesions with increased ASL signal on MRI. Clinical histories and follow-up information were obtained. Two readers assessed ASL signal location relative to the vascular lesion on MRI and, if available, the presence of arteriovenous shunting on DSA.Thirty patients with DVA-like lesions with increased ASL signal were identified. Clinical symptoms prompted MRI evaluation in 83%. Symptoms did not localize to the venous anomaly in 90%. Ten percent presented with acute symptoms, only one of whom presented with hemorrhage. ASL signal in relation to the venous anomaly was identified in: 50% in the adjacent parenchyma, 33% in the lesion, 7% in a distal draining vein/sinus, and 10% in at least two of these sites. Follow-up DSA confirmed arteriovenous shunting in 71% of ASL-positive venous anomalies. Interrater agreement was very good (? = .81-1.0, P < .001).A DVA-like lesion with increased ASL signal likely represents a TVA with arteriovenous shunting. Our study indicates that these lesions are usually incidentally detected and have a lower risk of hemorrhage than AVMs. ASL-MRI may be a useful tool to identify TVAs and guide further management of patients with TVAs.

    View details for PubMedID 29205641

  • Embolization followed by Radiosurgery for the Treatment of Brain Arteriovenous Malformations (AVMs). World neurosurgery Marks, M. P., Marcellus, M. L., Santarelli, J., Dodd, R. L., Do, H. M., Chang, S. D., Adler, J. R., Mlynash, M., Steinberg, G. K. 2016

    Abstract

    Embolization has been proposed to reduce the size of the arteriovenous malformation (AVM) nidus in advance of radiosurgical treatment. Embolization followed by radiosurgery for brain AVMs, however, is controversial.We assessed the impact of embolization on nidal size before radiosurgical treatment and evaluated cure rates and complications by using embolization followed by radiosurgery.A retrospective review of our institutional AVM database identified 91 patients treated from 1995 to 2009 with embolization followed by radiosurgery. Pre- and postembolization AVM volumes were measured with angiography, and the modified radiation-based AVM scores (RBAS) also were calculated pre- and postembolization. RBAS determined from pre-embolization volumes were correlated with postradiosurgical obliteration.Median AVM volume declined from 18.8 mL (interquartile range, 10.2-32.2 mL) to 9.9 mL (3.1-19.2 mL) after embolization, P < 0.00003. Median RBAS scores decreased from 2.6 mL (1.8-3.9 mL) to 1.8 mL (1.0-2.8 mL), P < 0.00003. Two of 91 (2.2%) had new fixed deficits after embolization; however, no patient had new disabling deficits (modified Rankin Scale score >2). A total of 71 of 91 (79%) have had >3 years' follow-up, and 40 (56%) had complete obliteration, with 38 (53%) having excellent outcomes (complete obliteration without neurologic decline). Excellent outcome was seen in 90% of patients with modified RBAS score <1, 66% of patients with score 1-1.5, 50% patients with score 1.5-2, and 43% of patients with score >2.These data suggest that embolization of brain AVMs can safely and effectively reduce the treatment volume before radiosurgery. Combined therapy with embolization and radiosurgery does not appear to adversely affect rates of excellent outcome.

    View details for DOI 10.1016/j.wneu.2016.12.059

    View details for PubMedID 28017742

  • Surgical outcomes of Majewski osteodysplastic primordial dwarfism Type II with intracranial vascular anomalies JOURNAL OF NEUROSURGERY-PEDIATRICS Teo, M., Johnson, J. N., Bell-Stephens, T. E., Marks, M. P., Do, H. M., Dodd, R. L., Bober, M. B., Steinberg, G. K. 2016; 18 (6): 717-723

    Abstract

    OBJECTIVE Majewski osteodysplastic primordial dwarfism Type II (MOPD II) is a rare genetic disorder. Features of it include extremely small stature, severe microcephaly, and normal or near-normal intelligence. Previous studies have found that more than 50% of patients with MOPD II have intracranial vascular anomalies, but few successful surgical revascularization or aneurysm-clipping cases have been reported because of the diminutive arteries and narrow surgical corridors in these patients. Here, the authors report on a large series of patients with MOPD II who underwent surgery for an intracranial vascular anomaly. METHODS In conjunction with an approved prospective registry of patients with MOPD II, a prospectively collected institutional surgical database of children with MOPD II and intracranial vascular anomalies who underwent surgery was analyzed retrospectively to establish long-term outcomes. RESULTS Ten patients with MOPD II underwent surgery between 2005 and 2012; 5 patients had moyamoya disease (MMD), 2 had intracranial aneurysms, and 3 had both MMD and aneurysms. Patients presented with transient ischemic attack (TIA) (n = 2), ischemic stroke (n = 2), intraparenchymal hemorrhage from MMD (n = 1), and aneurysmal subarachnoid hemorrhage (n = 1), and 4 were diagnosed on screening. The mean age of the 8 patients with MMD, all of whom underwent extracranial-intracranial revascularization (14 indirect, 1 direct) was 9 years (range 1-17 years). The mean age of the 5 patients with aneurysms was 15.5 years (range 9-18 years). Two patients experienced postoperative complications (1 transient weakness after clipping, 1 femoral thrombosis that required surgical repair). During a mean follow-up of 5.9 years (range 3-10 years), 3 patients died (1 of subarachnoid hemorrhage, 1 of myocardial infarct, and 1 of respiratory failure), and 1 patient had continued TIAs. All of the surviving patients recovered to their neurological baseline. CONCLUSIONS Patients with MMD presented at a younger age than those in whom aneurysms were more prevalent. Microneurosurgery with either intracranial bypass or aneurysm clipping is extremely challenging but feasible at expert centers in patients with MOPD II, and good long-term outcomes are possible.

    View details for DOI 10.3171/2016.6.PEDS16243

    View details for Web of Science ID 000388783200012

  • Response by Steinberg et al to Letter Regarding Article, "Clinical Outcomes of Transplanted Modified Bone Marrow-Derived Mesenchymal Stem Cells in Stroke: A Phase 1/2A Study" STROKE Steinberg, G. K., Kondziolka, D., Bates, D. 2016; 47 (12): E269-E269

    View details for DOI 10.1161/STROKEAHA.116.015209

    View details for Web of Science ID 000389424200004

    View details for PubMedID 27895304

  • Surgical outcomes of Majewski osteodysplastic primordial dwarfism Type II with intracranial vascular anomalies. Journal of neurosurgery. Pediatrics Teo, M., Johnson, J. N., Bell-Stephens, T. E., Marks, M. P., Do, H. M., Dodd, R. L., Bober, M. B., Steinberg, G. K. 2016; 25 (6): 717-723

    Abstract

    OBJECTIVE Majewski osteodysplastic primordial dwarfism Type II (MOPD II) is a rare genetic disorder. Features of it include extremely small stature, severe microcephaly, and normal or near-normal intelligence. Previous studies have found that more than 50% of patients with MOPD II have intracranial vascular anomalies, but few successful surgical revascularization or aneurysm-clipping cases have been reported because of the diminutive arteries and narrow surgical corridors in these patients. Here, the authors report on a large series of patients with MOPD II who underwent surgery for an intracranial vascular anomaly. METHODS In conjunction with an approved prospective registry of patients with MOPD II, a prospectively collected institutional surgical database of children with MOPD II and intracranial vascular anomalies who underwent surgery was analyzed retrospectively to establish long-term outcomes. RESULTS Ten patients with MOPD II underwent surgery between 2005 and 2012; 5 patients had moyamoya disease (MMD), 2 had intracranial aneurysms, and 3 had both MMD and aneurysms. Patients presented with transient ischemic attack (TIA) (n = 2), ischemic stroke (n = 2), intraparenchymal hemorrhage from MMD (n = 1), and aneurysmal subarachnoid hemorrhage (n = 1), and 4 were diagnosed on screening. The mean age of the 8 patients with MMD, all of whom underwent extracranial-intracranial revascularization (14 indirect, 1 direct) was 9 years (range 1-17 years). The mean age of the 5 patients with aneurysms was 15.5 years (range 9-18 years). Two patients experienced postoperative complications (1 transient weakness after clipping, 1 femoral thrombosis that required surgical repair). During a mean follow-up of 5.9 years (range 3-10 years), 3 patients died (1 of subarachnoid hemorrhage, 1 of myocardial infarct, and 1 of respiratory failure), and 1 patient had continued TIAs. All of the surviving patients recovered to their neurological baseline. CONCLUSIONS Patients with MMD presented at a younger age than those in whom aneurysms were more prevalent. Microneurosurgery with either intracranial bypass or aneurysm clipping is extremely challenging but feasible at expert centers in patients with MOPD II, and good long-term outcomes are possible.

    View details for PubMedID 27611897

  • Interventional therapy for brain arteriovenous malformations before and after ARUBA. Journal of clinical neuroscience Sussman, E. S., Iyer, A. K., Teo, M., Pendharkar, A. V., Ho, A. L., Steinberg, G. K. 2016

    Abstract

    The ARUBA trial (2014) concluded that medical management alone is superior to medical management plus interventional therapy for the treatment of unruptured brain arteriovenous malformations (bAVMs). This sparked considerable controversy among involved healthcare providers. Here, we evaluated the impact of ARUBA on the volume, type, and treatment modality of bAVMs referred to a large tertiary care center. This was achieved by conducting a retrospective review of a prospectively maintained database of all bAVMs treated at Stanford Health Care and Stanford Children's Health from January 2012 through July 2015. The case volume of bAVMs treated at Stanford has been relatively unchanged in the period of time leading up to and after ARUBA. Furthermore, there has been no significant change in the proportion of unruptured AVMs treated. Although differences existed in types of interventions administered, these differences are best explained by variations in the SM grades of AVMs treated during each study period, rather than by underlying changes in treatment strategy. Additional research is warranted to more thoroughly characterize the impact of ARUBA on the treatment patterns of bAVMS.

    View details for DOI 10.1016/j.jocn.2016.10.036

    View details for PubMedID 27810415

  • Quality of Life in Pediatric Moyamoya Disease. Pediatric neurology Ball, A. J., Steinberg, G. K., Elbers, J. 2016; 63: 60-65

    Abstract

    Moyamoya disease (MMD) is a progressive intracranial arteriopathy with high risk of stroke. Its impact on quality of life is unstudied. We surveyed children with moyamoya disease and compared their quality of life to chronically ill children and children with stroke to better understand the impact of this diagnosis.Children with moyamoya disease aged seven to 17 years from Stanford's Moyamoya Clinic between June 2014 and March 2015 were included. Children with syndromic neurodevelopmental diagnoses were excluded. Patients were surveyed using the Pediatric Quality of Life 4.0, in addition to the Pediatric Stroke Outcome Measure or Recovery Recurrence Questionnaire. Mean scores were compared to normative data sets. Linear regression models compared total quality of life scores in patients with and without stroke, after adjusting for confounders.This cross-sectional study included 30 children with moyamoya disease; ten were male, and the median age was 13.5 years (range, 7 to 17 years). Twenty children (67%) had a stroke, and 14 of these had good neurological outcome (70%). Mean parent-proxy Pediatric Quality of Life scores were lower in all domains compared to healthy controls (P < 0.05), and all scores were comparable to chronically ill children and children with non-moyamoya disease stroke. There was no significant difference in total quality of life between patients with and without stroke.Even in the absence of stroke, children with moyamoya disease have lower quality of life than healthy controls and a similar quality of life to chronically ill children and those with non-moyamoya disease stroke. Children with moyamoya disease would benefit from mental health support beyond what a mild physical presentation may indicate.

    View details for DOI 10.1016/j.pediatrneurol.2016.06.012

    View details for PubMedID 27473648

  • Editorial: Direct versus indirect bypass for moyamoya disease: ongoing controversy. Journal of neurosurgery Teo, M. K., Madhugiri, V. S., Steinberg, G. K. 2016: 1-3

    View details for PubMedID 27471893

  • The strokes that killed Churchill, Roosevelt, and Stalin. Neurosurgical focus Ali, R., Connolly, I. D., Li, A., Choudhri, O. A., Pendharkar, A. V., Steinberg, G. K. 2016; 41 (1): E7-?

    Abstract

    From February 4 to 11, 1945, President Franklin D. Roosevelt of the United States, Soviet Union Premier Joseph Stalin, and British Prime Minister Winston Churchill met near Yalta in Crimea to discuss how post-World War II (WWII) Europe should be organized. Within 2 decades of this conference, all 3 men had died. President Roosevelt died 2 months after the Yalta Conference due to a hemorrhagic stroke. Premier Stalin died 8 years later, also due to a hemorrhagic stroke. Finally, Prime Minister Churchill died 20 years after the conference because of complications due to stroke. At the time of Yalta, these 3 men were the leaders of the most powerful countries in the world. The subsequent deterioration of their health and eventual death had varying degrees of historical significance. Churchill's illness forced him to resign as British prime minister, and the events that unfolded immediately after his resignation included Britain's mismanagement of the Egyptian Suez Crisis and also a period of mistrust with the United States. Furthermore, Roosevelt was still president and Stalin was still premier at their times of passing, so their deaths carried huge political ramifications not only for their respective countries but also for international relations. The early death of Roosevelt, in particular, may have exacerbated post-WWII miscommunication between America and the Soviet Union-miscommunication that may have helped precipitate the Cold War.

    View details for DOI 10.3171/2016.4.FOCUS1575

    View details for PubMedID 27364260

  • Management of moyamoya syndrome in patients with Noonan syndrome JOURNAL OF CLINICAL NEUROSCIENCE Gupta, M., Choudhri, O. A., Feroze, A. H., Do, H. M., Grant, G. A., Steinberg, G. K. 2016; 28: 107-111

    Abstract

    A few isolated reports have described an association between Noonan syndrome and cerebrovascular abnormalities, including moyamoya syndrome. These reports have been limited to pediatric patients presenting with recurrent transient ischemic attacks (TIA) or headaches. Management has primarily been pharmacologic, with only one prior report of surgical revascularization to our knowledge. We report four cases of Noonan syndrome patients presenting with headaches and/or sensorimotor strokes in childhood that caused unilateral sensorimotor impairment. Cerebral angiography and MRI revealed bilateral moyamoya syndrome. All patients underwent successful bilateral extracranial-to-intracranial revascularization. The first patient was a 10-year-old girl who presented following a hemorrhagic stroke and recovered well after indirect bypass. The second patient was an adult with a history of childhood stroke whose symptoms progressed in adulthood. She underwent a direct bypass and improved, but continued to experience TIA at her 4 year follow-up. The third patient was a 7-year-old girl with headaches and a new onset TIA who failed pharmacological therapy and subsequently underwent bilateral indirect bypass. The fourth patient was a 24-year-old woman with worsening headaches and an occluded left middle cerebral artery from unilateral moyamoya syndrome. A left sided direct bypass was completed given delayed MRI perfusion with poor augmentation. To our knowledge these are the first reported surgical cases of combined Noonan and moyamoya syndrome. These cases highlight the need to recognize moyamoya syndrome in patients with Noonan syndrome. Early surgical revascularization should be pursued in order to prevent symptom progression.

    View details for DOI 10.1016/j.jocn.2015.11.017

    View details for Web of Science ID 000376714500021

    View details for PubMedID 26778511

  • OPTOGENETIC STIMULATION OF CEREBELLAR DENTATE NUCLEUS PROMOTES PERSISTENT FUNCTIONAL RECOVERY AFTER STROKE Shunsuke, I., Cheng, M. Y., Shah, A. M., Wang, E. H., Bautista, A. R., Sun, G., Steinberg, G. K. SAGE PUBLICATIONS INC. 2016: 304
  • Multiple Subsets of Brain Tumor Initiating Cells Coexist in Glioblastoma STEM CELLS Rennert, R. C., Achrol, A. S., Januszyk, M., Kahn, S. A., Liu, T. T., Liu, Y., Sahoo, D., Rodrigues, M., Maan, Z. N., Wong, V. W., Cheshier, S. H., Chang, S. D., Steinberg, G. K., Harsh, G. R., Gurtner, G. C. 2016; 34 (6): 1702-1707

    Abstract

    Brain tumor-initiating cells (BTICs) are self-renewing multipotent cells critical for tumor maintenance and growth. Using single-cell microfluidic profiling, we identified multiple subpopulations of BTICs co-existing in human glioblastoma, characterized by distinct surface marker expression and single-cell molecular profiles relating to distinct bulk tissue molecular subtypes. These data suggest BTIC subpopulation heterogeneity as an underlying source of intra-tumoral bulk tissue molecular heterogeneity, and will support future studies into BTIC subpopulation-specific therapies. This article is protected by copyright. All rights reserved.

    View details for DOI 10.1002/stem.2359

    View details for Web of Science ID 000378089500025

    View details for PubMedID 26991945

  • Optogenetic modulation in stroke recovery NEUROSURGICAL FOCUS Pendharkar, A. V., Levy, S. L., Ho, A. L., Sussman, E. S., Cheng, M. Y., Steinberg, G. K. 2016; 40 (5)

    Abstract

    Stroke is one of the leading contributors to morbidity, mortality, and health care costs in the United States. Although several preclinical strategies have shown promise in the laboratory, few have succeeded in the clinical setting. Optogenetics represents a promising molecular tool, which enables highly specific circuit-level neuromodulation. Here, the conceptual background and preclinical body of evidence for optogenetics are reviewed, and translational considerations in stroke recovery are discussed.

    View details for DOI 10.3171/2016.2.FOCUS163

    View details for Web of Science ID 000375119300003

    View details for PubMedID 27132527

  • Neurorestoration after stroke NEUROSURGICAL FOCUS Azad, T. D., Veeravagu, A., Steinberg, G. K. 2016; 40 (5)

    Abstract

    Recent advancements in stem cell biology and neuromodulation have ushered in a battery of new neurorestorative therapies for ischemic stroke. While the understanding of stroke pathophysiology has matured, the ability to restore patients' quality of life remains inadequate. New therapeutic approaches, including cell transplantation and neurostimulation, focus on reestablishing the circuits disrupted by ischemia through multidimensional mechanisms to improve neuroplasticity and remodeling. The authors provide a broad overview of stroke pathophysiology and existing therapies to highlight the scientific and clinical implications of neurorestorative therapies for stroke.

    View details for DOI 10.3171/2016.2.FOCUS15637

    View details for Web of Science ID 000375119300001

    View details for PubMedID 27132523

    View details for PubMedCentralID PMC4916840

  • Impaired Arm Function and Finger Dexterity in a Nonhuman Primate Model of Stroke Motor and Cognitive Assessments STROKE McEntire, C. R., Choudhury, G. R., Torres, A., Steinberg, G. K., Redmond, D. E., Daadi, M. M. 2016; 47 (4): 1109-1116

    Abstract

    Ischemic stroke is the leading cause of upper extremity motor impairments. Although several well-characterized experimental stroke models exist, modeling of upper extremity motor impairments, which are unique to primates, is not well established. Cortical representation of dexterous movements in nonhuman primates is functionally and topographically similar to that in humans. In this study, we characterize the African green monkey model of focal ischemia reperfusion with a defined syndrome, impaired dexterous movements.Cerebral ischemia was induced by transient occlusion of the M3 segment of the left middle cerebral artery. Motor and cognitive functions after stroke were evaluated using the object retrieval task with barrier-detour. Postmortem magnetic resonance imaging and histopathology were performed to map and characterize the infarct.The middle cerebral artery occlusion consistently produced a necrotic infarct localized in the sensorimotor cortex in the middle cerebral artery territory. The infarction was reproducible and resulted in significant loss of fine motor function characterized by impaired dexterity. No significant cognitive impairment was detected. Magnetic resonance imaging and histopathology demonstrated consistent and significant loss of tissue on the left parietal cortex by the central sulcus covering the sensorimotor area. The results suggest that this species has less collateralization, which closely resembles humans.The reported nonhuman primate model produces a defined and reproducible syndrome relevant to our understanding of ischemic stroke, cortical representation, and sensorimotor integration controlling dexterous movements. This model will be useful in basic and translational research addressing loss of arm function and dexterity.

    View details for DOI 10.1161/STROKEAHA.115.012506

    View details for Web of Science ID 000372853200030

  • Treatment of Nystagmus in Brainstem Cavernous Malformation with Botulinum Toxin CUREUS Chen, Y., Fredrick, D., Steinberg, G. K., Liao, Y. J. 2016; 8 (4)

    View details for DOI 10.7759/cureus.553

    View details for Web of Science ID 000453611400003

  • Laparoscopic harvesting of omental pedicle flap for cerebral revascularization in children with moyamoya disease JOURNAL OF PEDIATRIC SURGERY Bruzoni, M., Steinberg, G. K., Dutta, S. 2016; 51 (4): 592-597

    Abstract

    An abundance of angiogenic and immunologic factors makes the omentum an ideal tissue for reconstruction and revascularization of a variety of extraperitoneal wounds and defects. Omental harvesting was historically performed through a large laparotomy and subcutaneous tunneling to the site of disease. Several complications of the open procedure including abdominal wound infection, fascial dehiscence, ventral hernia, and postoperative ileus have been described. The use of laparoscopy to harvest the omentum has the potential to reduce such complications. We describe the surgical technique and outcomes of a series of patients undergoing laparoscopic pedicled omental flap mobilization for cerebral revascularization in moyamoya disease.A retrospective chart review of all patients undergoing laparoscopic omental cerebral transposition for moyamoya disease between 2011 and 2014 was performed. Clinical indication, surgical technique, operative times, complications, and outcomes at follow-up were reviewed.A total of 7 children underwent the procedure. The general surgery team performed laparoscopic omental mobilization, extraperitonealization, and subcutaneous tunneling, while the neurosurgical team performed craniotomy and cerebral application of the graft. The patients were followed postoperatively with clinic visits and angiography. There was one intraoperative complication (colon injury) and one postoperative complication (intermittent omental hernia at fascial defect for pedicle). All patients had partial to complete symptomatic resolution and demonstrated adequate intracranial revascularization on angiography.Laparoscopic omental pedicle flap mobilization and subcutaneous transposition is feasible in children who require salvage cerebral revascularization for moyamoya disease. The procedure should be considered for other conditions requiring extraperitoneal revascularization.

    View details for DOI 10.1016/j.jpedsurg.2015.10.048

    View details for Web of Science ID 000374482200016

    View details for PubMedID 26611331

  • High-Resolution Microfluidic Single-Cell Transcriptional Profiling Reveals Clinically Relevant Subtypes among Human Stem Cell Populations Commonly Utilized in Cell-Based Therapies FRONTIERS IN NEUROLOGY Rennert, R. C., Schaefer, R., Bliss, T., Januszyk, M., Sorkin, M., Achrol, A. S., Rodrigues, M., Maan, Z. N., Kluba, T., Steinberg, G. K., Gurtner, G. C. 2016; 7

    Abstract

    Stem cell therapies can promote neural repair and regeneration, yet controversy regarding optimal cell source and mechanism of action has slowed clinical translation, potentially due to undefined cellular heterogeneity. Single-cell resolution is needed to identify clinically relevant subpopulations with the highest therapeutic relevance. We combine single-cell microfluidic analysis with advanced computational modeling to study for the first time two common sources for cell-based therapies, human NSCs and MSCs. This methodology has the potential to logically inform cell source decisions for any clinical application.

    View details for DOI 10.3389/fneur.2016.00041

    View details for Web of Science ID 000372534400001

    View details for PubMedCentralID PMC4801858

  • Acute Preoperative Infarcts and Poor Cerebrovascular Reserve Are Independent Risk Factors for Severe Ischemic Complications following Direct Extracranial-Intracranial Bypass for Moyamoya Disease AMERICAN JOURNAL OF NEURORADIOLOGY Antonucci, M. U., Burns, T. C., Pulling, T. M., Rosenberg, J., Marks, M. P., Steinberg, G. K., Zaharchuk, G. 2016; 37 (2): 228-235

    Abstract

    Severe ischemic changes are a rare but devastating complication following direct superficial temporal artery to MCA bypass in patients with Moyamoya disease. This study was undertaken to determine whether preoperative MR imaging and/or cerebrovascular reserve assessment by using reference standard stable xenon-enhanced CT could predict such complications.Among all adult patients undergoing direct bypass at our institution between 2005 and 2010 who received a clinically interpretable xenon-enhanced CT examination, we identified index cases (patients with >15-mL postoperative infarcts) and control cases (patients without postoperative infarcts and without transient or permanent ischemic symptoms). Differences between groups were evaluated by using the Mann-Whitney U test. Univariate and multivariate generalized linear model regression was used to test predictors of postoperative infarct.Six index cases were identified and compared with 25 controls. Infarct size in the index cases was 95 ± 55 mL. Four of 6 index cases (67%), but no control patients, had preoperative acute infarcts. Baseline CBF was similar, but cerebrovascular reserve was significantly lower in the index cases compared with control cases. For example, in the anterior circulation, median cerebrovascular reserve was -0.4% (range, -38.0%-16.6%) in index versus 26.3% (range, -8.2%-60.5%) in control patients (P = .003). Multivariate analysis demonstrated that the presence of a small preoperative infarct (regardless of location) and impaired cerebrovascular reserve were independent, significant predictors of severe postoperative ischemic injury.Acute infarcts and impaired cerebrovascular reserve on preoperative imaging are independent risk factors for severe ischemic complications following superficial temporal artery to MCA bypass in Moyamoya disease.

    View details for DOI 10.3174/ajnr.A4535

    View details for Web of Science ID 000369111200013

    View details for PubMedCentralID PMC4752884

  • Cerebellar Dentate Nucleus is an Effective Brain Stimulation Target for Post-stroke Recovery Ishizaka, S., Cheng, M., Shah, A., Wang, E., Bautista, A., Sun Guohua, Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2016
  • Whole Brain Screening of Cellular and Molecular Changes After Stroke Aswendt, M., Hsueh, B., Ishizaka, S., Sun Guohua, Cheng, M., Deisseroth, K., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2016
  • Optogenetic Neuronal Stimulation Reduces Neuronal Nitric Oxide Synthase After Stroke Cheng, M. Y., Gonzales, L., Wang, E. H., Wang, S., Ishizaka, S., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2016
  • Interventional Therapy for Brain AVMs Before and After ARUBA Sussman, E., Teo, M., Iyer, A., Ho, A., Pendharkar, A., Dodd, R., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2016
  • Purification and Characterization of Progenitor and Mature Human Astrocytes Reveals Transcriptional and Functional Differences with Mouse NEURON Zhang, Y., Sloan, S. A., Clarke, L. E., Caneda, C., Plaza, C. A., Blumenthal, P. D., Vogel, H., Steinberg, G. K., Edwards, M. S., Li, G., Duncan, J. A., Cheshier, S. H., Shuer, L. M., Chang, E. F., Grant, G. A., Gephart, M. G., Barres, B. A. 2016; 89 (1): 37-53

    Abstract

    The functional and molecular similarities and distinctions between human and murine astrocytes are poorly understood. Here, we report the development of an immunopanning method to acutely purify astrocytes from fetal, juvenile, and adult human brains and to maintain these cells in serum-free cultures. We found that human astrocytes have abilities similar to those of murine astrocytes in promoting neuronal survival, inducing functional synapse formation, and engulfing synaptosomes. In contrast to existing observations in mice, we found that mature human astrocytes respond robustly to glutamate. Next, we performed RNA sequencing of healthy human astrocytes along with astrocytes from epileptic and tumor foci and compared these to human neurons, oligodendrocytes, microglia, and endothelial cells (available at http://www.brainrnaseq.org). With these profiles, we identified novel human-specific astrocyte genes and discovered a transcriptome-wide transformation between astrocyte precursor cells and mature post-mitotic astrocytes. These data represent some of the first cell-type-specific molecular profiles of the healthy and diseased human brain.

    View details for DOI 10.1016/j.neuron.2015.11.013

    View details for PubMedID 26687838

  • Disease Variant Landscape of a Large Multiethnic Population of Moyamoya Patients by Exome Sequencing G3-GENES GENOMES GENETICS Shoemaker, L. D., Clark, M. J., Patwardhan, A., Chandratillake, G., Garcia, S., Chen, R., Morgan, A. A., Leng, N., Kirk, S., Chen, R., Cook, D. J., Snyder, M., Steinberg, G. K. 2016; 6 (1): 41-49

    Abstract

    Moyamoya disease (MMD) is a rare disorder characterized by cerebrovascular occlusion and development of hemorrhage-prone collateral vessels. Approximately 10-12% of cases are familial, with a presumed low penetrance autosomal dominant pattern of inheritance. Diagnosis commonly occurs only after clinical presentation. The recent identification of the RNF213 founder mutation (p.R4810K) in the Asian population has made a significant contribution, but the etiology of this disease remains unclear. To further develop the variant landscape of MMD, we performed high-depth whole exome sequencing of 125 unrelated, predominantly nonfamilial, ethnically diverse MMD patients in parallel with 125 internally sequenced, matched controls using the same exome and analysis platform. Three subpopulations were established: Asian, Caucasian, and non-RNF213 founder mutation cases. We provided additional support for the previously observed RNF213 founder mutation (p.R4810K) in Asian cases (P = 6.01×10(-5)) that was enriched among East Asians compared to Southeast Asian and Pacific Islander cases (P = 9.52×10(-4)) and was absent in all Caucasian cases. The most enriched variant in Caucasian (P = 7.93×10(-4)) and non-RNF213 founder mutation (P = 1.51×10(-3)) cases was ZXDC (p.P562L), a gene involved in MHC Class II activation. Collapsing variant methodology ranked OBSCN, a gene involved in myofibrillogenesis, as most enriched in Caucasian (P = 1.07×10(-4)) and non-RNF213 founder mutation cases (P = 5.31×10(-5)). These findings further support the East Asian origins of the RNF213 (p.R4810K) variant and more fully describe the genetic landscape of multiethnic MMD, revealing novel, alternative candidate variants and genes that may be important in MMD etiology and diagnosis.

    View details for DOI 10.1534/g3.115.020321

    View details for Web of Science ID 000367725000004

    View details for PubMedCentralID PMC4704723

  • Treatment of Nystagmus in Brainstem Cavernous Malformation with Botulinum Toxin. Cure¯us Chen, Y., Fredrick, D., Steinberg, G. K., Liao, Y. J. 2016; 8 (4)

    Abstract

    We report a long-term eye movement study of a 68-year-old female with pontomedullary junction cavernous malformation whose dysconjugate nystagmus was treated with retrobulbar botulinum toxin A injections. Sequential, bilateral retrobulbar injections of botulinum toxin A were performed. Injections immediately decreased oscillopsia and nystagmus, and improved visual acuities. One to three months following injection, three-dimensional infrared oculography measured a significant 39-100% (P = 0.001) decrease in nystagmus amplitudes at multiple dimensions. This improvement diminished by six months in the right eye but sustained for about one year in the left eye. Over two years, botulinum toxin A injections were performed twice in the left eye and five times in the right eye. Our study supported the safe and effective use of repetitive retrobulbar botulinum toxin A injections in symptomatic nystagmus that failed medical therapy.

    View details for DOI 10.7759/cureus.553

    View details for PubMedID 27182467

    View details for PubMedCentralID PMC4852187

  • Surgical Therapy INTRACRANIAL ATHEROSCLEROSIS: PATHOPHYSIOLOGY, DIAGNOSIS AND TREATMENT Oh, C., Steinberg, G. K., Kim, J. S., Caplan, L. R., Wong, K. S. 2016; 40: 164?78

    Abstract

    Many prior investigations have indicated the important role of medical treatment to prevent stroke in patients with intracranial atherosclerosis, with angioplasty and stenting occasionally being performed. In a subgroup of patients with severe hemodynamic impairment, extracranial-intracranial (EC-IC) bypass surgery may be considered. Additionally, in patients with massive infarctions due to middle cerebral artery (MCA) occlusion, the use of decompressive craniectomy may lower mortality rates and improve long-term quality of life. However, the benefit of these surgical procedures in patients with intracranial atherosclerosis has long been controversial. In this chapter, we review the surgical therapies for patients with intracranial atherosclerosis. This review does not include EC-IC bypass surgery for moyamoya disease, which is discussed in another chapter.

    View details for DOI 10.1159/000448312

    View details for Web of Science ID 000411854800013

    View details for PubMedID 27960189

  • Acute Preoperative Infarcts and Poor Cerebrovascular Reserve Are Independent Risk Factors for Severe Ischemic Complications following Direct Extracranial-Intracranial Bypass for Moyamoya Disease. AJNR. American journal of neuroradiology Antonucci, M. U., Burns, T. C., Pulling, T. M., Rosenberg, J. n., Marks, M. P., Steinberg, G. K., Zaharchuk, G. n. 2016; 37 (2): 228?35

    Abstract

    Severe ischemic changes are a rare but devastating complication following direct superficial temporal artery to MCA bypass in patients with Moyamoya disease. This study was undertaken to determine whether preoperative MR imaging and/or cerebrovascular reserve assessment by using reference standard stable xenon-enhanced CT could predict such complications.Among all adult patients undergoing direct bypass at our institution between 2005 and 2010 who received a clinically interpretable xenon-enhanced CT examination, we identified index cases (patients with >15-mL postoperative infarcts) and control cases (patients without postoperative infarcts and without transient or permanent ischemic symptoms). Differences between groups were evaluated by using the Mann-Whitney U test. Univariate and multivariate generalized linear model regression was used to test predictors of postoperative infarct.Six index cases were identified and compared with 25 controls. Infarct size in the index cases was 95 ± 55 mL. Four of 6 index cases (67%), but no control patients, had preoperative acute infarcts. Baseline CBF was similar, but cerebrovascular reserve was significantly lower in the index cases compared with control cases. For example, in the anterior circulation, median cerebrovascular reserve was -0.4% (range, -38.0%-16.6%) in index versus 26.3% (range, -8.2%-60.5%) in control patients (P = .003). Multivariate analysis demonstrated that the presence of a small preoperative infarct (regardless of location) and impaired cerebrovascular reserve were independent, significant predictors of severe postoperative ischemic injury.Acute infarcts and impaired cerebrovascular reserve on preoperative imaging are independent risk factors for severe ischemic complications following superficial temporal artery to MCA bypass in Moyamoya disease.

    View details for PubMedID 26564435

  • Personalized Medicine in Cerebrovascular Neurosurgery: Precision Neurosurgical Management of Cerebral Aneurysms and Subarachnoid Hemorrhage. Frontiers in surgery Achrol, A. S., Steinberg, G. K. 2016; 3: 34-?

    Abstract

    Cerebral aneurysms are common vascular lesions. Little is known about the pathogenesis of these lesions and the process by which they destabilize and progress to rupture. Treatment decisions are motivated by a desire to prevent rupture and the devastating morbidity and mortality associated with resulting subarachnoid hemorrhage (SAH). For patients presenting with SAH, urgent intervention is required to stabilize the lesion and prevent re-rupture. Those patients fortunate enough to survive a presenting SAH and subsequent securing of their aneurysm must still face a spectrum of secondary sequelae, which can include cerebral vasospasm, delayed ischemia, seizures, cerebral edema, hydrocephalus, and endocrinologic and catecholamine-induced systemic dysfunction in cardiac, pulmonary, and renal systems. Increased focus on understanding the pathophysiology and molecular characteristics of these secondary processes will enable the development of targeted therapeutics and novel diagnostics for improved patient selection in personalized medicine trials for SAH. In unruptured cerebral aneurysms, treatment decisions are less clear and currently based solely on treating larger lesions, using rigid aneurysm size cutoffs generalized from recent studies that are the subject of ongoing controversy. Further compounding this controversy is the fact that the vast majority of aneurysms that come to clinical attention at the time of a hemorrhagic presentation are of smaller size, suggesting that small aneurysms are indeed not benign lesions. As such, patient-specific biomarkers that better predict which aneurysms represent high-risk lesions that warrant clinical intervention are of vital importance. Recent advancements in genomic and proteomic technologies have enabled the identification of molecular characteristics that may prove useful in tracking aneurysm growth and progression and identifying targets for prophylactic therapeutic interventions. Novel quantitative neuroimaging technologies have also recently emerged, capable of non-invasive characterization of hemodynamic factors, inflammation, and structural changes in aneurysmal walls. The combined use of these quantitative neuroimaging and molecular-based approaches, called Radiogenomics, is a technique that holds great promise in better characterizing individual aneurysms. In the near future, these radiogenomic techniques may help improve quality of life and patient outcomes via patient-specific approaches to the treatment of unruptured cerebral aneurysms and personalized medical management of secondary processes following aneurysmal SAH.

    View details for DOI 10.3389/fsurg.2016.00034

    View details for PubMedID 27446925

    View details for PubMedCentralID PMC4916172

  • Microsurgical treatment of a tentorial galenic dural arteriovenous fistula NEUROSURGICAL FOCUS Choudhri, O., Steinberg, G. K. 2016; 40

    Abstract

    Tentorial dural arteriovenous fistulae (TDAVFs) are complex lesions with the arteriovenous fistula located between the leaves of the tentorium cerebelli. While a large portion of dural arteriovenous fistulae are treated endovascularly, TDAVF may require additional microsurgical treatment given their high risk of hemorrhage and multitude of feeders. We describe the case of a 65-year-old male who presented with hemorrhage from a straight sinus and galenic TDAVF. The straight sinus portion of the fistula was obliterated by 3 endovascular treatments and 1 microsurgical treatment. The galenic component of the TDAVF persisted and was approached via a posterior interhemispheric approach in a lateral position. This video demonstrates surgical technique and anatomy associated with this rarely seen dural arteriovenous fistula. The video can be found here: https://youtu.be/iOLzWOabLZ0 .

    View details for DOI 10.3171/2016.1.FocusVid.15420

    View details for Web of Science ID 000379788500006

  • Optogenetic Stimulation of Neural Grafts Enhances Neurotransmission and Downregulates the Inflammatory Response in Experimental Stroke Model. Cell transplantation Daadi, M. M., Klausner, J. Q., Bajar, B., Goshen, I., Lee-Messer, C., Lee, S. Y., Winge, M. C., Ramakrishnan, C., Lo, M., Sun, G., Deisseroth, K., Steinberg, G. K. 2016; 25 (7): 1371-1380

    Abstract

    Compelling evidence suggests that transplantation of neural stem cells (NSCs) from multiple sources ameliorates motor deficits after stroke. However, it is currently unknown to what extent the electrophysiological activity of grafted NSC progeny participates in the improvement of motor deficits and whether excitatory phenotypes of the grafted cells are beneficial or deleterious to sensorimotor performances. To address this question, we used optogenetic tools to drive the excitatory outputs of the grafted NSCs and assess the impact on local circuitry and sensorimotor performance. We genetically engineered NSCs to express the Channelrhodopsin-2 (ChR2), a light-gated cation channel that evokes neuronal depolarization and initiation of action potentials with precise temporal control to light stimulation. To test the function of these cells in a stroke model, rats were subjected to an ischemic stroke and grafted with ChR2-NSCs. The grafted NSCs identified with a human-specific nuclear marker survived in the peri-infarct tissue and coexpressed the ChR2 transgene with the neuronal markers TuJ1 and NeuN. Gene expression analysis in stimulated versus vehicle-treated animals showed a differential upregulation of transcripts involved in neurotransmission, neuronal differentiation, regeneration, axonal guidance, and synaptic plasticity. Interestingly, genes involved in the inflammatory response were significantly downregulated. Behavioral analysis demonstrated that chronic optogenetic stimulation of the ChR2-NSCs enhanced forelimb use on the stroke-affected side and motor activity in an open field test. Together these data suggest that excitatory stimulation of grafted NSCs elicits beneficial effects in experimental stroke model through cell replacement and non-cell replacement, anti-inflammatory/neurotrophic effects.

    View details for DOI 10.3727/096368915X688533

    View details for PubMedID 26132738

  • Microsurgical treatment of a tentorial galenic dural arteriovenous fistula. Neurosurgical focus Choudhri, O., Steinberg, G. K. 2016; 40 Video: 1-?

    Abstract

    Tentorial dural arteriovenous fistulae (TDAVFs) are complex lesions with the arteriovenous fistula located between the leaves of the tentorium cerebelli. While a large portion of dural arteriovenous fistulae are treated endovascularly, TDAVF may require additional microsurgical treatment given their high risk of hemorrhage and multitude of feeders. We describe the case of a 65-year-old male who presented with hemorrhage from a straight sinus and galenic TDAVF. The straight sinus portion of the fistula was obliterated by 3 endovascular treatments and 1 microsurgical treatment. The galenic component of the TDAVF persisted and was approached via a posterior interhemispheric approach in a lateral position. This video demonstrates surgical technique and anatomy associated with this rarely seen dural arteriovenous fistula. The video can be found here: https://youtu.be/iOLzWOabLZ0 .

    View details for DOI 10.3171/2016.1.FocusVid.15420

    View details for PubMedID 26722680

  • An Alternative Display Could Lead to Earlier Diagnosis of Intracerebral Pathology with a Hemedex Flow Probe In Situ WORLD NEUROSURGERY Mukerji, N., Cook, D. J., Steinberg, G. K. 2015; 84 (6)

    Abstract

    To report 2 cases of patients who had an ischemic stroke and an intracerebral hematoma after a superficial temporal artery-middle cerebral artery bypass with a thermal diffusion blood flow probe in situ and emphasize how a change in the way the data are presented could have led to an earlier diagnosis.Both patients had flow probes within 2 cm of the graft site and were thus close enough to be representative of local or regional rather than global perfusion. Data smoothening was applied to the raw data that were available and displayed on the monitor. Both the smoothed plots and the raw plots were analyzed.Good clinical correlation was observed between the flow probe data and the clinical condition of both patients. This was more apparent when viewing the smoothed plots.Although there was good clinical correlation, data displayed on the perfusion monitor can be incorrectly interpreted because the signal-to-noise ratio is small. We therefore suggest an alternative presentation of perfusion data for clinicians to recognize hypoperfusion and to take informed action before a stroke or hematoma is clinically manifest.

    View details for DOI 10.1016/j.wneu.2015.08.032

    View details for Web of Science ID 000366286300113

    View details for PubMedID 26341435

  • Pediatric Quality of Life in Children with Moyamoya Disease and Stroke Ball, A. J., Steinberg, G. K., Elbers, J. M. WILEY-BLACKWELL. 2015: S214?S215
  • Extracorporeal membrane oxygenation for cardiac arrest during moyamoya cerebral revascularization surgery: case report JOURNAL OF NEUROSURGERY Choudhri, O., Shah, A., Basarab-Tung, J., Jaffe, R. A., Steinberg, G. K. 2015; 123 (3): 693-698

    Abstract

    The authors describe the case of a 51-year-old man with bilateral moyamoya disease and prior strokes who developed an asystolic cardiac arrest while undergoing revascularization surgery under mild hypothermia. The patient was successfully treated with venoarterial (VA) extracorporeal membrane oxygenation (ECMO) after manual cardiopulmonary resuscitation (CPR) was unsuccessful for 45 minutes. ECMO is a cardiopulmonary support system that is indicated for respiratory failure in pediatric and adult patients. It is increasingly being used as an extension to mechanical CPR for patients who have suffered cardiac arrest if the underlying cause of cardiac arrest is thought to be reversible. Identifying which patients should be placed on emergency ECMO after cardiac arrest is controversial given its high morbidity and mortality. ECMO in neurosurgical settings has associated risks of intracranial hemorrhage and neurological compromise, while resource utilization is paramount given the high costs of this treatment. This paper is significant because it describes the use of ECMO in an unindicated setting. Limited data are available for ECMO usage after cardiac arrest with baseline cerebral ischemia. Furthermore, this paper raises important considerations for extracorporeal CPR use in a patient who had recently undergone craniotomy. The patient in this report remained on ECMO for 48 hours, after which he was successfully weaned. He developed a pericardial effusion and compartment syndrome from the ECMO but made a complete neurological recovery. Use of ECMO emergently in an appropriately chosen neurosurgical patient is safe, even in the setting of baseline cerebral ischemia and recent craniotomy.

    View details for DOI 10.3171/2014.11.JNS141054

    View details for Web of Science ID 000360027600025

  • Glioblastoma Multiforme: Exploratory Radiogenomic Analysis by Using Quantitative Image Features. Radiology Gevaert, O., Mitchell, L. A., Achrol, A. S., Xu, J., Echegaray, S., Steinberg, G. K., Cheshier, S. H., Napel, S., Zaharchuk, G., Plevritis, S. K. 2015; 276 (1): 313-?

    View details for DOI 10.1148/radiol.2015154019

    View details for PubMedID 26101929

  • Use of thromboelastography to tailor dual-antiplatelet therapy in patients undergoing treatment of intracranial aneurysms with the Pipeline embolization device. Journal of neurointerventional surgery McTaggart, R. A., Choudhri, O. A., Marcellus, M. L., Brennan, T., Steinberg, G. K., Dodd, R. L., Do, H. M., Marks, M. P. 2015; 7 (6): 425-430

    Abstract

    Platelet function testing is controversial and not well studied in patients with neurovascular disease.To evaluate the performance of thromboelastography (TEG) as a platelet function test in neurovascular patients treated with the Pipeline embolization device (PED).A prospective protocol was instituted for platelet function testing in patients undergoing repair of intracranial aneurysms with the PED. All patients received dual antiplatelet therapy (DAT) and their response to both P2Y12 inhibitors and aspirin was quantified with TEG. Each patient's DAT induction strategy was tailored based on the percentage ADP-induced and percentage arachidonic acid-induced platelet inhibition reported by TEG. Data collected included clinical presentation, aneurysm characteristics, treatment details, and periprocedural events. Patients were followed up clinically and/or angiographically at 30 days, 6 months, and 1 year.Thirty-four PED procedures were performed on 31 patients. TEG results altered the DAT strategy in 35% of patients. Technical success with the Pipeline placement was 100%. Two patients had minor strokes and five had transient ischemic attacks (TIAs). There have been no hemorrhagic complications. No patient had permanent neurologic deficits. Six of eight (75%) of patients with thromboembolic/TIA events were ADP-induced hyporesponders by TEG. Our 6- and 12-month angiographic occlusion rates were 78.9% and 89.5%, respectively. The 19 major branches covered by the PED that were assessed by follow-up imaging have all remained patent.Platelet function testing with TEG altered our DAT induction strategy in a significant number of cases. No hemorrhagic or disabling thromboembolic complications were seen in this series. Future studies should compare methods of platelet function testing and, possibly, no platelet function testing in neurovascular patients undergoing flow diversion and/or stent-assisted treatment of intracranial aneurysms.

    View details for DOI 10.1136/neurintsurg-2013-011089

    View details for PubMedID 24739599

  • Electroencephalographic features of moyamoya in adults CLINICAL NEUROPHYSIOLOGY Frechette, E. S., Bell-Stephens, T. E., Steinberg, G. K., Fisher, R. S. 2015; 126 (3): 481-485

    Abstract

    Electroencephalography is useful for evaluating transient neurological events in the setting of moyamoya disease.EEG findings of adults with moyamoya seen at a large moyamoya referral center are summarized. Patients were identified by retrospective chart review.EEGs were ordered after cerebral revascularization for altered mental status, aphasia, limb shaking, or facial twitching. Among the study population of 103 patients having EEGs, 24% of adults with moyamoya had a history of clinical seizures. Ischemic or hemorrhagic strokes were associated with a twofold relative risk of seizures. Overall, 90% of EEGs were abnormal, most commonly focally (78%), or diffusely slow (68%). Epileptiform EEG discharges were seen in 24%. Whereas hemispheres with an ischemic stroke had a 19% risk of epileptiform discharges and an 8% risk of seizures on EEG, hemispheres with hemorrhagic stroke had a 35% risk of epileptiform discharges and 19% risk of seizures on EEG. Focal amplitude attenuation was seen in 19%, breach rhythm in 15%, rhythmic delta in 14%, and electrographic seizures in 12%.Seizures and epileptiform EEG changes are common in patients with moyamoya disease.Transient events in patients with moyamoya can result from seizures as well as ischemia.

    View details for DOI 10.1016/j.clinph.2014.06.033

    View details for Web of Science ID 000349616700010

    View details for PubMedID 25065300

  • Development of Arteriovenous Fistula After Revascularization Bypass for Moyamoya Disease: Case Report OPERATIVE NEUROSURGERY Feroze, A. H., Kushkuley, J., Choudhri, O., Heit, J. J., Steinberg, G. K., Do, H. M. 2015; 11 (1): E202-E206

    View details for DOI 10.1227/NEU.0000000000000558

    View details for Web of Science ID 000364210300001

    View details for PubMedID 25251198

  • Persistent trigeminal artery supply to an intrinsic trigeminal nerve arteriovenous malformation: A rare cause of trigeminal neuralgia. Journal of clinical neuroscience Choudhri, O., Heit, J. J., Feroze, A. H., Chang, S. D., Dodd, R. L., Steinberg, G. K. 2015; 22 (2): 409-412

    Abstract

    Infratentorial arteriovenous malformations (AVM) associated with the trigeminal nerve root entry zone are a known cause of secondary trigeminal neuralgia (TN). The treatment of both TN and AVM can be challenging, especially if the AVM is embedded within the trigeminal nerve. A persistent trigeminal artery (PTA) can rarely supply these intrinsic trigeminal nerve AVM. We present a 64-year-old man with TN from a right trigeminal nerve AVM supplied by a PTA variant. The patient underwent microvascular decompression and a partial resection of the AVM with relief of facial pain symptoms. His residual AVM was subsequently treated with CyberKnife radiosurgery (Accuray, Sunnyvale, CA, USA). A multimodality approach may be required for the treatment of trigeminal nerve associated PTA AVM and important anatomic patterns need to be recognized before any treatment. Herein, we report to our knowledge the third documented patient with a posterior fossa AVM supplied by a PTA and the first PTA AVM presenting as facial pain.

    View details for DOI 10.1016/j.jocn.2014.06.007

    View details for PubMedID 25070632

  • Internal carotid artery surgical revascularization in a pediatric patient with Schimke immuno-osseous dysplasia JOURNAL OF NEUROSURGERY-PEDIATRICS Westbroek, E. M., Mukerji, N., Kalanithi, P., Steinberg, G. K. 2015; 15 (2): 189-191

    Abstract

    Schimke immuno-osseous dysplasia (SIOD) is a rare autosomal recessive disorder characterized by spondyloepiphyseal dysplasia, episodic lymphopenia, renal failure, and cerebrovascular disease secondary to arteriosclerosis and myointimal hyperplasia. In this paper the authors report the first known application of internal carotid artery (ICA) surgical revascularization to relieve a high-grade focal stenosis of the ICA in a pediatric patient, a 6-year-old boy with SIOD. The clinical presentation, imaging features, operative technique, and postoperative course are described and the molecular genetics, pathophysiology, and treatment considerations in SIOD are discussed.

    View details for DOI 10.3171/2014.10.PEDS14141

    View details for Web of Science ID 000348409100009

    View details for PubMedID 25431900

  • Optogenetic approaches to study stroke recovery. ACS chemical neuroscience Cheng, M. Y., Wang, E. H., Steinberg, G. K. 2014; 5 (12): 1144-1145

    Abstract

    Treatment for stroke is very limited, and potential new therapies are focusing on promoting brain repair and plasticity, as they offer a longer therapeutic time window than the current U.S. Food and Drug Administration approved drug. Functional recovery can occur after stroke, and strategies such as direct brain stimulations that promote recovery are promising. Here we review how selective stimulation of neurons in the motor cortex using optogenetics enhances plasticity mechanisms and promotes functional recovery after stroke.

    View details for DOI 10.1021/cn500216f

    View details for PubMedID 25259689

  • Human brain arteriovenous malformations express lymphatic-associated genes. Annals of clinical and translational neurology Shoemaker, L. D., Fuentes, L. F., Santiago, S. M., Allen, B. M., Cook, D. J., Steinberg, G. K., Chang, S. D. 2014; 1 (12): 982-995

    Abstract

    Brain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may have a role in AVM disease biology.We examined 40 human brain AVMs by immunohistochemistry (IHC) and qRT-PCR for the expression of COUP-TFII as well as other genes involved in venous and lymphatic development, maintenance, and signaling. We also examined proliferation and EC tube formation with human umbilical ECs (HUVEC) following COUP-TFII overexpression.We report that AVMs expressed COUP-TFII, SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, Podoplanin, and vascular endothelial growth factor (VEGF)-C, contained Ki67-positive cells and heterogeneously expressed genes involved in Hedgehog, Notch, Wnt, and VEGF signaling pathways. Overexpression of COUP-TFII alone in vitro resulted in increased EC proliferation and dilated tubes in an EC tube formation assay in HUVEC.This suggests AVM ECs are further losing their arterial/venous specificity and acquiring a partial lymphatic molecular phenotype. There was significant correlation of gene expression with presence of clinical edema and acute hemorrhage. While the precise role of these genes in the formation, stabilization, growth and risk of hemorrhage of AVMs remains unclear, these findings have potentially important implications for patient management and treatment choice, and opens new avenues for future work on AVM disease mechanisms.

    View details for DOI 10.1002/acn3.142

    View details for PubMedID 25574473

    View details for PubMedCentralID PMC4284124

  • Human brain arteriovenous malformations express lymphatic-associated genes ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY Shoemaker, L. D., Fuentes, L. F., Santiago, S. M., Allen, B. M., Cook, D. J., Steinberg, G. K., Chang, S. D. 2014; 1 (12): 982-995

    Abstract

    Brain arteriovenous malformations (AVMs) are devastating, hemorrhage-prone, cerebrovascular lesions characterized by well-defined feeding arteries, draining vein(s) and the absence of a capillary bed. The endothelial cells (ECs) that comprise AVMs exhibit a loss of arterial and venous specification. Given the role of the transcription factor COUP-TFII in vascular development, EC specification, and pathological angiogenesis, we examined human AVM tissue to determine if COUP-FTII may have a role in AVM disease biology.We examined 40 human brain AVMs by immunohistochemistry (IHC) and qRT-PCR for the expression of COUP-TFII as well as other genes involved in venous and lymphatic development, maintenance, and signaling. We also examined proliferation and EC tube formation with human umbilical ECs (HUVEC) following COUP-TFII overexpression.We report that AVMs expressed COUP-TFII, SOX18, PROX1, NFATC1, FOXC2, TBX1, LYVE1, Podoplanin, and vascular endothelial growth factor (VEGF)-C, contained Ki67-positive cells and heterogeneously expressed genes involved in Hedgehog, Notch, Wnt, and VEGF signaling pathways. Overexpression of COUP-TFII alone in vitro resulted in increased EC proliferation and dilated tubes in an EC tube formation assay in HUVEC.This suggests AVM ECs are further losing their arterial/venous specificity and acquiring a partial lymphatic molecular phenotype. There was significant correlation of gene expression with presence of clinical edema and acute hemorrhage. While the precise role of these genes in the formation, stabilization, growth and risk of hemorrhage of AVMs remains unclear, these findings have potentially important implications for patient management and treatment choice, and opens new avenues for future work on AVM disease mechanisms.

    View details for DOI 10.1002/acn3.142

    View details for Web of Science ID 000209815800003

    View details for PubMedCentralID PMC4284124

  • RNF213 Rare Variants in an Ethnically Diverse Population With Moyamoya Disease STROKE Cecchi, A. C., Guo, D., Ren, Z., Flynn, K., Santos-Cortez, R. L., Leal, S. M., Wang, G. T., Regalado, E. S., Steinberg, G. K., Shendure, J., Bamshad, M. J., Grotta, J. C., Nickerson, D. A., Pannu, H., Milewicz, D. M. 2014; 45 (11): 3200-3207

    Abstract

    Moyamoya disease (MMD) is a rare, genetically heterogeneous cerebrovascular disease resulting from occlusion of the distal internal carotid arteries. A variant in the Ring Finger 213 gene (RNF213), altering arginine at position 4810 (p.R4810K), is associated with MMD in Asian populations. However, there are a lack of data on the role of RNF213 in patients with MMD of additional ethnicities and diasporic Asian populations. We investigate the contribution of RNF213 alterations to MMD in an ethnically diverse population based in the United States.We initially sequenced RNF213 exons 43, 44, and 45 (encoding the eponymous RING finger domain) and exon 60 (encoding p.R4810K) in 86 ethnically diverse patients with MMD. Comprehensive exome sequencing data from 24 additional patients with MMD was then analyzed to identify RNF213 variants globally. Segregation of variants with MMD and other vascular diseases was assessed in families.RNF213 p.R4810K was identified in 56% (9/16) of patients with MMD of Asian descent and not in 94 patients of non-Asian descent. 3.6% (4/110) of patients had variants in the exons encoding the RING finger domain. Seven additional variants were identified in 29% (7/24) of patients with MMD who underwent exome sequencing. Segregation analysis supported an association with MMD for 2 variants and a lack of association with disease for 1 variant.These results confirm that alterations in RNF213 predispose patients of diverse ethnicities to MMD, and that the p.R4810K variant predisposes individuals of Asian descent in the United States to MMD.

    View details for DOI 10.1161/STROKEAHA.114.006244

    View details for Web of Science ID 000344351500022

    View details for PubMedID 25278557

    View details for PubMedCentralID PMC4420622

  • Glioblastoma Multiforme: Exploratory Radiogenomic Analysis by Using Quantitative Image Features RADIOLOGY Gevaert, O., Mitchell, L. A., Achrol, A. S., Xu, J., Echegaray, S., Steinberg, G. K., Cheshier, S. H., Napel, S., Zaharchuk, G., Plevritis, S. K. 2014; 273 (1): 168-174

    Abstract

    To derive quantitative image features from magnetic resonance (MR) images that characterize the radiographic phenotype of glioblastoma multiforme (GBM) lesions and to create radiogenomic maps associating these features with various molecular data.Clinical, molecular, and MR imaging data for GBMs in 55 patients were obtained from the Cancer Genome Atlas and the Cancer Imaging Archive after local ethics committee and institutional review board approval. Regions of interest (ROIs) corresponding to enhancing necrotic portions of tumor and peritumoral edema were drawn, and quantitative image features were derived from these ROIs. Robust quantitative image features were defined on the basis of an intraclass correlation coefficient of 0.6 for a digital algorithmic modification and a test-retest analysis. The robust features were visualized by using hierarchic clustering and were correlated with survival by using Cox proportional hazards modeling. Next, these robust image features were correlated with manual radiologist annotations from the Visually Accessible Rembrandt Images (VASARI) feature set and GBM molecular subgroups by using nonparametric statistical tests. A bioinformatic algorithm was used to create gene expression modules, defined as a set of coexpressed genes together with a multivariate model of cancer driver genes predictive of the module's expression pattern. Modules were correlated with robust image features by using the Spearman correlation test to create radiogenomic maps and to link robust image features with molecular pathways.Eighteen image features passed the robustness analysis and were further analyzed for the three types of ROIs, for a total of 54 image features. Three enhancement features were significantly correlated with survival, 77 significant correlations were found between robust quantitative features and the VASARI feature set, and seven image features were correlated with molecular subgroups (P < .05 for all). A radiogenomics map was created to link image features with gene expression modules and allowed linkage of 56% (30 of 54) of the image features with biologic processes.Radiogenomic approaches in GBM have the potential to predict clinical and molecular characteristics of tumors noninvasively. Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.14131731

    View details for Web of Science ID 000344232100019

    View details for PubMedCentralID PMC4263772

  • Glioblastoma multiforme: exploratory radiogenomic analysis by using quantitative image features. Radiology Gevaert, O., Mitchell, L. A., Achrol, A. S., Xu, J., Echegaray, S., Steinberg, G. K., Cheshier, S. H., Napel, S., Zaharchuk, G., Plevritis, S. K. 2014; 273 (1): 168-174

    Abstract

    To derive quantitative image features from magnetic resonance (MR) images that characterize the radiographic phenotype of glioblastoma multiforme (GBM) lesions and to create radiogenomic maps associating these features with various molecular data.Clinical, molecular, and MR imaging data for GBMs in 55 patients were obtained from the Cancer Genome Atlas and the Cancer Imaging Archive after local ethics committee and institutional review board approval. Regions of interest (ROIs) corresponding to enhancing necrotic portions of tumor and peritumoral edema were drawn, and quantitative image features were derived from these ROIs. Robust quantitative image features were defined on the basis of an intraclass correlation coefficient of 0.6 for a digital algorithmic modification and a test-retest analysis. The robust features were visualized by using hierarchic clustering and were correlated with survival by using Cox proportional hazards modeling. Next, these robust image features were correlated with manual radiologist annotations from the Visually Accessible Rembrandt Images (VASARI) feature set and GBM molecular subgroups by using nonparametric statistical tests. A bioinformatic algorithm was used to create gene expression modules, defined as a set of coexpressed genes together with a multivariate model of cancer driver genes predictive of the module's expression pattern. Modules were correlated with robust image features by using the Spearman correlation test to create radiogenomic maps and to link robust image features with molecular pathways.Eighteen image features passed the robustness analysis and were further analyzed for the three types of ROIs, for a total of 54 image features. Three enhancement features were significantly correlated with survival, 77 significant correlations were found between robust quantitative features and the VASARI feature set, and seven image features were correlated with molecular subgroups (P < .05 for all). A radiogenomics map was created to link image features with gene expression modules and allowed linkage of 56% (30 of 54) of the image features with biologic processes.Radiogenomic approaches in GBM have the potential to predict clinical and molecular characteristics of tumors noninvasively. Online supplemental material is available for this article.

    View details for DOI 10.1148/radiol.14131731

    View details for PubMedID 24827998

  • Temporary clipping for unruptured aneurysms. World neurosurgery Mukerji, N., Cook, D. J., Steinberg, G. K. 2014; 82 (3-4): 309-311

    View details for DOI 10.1016/j.wneu.2013.07.094

    View details for PubMedID 23924966

  • Case Report: Glioblastoma Multiforme Complicating Familial Cavernous Malformations CLINICAL NEURORADIOLOGY Wilson, D. M., Cohen, B., Keshari, K., Vogel, H., Steinberg, G., Dillon, W. 2014; 24 (3): 293?96

    View details for DOI 10.1007/s00062-013-0249-3

    View details for Web of Science ID 000341376500017

    View details for PubMedID 23942770

  • Evidence that Meningeal Mast Cells Can Worsen Stroke Pathology in Mice AMERICAN JOURNAL OF PATHOLOGY Arac, A., Grimbaldeston, M. A., Nepomuceno, A. R., Olayiwola, O., Pereira, M. P., Nishiyama, Y., Tsykin, A., Goodall, G. J., Schlecht, U., Vogel, H., Tsai, M., Galli, S. J., Bliss, T. M., Steinbergtt, G. K. 2014; 184 (9): 2493-2504

    Abstract

    Stroke is the leading cause of adult disability and the fourth most common cause of death in the United States. Inflammation is thought to play an important role in stroke pathology, but the factors that promote inflammation in this setting remain to be fully defined. An understudied but important factor is the role of meningeal-located immune cells in modulating brain pathology. Although different immune cells traffic through meningeal vessels en route to the brain, mature mast cells do not circulate but are resident in the meninges. With the use of genetic and cell transfer approaches in mice, we identified evidence that meningeal mast cells can importantly contribute to the key features of stroke pathology, including infiltration of granulocytes and activated macrophages, brain swelling, and infarct size. We also obtained evidence that two mast cell-derived products, interleukin-6 and, to a lesser extent, chemokine (C-C motif) ligand 7, can contribute to stroke pathology. These findings indicate a novel role for mast cells in the meninges, the membranes that envelop the brain, as potential gatekeepers for modulating brain inflammation and pathology after stroke.

    View details for DOI 10.1016/j.ajpath.2014.06.003

    View details for PubMedID 25134760

  • E-014 changes in posterior circulation arterial flows after revascularization surgery in moyamoya disease: a quantitative MRI study. Journal of neurointerventional surgery Navarro, R., Feroze, A., Choudhri, O., Lober, R., Khan, N., Steinberg, G. 2014; 6: A44-?

    Abstract

    Moyamoya disease and syndrome are well known to affect the anterior cerebral circulation by progressive steno-occlusive disease of the supraclinoid internal carotid arteries. Less attention has been paid to changes in posterior arterial circulation hemodynamics in this condition. We sought to better understand the latter using a relatively novel noninvasive imaging technique, quantitative magnetic resonance angiography (qMRA). We assessed the diagnostic utility of qMRA for posterior arterial circulation flows before and after surgical revascularization.This retrospective review included patients who met the following inclusion criteria: (1) diagnosis of moyamoya disease or syndrome with revascularization surgery at Stanford University between September 2008 and March 2012; (2) preoperative and postoperative qMRA scans on record within a two-year time frame; and (3) high-quality qMRA images without motion artefact. Cerebral blood-vessel flow was quantified after non-contrast magnetic resonance imaging (MRI) through the use of a commercially available software tool, non-invasive optimal vessel analysis (NOVA, VasSol, Chicago, USA).A total of 191 patients underwent 281 surgeries during this period of time. Of these, a cohort of 64 patients (78% female, mean age 38.5 years, 55% unilateral disease) had pre- and post-operative qMRA studies. Preoperative arterial flows in the posterior circulation were markedly elevated compared to normal controls. These flows significantly decreased after revascularization (94% direct STA-MCA bypass) with right PCA flow 145 mL/min pre-surgery vs. 123 mL/min post-surgery (p = 0.005, n = 51) and basilar artery flow 264 mL/min pre-surgery vs. 222 mL/min post-surgery (p < 0.001, n = 58). A notable decrease in flow rates was also appreciated within the left PCA distribution, albeit not to a statistically significant degree (p = 0.121, n = 53). No statistically significant changes were noted in posterior communicating artery flows.Quantitative MRA shows that posterior circulation arterial flows are markedly increased in patients with moyamoya disease. After revascularization, there is an overall decrease in these flows that is significant in the basilar artery and right posterior cerebral artery. Further use of qMRA might be warranted to better understand moyamoya hemodynamics before and after surgery.MMD = moyamoya disease NOVA = noninvasive optimal vessel analysis; qMRA = quantitative magnetic resonance angiographymoyamoya disease, quantitative magnetic resonance angiography, cerebral blood flowR. Navarro: None. A. Feroze: None. O. Choudhri: None. R. Lober: None. N. Khan: None. G. Steinberg: None.

    View details for DOI 10.1136/neurintsurg-2014-011343.81

    View details for PubMedID 25064929

  • Acute lung injury in patients with subarachnoid hemorrhage: a nationwide inpatient sample study. World neurosurgery Veeravagu, A., Chen, Y., Ludwig, C., Rincon, F., Maltenfort, M., Jallo, J., Choudhri, O., Steinberg, G. K., Ratliff, J. K. 2014; 82 (1-2): e235-41

    Abstract

    Subarachnoid hemorrhage (SAH) causes significant morbidity and mortality. Pulmonary complications may be particularly frequent, but national data is lacking on the outcomes associated with acute respiratory distress syndrome (ARDS) in SAH patients. The aim of this study is to determine national trends for SAH patients with ARDS.The Nationwide Inpatient Sample Database (NIS) was utilized to sample 193,209 admissions for SAH with and without ARDS from 1993 to 2008 using ICD-9-CM coding. A multivariate stepwise regression analysis was performed.The incidence of ARDS in SAH has increased from 35.51% in 1993 to 37.60% in 2008. However, the overall mortality in SAH patients and in SAH patients with ARDS has decreased in the same period, from 42.30% to 31.99% and from 75.13% to 60.76% respectively. Multivariate analysis showed that the predictors of developing ARDS in SAH patients include older age, larger hospital size, and comorbidities such as epilepsy, cardiac arrest, sepsis, congestive heart failure, hypertension, chronic obstructive pulmonary disease, and hematologic, renal, or neurological dysfunction. Predictors of mortality in SAH patients include age and hospital complications such as coronary artery disease, ARDS, cancer, and hematologic, or renal dysfunction.SAH patients are at increased risk of developing ARDS and the identification of certain risk factors may alert and aid the practitioner in preventing worsening disease.

    View details for DOI 10.1016/j.wneu.2014.02.030

    View details for PubMedID 24560705

  • Temporary artery occlusion in ruptured aneurysms. World neurosurgery Mukerji, N., Cook, D. J., Steinberg, G. K. 2014; 82 (1-2): 43-45

    View details for DOI 10.1016/j.wneu.2013.07.095

    View details for PubMedID 23920285

  • Acute Lung Injury in Patients with Subarachnoid Hemorrhage: A Nationwide Inpatient Sample Study WORLD NEUROSURGERY Veeravagu, A., Chen, Y., Ludwig, C., Rincon, F., Maltenfort, M., Jallo, J., Choudhri, O., Steinberg, G. K., Ratliff, J. K. 2014; 82 (1-2): E235-E241

    Abstract

    Subarachnoid hemorrhage (SAH) causes significant morbidity and mortality. Pulmonary complications may be particularly frequent, but national data is lacking on the outcomes associated with acute respiratory distress syndrome (ARDS) in SAH patients. The aim of this study is to determine national trends for SAH patients with ARDS.The Nationwide Inpatient Sample Database (NIS) was utilized to sample 193,209 admissions for SAH with and without ARDS from 1993 to 2008 using ICD-9-CM coding. A multivariate stepwise regression analysis was performed.The incidence of ARDS in SAH has increased from 35.51% in 1993 to 37.60% in 2008. However, the overall mortality in SAH patients and in SAH patients with ARDS has decreased in the same period, from 42.30% to 31.99% and from 75.13% to 60.76% respectively. Multivariate analysis showed that the predictors of developing ARDS in SAH patients include older age, larger hospital size, and comorbidities such as epilepsy, cardiac arrest, sepsis, congestive heart failure, hypertension, chronic obstructive pulmonary disease, and hematologic, renal, or neurological dysfunction. Predictors of mortality in SAH patients include age and hospital complications such as coronary artery disease, ARDS, cancer, and hematologic, or renal dysfunction.SAH patients are at increased risk of developing ARDS and the identification of certain risk factors may alert and aid the practitioner in preventing worsening disease.

    View details for DOI 10.1016/j.wneu.2014.02.030

    View details for Web of Science ID 000342911400067

  • E-012 national trends for the utilization of cerebral angiography in patients with unruptured aneurysms: 1999-2009. Journal of neurointerventional surgery Choudhri, O., Feroze, A., Mantha, A., Steinberg, G., Do, H. 2014; 6: A43-?

    Abstract

    The utilization of cerebral angiography in the diagnosis and management of patients with unruptured cerebral aneurysms varies across the United States. Given advances in noninvasive imaging, such as CT and MR angiography, patients with unruptured aneurysms may never undergo cerebral angiography. This study explores shifting trends in the utilization of angiography for management of such lesions across the U. S. from 1999-2009.The National Inpatient Sample was used to identify patients carrying a primary ICD-9 diagnosis code of unruptured aneurym (430.0) between 1999-2009. The primary outcomes were compared across subgroups undergoing cerebral angiography in the management of their pathology versus those who did not. The data were analyzed using univariate and multivariate regression (SAS).There were 127579 total admissions with a primary ICD-9 diagnosis of unruptured aneurysms between 1999-2009 per NIS weighted estimates. The total number of patients who underwent cerebral angiography and subsequent clipping were 19412 between 1999-2009. During the same time period 28095 patients underwent coiling after cerebral angiography. For the year 1999, 77% patients were clipped and 23% coiled after cerebral angiography (p < 0.0001). Conversely for the year 2009, 29% patients were clipped and 71% coiled after cerebral angiography (p < 0.0001). These trends were less pronounced though significant in the patients who did not undergo initial cerebral angiography, such that for the year 1999, 88% patients with unruptured aneurysms were clipped while only 12% were coiled.Patients with unruptured cerebral aneuryms who undergo cerebral angiography are more likely to undergo endovascular coiling rather than clipping.O. Choudhri: None. A. Feroze: None. A. Mantha: None. G. Steinberg: None. H. Do: None.

    View details for DOI 10.1136/neurintsurg-2014-011343.79

    View details for PubMedID 25064927

  • Multiple Sclerosis and Moyamoya Disease Dorfman, L. J., Fischbein, N. J., Zeifert, P. D., Woodard, J. I., Choudhri, O., Bell-Stephens, T. E., Lee, J., Steinberg, G. K., CNRN, NP SAGE PUBLICATIONS LTD. 2014: 956
  • Stepwise Recruitment of Transcellular and Paracellular Pathways Underlies Blood-Brain Barrier Breakdown in Stroke NEURON Knowland, D., Arac, A., Sekiguchi, K. J., Hsu, M., Lutz, S. E., Perrino, J., Steinberg, G. K., Barres, B. A., Nimmerjahn, A., Agalliu, D. 2014; 82 (3): 603-617

    Abstract

    Brain endothelial cells form a paracellular and transcellular barrier to many blood-borne solutes via tight junctions (TJs) and scarce endocytotic vesicles. The blood-brain barrier (BBB) plays a pivotal role in the healthy and diseased CNS. BBB damage after ischemic stroke contributes to increased mortality, yet the contributions of paracellular and transcellular mechanisms to this process in vivo are unknown. We have created a transgenic mouse strain whose endothelial TJs are labeled with eGFP and have imaged dynamic TJ changes and fluorescent tracer leakage across the BBB in vivo, using two-photon microscopy in the t-MCAO stroke model. Although barrier function is impaired as early as 6 hr after stroke, TJs display profound structural defects only after 2 days. Conversely, the number of endothelial caveolae and transcytosis rate increase as early as 6 hr after stroke. Therefore, stepwise impairment of transcellular followed by paracellular barrier mechanisms accounts for the BBB deficits in stroke.

    View details for DOI 10.1016/j.neuron.2014.03.003

    View details for Web of Science ID 000335503200012

    View details for PubMedID 24746419

    View details for PubMedCentralID PMC4016169

  • Intraarterial transplantation of human umbilical cord blood mononuclear cells is more efficacious and safer compared with umbilical cord mesenchymal stromal cells in a rodent stroke model STEM CELL RESEARCH & THERAPY Karlupia, N., Manley, N. C., Prasad, K., Schaefer, R., Steinberg, G. K. 2014; 5

    Abstract

    Stroke is the second leading cause of death worldwide, claims six lives every 60 seconds, and is a leading cause of adult disability across the globe. Tissue plasminogen activator, the only United States Food and Drug Administration (FDA)-approved drug currently available, has a narrow therapeutic time window of less than 5 hours. In the past decade, cells derived from the human umbilical cord (HUC) have emerged as a potential therapeutic alternative for stroke; however, the most effective HUC-derived cell population remains unknown.We compared three cell populations derived from the human umbilical cord: cord blood mononuclear cells (cbMNCs); cord blood mesenchymal stromal cells (cbMSCs), a subpopulation of cbMNCs; and cord matrix MSCs (cmMSCs). We characterized these cells in vitro with flow cytometry and assessed the cells' in vivo efficacy in a 2-hour transient middle cerebral artery occlusion (MCAo) rat model of stroke. cbMNCs, cbMSCs, and cmMSCs were each transplanted intraarterially at 24 hours after stroke.A reduction in neurologic deficit and infarct area was observed in all three cell groups; however, this reduction was significantly enhanced in the cbMNC group compared with the cmMSC group. At 2 weeks after stroke, human nuclei-positive cells were present in the ischemic hemispheres of immunocompetent stroke rats in all three cell groups. Significantly decreased expression of rat brain-derived neurotrophic factor mRNA was observed in the ischemic hemispheres of all three cell-treated and phosphate-buffered saline (PBS) group animals compared with sham animals, although the decrease was least in cbMNC-treated animals. Significantly decreased expression of rat interleukin (IL)-2 mRNA and IL-6 mRNA was seen only in the cbMSC group. Notably, more severe complications (death, eye inflammation) were observed in the cmMSC group compared with the cbMNC and cbMSC groups.All three tested cell types promoted recovery after stroke, but cbMNCs showed enhanced recovery and fewer complications compared with cmMSCs.

    View details for DOI 10.1186/scrt434

    View details for Web of Science ID 000335060600001

    View details for PubMedID 24690461

    View details for PubMedCentralID PMC4055161

  • Composite pleomorphic xanthoastrocytoma-epithelioid glioneuronal tumor with BRAF V600E mutation - report of three cases CLINICAL NEUROPATHOLOGY Aisner, D. L., Newell, K. L., Pollack, A. G., Kleinschmidt-Demasters, B. K., Steinberg, G. K., Smyth, L. T., Vogel, H. 2014; 33 (2): 112-121

    Abstract

    We report three examples of a composite pleomorphic xanthoastrocytoma-epithelioid glioneuronal tumor (PXAEGT) occurring in an adolescent male and two young women. All were superficial and two were located in proximity to the optic nerves. Previously reported composite PXA-gangliogliomas (PXA-GG), have been considered "collision tumors" since little intermingling of the two elements has been present. In contrast, we hypothesized that the two elements of the PXA-EGT might instead derive from a common origin. To test this, we sampled the separate regions of these biphasic tumors and assessed each component for the BRAF V600E mutation, a genetic feature seen in two-thirds of pure PXAs. The BRAF mutation was found in both tumor areas in all cases, suggesting a common origin for the components, rather than a collision tumor. These biphasic PXA-EGT cases represent a new histomorphological combination of neuroepithelial neoplastic elements. These cases further expand the range of glial neoplasia in which epithelioid morphology is encountered, and add to the growing list of biphasic tumors harboring the BRAF V600E mutation.

    View details for DOI 10.5414/NP300679

    View details for Web of Science ID 000333860500003

    View details for PubMedID 24321241

  • Less Invasive Pedicled Omental-Cranial Transposition in Pediatric Patients With Moyamoya Disease and Failed Prior Revascularization OPERATIVE NEUROSURGERY Navarro, R., Chao, K., Gooderham, P. A., Bruzoni, M., Dutta, S., Steinberg, G. K. 2014; 10 (1): 1?14
  • Flexible Omnidirectional Carbon Dioxide Laser as an Effective Tool for Resection of Brainstem, Supratentorial, and Intramedullary Cavernous Malformations OPERATIVE NEUROSURGERY Choudhri, O., Karamchandani, J., Gooderham, P., Steinberg, G. K. 2014; 10 (1): 34?44
  • Stem Cells as an Emerging Paradigm in Stroke 3 Enhancing the Development of Clinical Trials STROKE Savitz, S. I., Cramer, S. C., Wechsler, L., Aronowski, J., Boltze, J., Borlongan, C., Case, C., Chase, T., Chopp, M., Carmichael, S. T., Cramer, S. C., Duncan, P., Finklestein, S., Fischkoff, S., Guzman, R., Hess, D. C., Huang, D., Hinson, J., Kautz, S., Kondziolka, D., Mays, R., Misra, V., Mitsias, P., Modo, M., Muir, K., Savitz, S. I., Sinden, J., Snyder, E., Steinberg, G., Vahidy, F., Wechsler, L., Willing, A., Wolf, S., Yankee, E., Yavagal, D. R. 2014; 45 (2): 634-639

    View details for DOI 10.1161/STROKEAHA.113.003379

    View details for Web of Science ID 000330312500063

    View details for PubMedID 24368562

  • Moderate Hypothermia Inhibits Brain Inflammation and Attenuates Stroke-Induced Immunodepression in Rats CNS NEUROSCIENCE & THERAPEUTICS Gu, L., Xiong, X., Ito, T., Lee, J., Xu, B., Krams, S., Steinberg, G. K., Zhao, H. 2014; 20 (1): 67-75

    Abstract

    Stroke causes both brain inflammation and immunodepression. Mild-to-moderate hypothermia is known to attenuate brain inflammation, but its role in stroke-induced immunodepression (SIID) of the peripheral immune system remains unknown. This study investigated the effects in rats of moderate intra-ischemic hypothermia on SIID and brain inflammation.Stroke was induced in rats by permanent distal middle cerebral artery occlusion combined with transient bilateral common carotid artery occlusion, while body temperature was reduced to 30°C. Real-time PCR, flow cytometry, in vitro T-cell proliferation assays, in vivo delayed-type hypersensitivity (DTH) reaction and confocal microscopy were used to study SIID and brain inflammation.Brief intra-ischemic hypothermia helped maintain certain leukocytes in the peripheral blood and spleen and enhanced T-cell proliferation in vitro and delayed-type hypersensitivity in vivo, suggesting that hypothermia reduces SIID. In contrast, in the brain, brief intra-Ischemic hypothermia inhibited mRNA expression of anti-inflammatory cytokine IL-10 and proinflammatory mediators INF-?, TNF-?, IL-2, IL-1? and MIP-2. Brief intra-Ischemic hypothermia also attenuated the infiltration of lymphocytes, neutrophils (MPO(+) cells) and macrophages (CD68(+) cells) into the ischemic brain, suggesting that hypothermia inhibited brain inflammation.Brief intra-ischemic hypothermia attenuated SIID and protected against acute brain inflammation.

    View details for DOI 10.1111/cns.12160

    View details for Web of Science ID 000328572400009

    View details for PubMedID 23981596

    View details for PubMedCentralID PMC3867545

  • Long-term Results after Cerebral Revascularization in Adult Moyamoya MOYAMOYA DISEASE: DIAGNOSIS AND TREATMENT Navarro, R. L., Burns, T. C., Gooderham, P. A., Steinberg, G. K., Wanebo, J., Khan, N., Zabramski, J., Spetzler, R. 2014: 169?73
  • Exome sequencing of a large multi-ethnic moyamoya (MMD) patient population reveals novel disease-associated genes and provides evidence for ethnic specificity in MMD disease variants Shoemaker, L., Clark, M., Patwardhan, A., Cook, D. J., Steinberg, G. SPRINGER. 2014: 309
  • Phase 1 Clinical Assessment of Human Embryonic Stem Cell (hFSC)-Derived Oligodendrocyte Progenitors in Patients With Neurologically Complete Thoracic Spinal Cord Injuries Lebkowski, J., Fessler, R., Jones, L., Steinberg, G., McKenna, S., Apple, D., Wirth, E. COGNIZANT COMMUNICATION CORP. 2014: 775?76
  • Burr holes for Moyamoya. World neurosurgery Mukerji, N., Steinberg, G. K. 2014; 81 (1): 29-31

    View details for DOI 10.1016/j.wneu.2013.10.002

    View details for PubMedID 24103546

  • Stem cell therapy for acute cerebral injury: what do we know and what will the future bring? CURRENT OPINION IN NEUROLOGY Lemmens, R., Steinberg, G. K. 2013; 26 (6): 617-625

    Abstract

    The central nervous system has limited capacity for regeneration after acute and chronic injury. An attractive approach to stimulate neural plasticity in the brain is to transplant stem cells in order to restore function. Here, we discuss potential mechanisms of action, current knowledge and future perspectives of clinical stem cell research for stroke and traumatic brain injury.Preclinical data using various models suggest stem cell therapy to be a promising therapeutic avenue. Progress has been made in elucidating the mechanism of action of various cell types used, shifting the hypothesis from neural replacement to enhancing endogenous repair processes. Translation of these findings in clinical trials is currently being pursued with emphasis on both safety as well as efficacy.Clinical trials are currently recruiting patients in phase I and II trials to gain more insight in the therapeutic potential of stem cells in acute cerebral injury. A close interplay between results of these clinical trials and more extensive basic research is essential for future trial design, choosing the optimal transplantation strategy and selecting the right patients.

    View details for DOI 10.1097/WCO.0000000000000023

    View details for Web of Science ID 000327554300004

    View details for PubMedID 24136128

  • Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nature immunology Garris, C. S., Wu, L., Acharya, S., Arac, A., Blaho, V. A., Huang, Y., Moon, B. S., Axtell, R. C., Ho, P. P., Steinberg, G. K., Lewis, D. B., Sobel, R. A., Han, D. K., Steinman, L., Snyder, M. P., Hla, T., Han, M. H. 2013; 14 (11): 1166-1172

    View details for DOI 10.1038/ni.2730

    View details for PubMedID 24076635

  • Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nature immunology Garris, C. S., Wu, L., Acharya, S., Arac, A., Blaho, V. A., Huang, Y., Moon, B. S., Axtell, R. C., Ho, P. P., Steinberg, G. K., Lewis, D. B., Sobel, R. A., Han, D. K., Steinman, L., Snyder, M. P., Hla, T., Han, M. H. 2013; 14 (11): 1166-1172

    Abstract

    Sphingosine 1-phosphate (S1P) signaling regulates lymphocyte egress from lymphoid organs into systemic circulation. The sphingosine phosphate receptor 1 (S1P1) agonist FTY-720 (Gilenya) arrests immune trafficking and prevents multiple sclerosis (MS) relapses. However, alternative mechanisms of S1P-S1P1 signaling have been reported. Phosphoproteomic analysis of MS brain lesions revealed S1P1 phosphorylation on S351, a residue crucial for receptor internalization. Mutant mice harboring an S1pr1 gene encoding phosphorylation-deficient receptors (S1P1(S5A)) developed severe experimental autoimmune encephalomyelitis (EAE) due to autoimmunity mediated by interleukin 17 (IL-17)-producing helper T cells (TH17 cells) in the peripheral immune and nervous system. S1P1 directly activated the Jak-STAT3 signal-transduction pathway via IL-6. Impaired S1P1 phosphorylation enhances TH17 polarization and exacerbates autoimmune neuroinflammation. These mechanisms may be pathogenic in MS.

    View details for DOI 10.1038/ni.2730

    View details for PubMedID 24076635

  • CANCER STEM CELL TRANSCRIPTIONAL SUBTYPING OF GLIOBLASTOMA MULTIFORME CORRELATES WITH CLINICALLY RELEVANT MOLECULAR AND IMAGING PHENOTYPES Gevaert, O., Achrol, A., Gholamin, S., Mitra, S., Westbroek, E., Loya, J., Mitchell, L., Chang, S., Steinberg, G., Plevritis, S., Cheshier, S. OXFORD UNIV PRESS INC. 2013: 140
  • CREATING A RADIOGENOMICS MAP OF MULTI-OMICS AND QUANTITATIVE IMAGE FEATURES IN GLIOBLASTOMA MULTIFORME Gevaert, O., Mitchell, L., Achrol, A., Xu, J., Steinberg, G., Cheshier, S., Napel, S., Zaharchuk, G., Plevritis, S. OXFORD UNIV PRESS INC. 2013: 140?41
  • GLIOMETH: A NOVEL DNA METHYLATION SIGNATURE PREDICTS OVERALL SURVIVAL IN GLIOBLASTOMA MULTIFORME Gevaert, O., Achrol, A., Chang, S., Harsh, G., Steinberg, G., Cheshier, S., Plevritis, S. OXFORD UNIV PRESS INC. 2013: 141
  • Microsurgical management of distal anterior cerebral artery aneurysms: from basic to complex, a video review of four cases ACTA NEUROCHIRURGICA Navarro, R., Chao, K., Steinberg, G. K. 2013; 155 (11): 2115-2119

    Abstract

    Distal anterior cerebral artery (DACA) aneurysms represent 2-9 % of intracranial aneurysms. They are often more amenable to surgical rather than endovascular treatment due to the size of parent vessels.We illustrate surgical approaches for DACA aneurysms arising from different segments of the anterior cerebral artery. Cases range from simple unruptured aneurysms to complex ruptured aneurysms requiring reconstruction and intracranial bypass.The interhemispheric approach typically provides an adequate surgical corridor for surgical clipping of DACA aneurysms. Patient positioning, image guidance, and preoperative angiography help maximize safety and efficacy of surgery.

    View details for DOI 10.1007/s00701-013-1855-1

    View details for Web of Science ID 000325815600014

    View details for PubMedID 24046060

  • Moyamoya syndrome with sickle cell trait INTERNATIONAL JOURNAL OF LABORATORY HEMATOLOGY Agrawal, R., Berube, C., Steinberg, G., George, T. I. 2013; 35 (5): E8?E9

    View details for DOI 10.1111/ijlh.12048

    View details for Web of Science ID 000325079000003

    View details for PubMedID 23369159

  • Complete visual recovery after incipient crao due to ocular hypoperfusion in a patient with moyamoya disease. Retinal cases & brief reports Lad, E. M., Lad, S. P., Ung, C., Jain, A., Steinberg, G. K., Gaynon, M. W. 2013; 7 (3): 248-251

    Abstract

    The purpose of this study was to report a case of an impending central retinal artery occlusion with hypoperfusion in a moyamoya patient.A young, surgically revascularized moyamoya patient experienced severe unilateral vision loss from 20/25 to hand motions because of impending central retinal artery occlusion. The patient was treated with a combination of intermittent ocular massage, intraocular pressure-lowering medications, and aspirin.A case of a moyamoya patient at Stanford University Medical Center.Visual acuity was restored to baseline by improving the ocular arterial-venous gradient after prompt administration of ocular massage, intraocular pressure-lowering drops, and aspirin.This dramatic result suggests that, if performed in a timely manner, augmentation of ocular perfusion can result in complete restoration of vision in some cases of incipient central retinal artery occlusion.

    View details for DOI 10.1097/ICB.0b013e31828eef20

    View details for PubMedID 25391116

  • Delayed retraction of the pipeline embolization device and corking failure: pitfalls of pipeline embolization device placement in the setting of a ruptured aneurysm. Neurosurgery McTaggart, R. A., Santarelli, J. G., Marcellus, M. L., Steinberg, G. K., Dodd, R. L., Do, H. M., Marks, M. P. 2013; 72 (2): onsE245-51

    Abstract

    : The safety of flow-diverting stents for the treatment of ruptured intracranial aneurysms is unknown.: A 35-year-old woman with a ruptured dissecting aneurysm of the intradural right vertebral artery and incorporating the right posterior inferior cerebellar artery was treated with a Pipeline Embolization Device (PED). Five days after reconstruction of the diseased right vertebral segment, she was treated for vasospasm, and retraction of the PED was observed, leaving her dissecting aneurysm unprotected. A second PED was placed with coverage of the aneurysm, but vasospasm complicated optimal positioning of the device.: In addition to the potential risks of dual antiplatelet therapy in these patients, this case illustrates 2 pitfalls of flow-diverting devices in vessels in vasospasm: delayed retraction of the device and difficulty positioning the device for deployment in the setting of vasospasm.: ANR, aneurysmPED, Pipeline Embolization DevicePICA, posterior inferior cerebellar arterySAH, subarachnoid hemorrhage.

    View details for DOI 10.1227/NEU.0b013e31827fc9be

    View details for PubMedID 23190640

  • A Concerted Appeal for International Cooperation in Preclinical Stroke Research STROKE Dirnagl, U., Hakim, A., Macleod, M., Fisher, M., Howells, D., Alan, S. M., Steinberg, G., Planas, A., Boltze, J., Savitz, S., Iadecola, C., Meairs, S. 2013; 44 (6): 1754-1760

    View details for DOI 10.1161/STROKEAHA.113.000734

    View details for Web of Science ID 000319465400054

    View details for PubMedID 23598526

    View details for PubMedCentralID PMC3933930

  • Delayed Retraction of the Pipeline Embolization Device and Corking Failure: Pitfalls of Pipeline Embolization Device Placement in the Setting of a Ruptured Aneurysm NEUROSURGERY McTaggart, R. A., Santarelli, J. G., Marcelus, M. L., Steinberg, G. K., Dodd, R. L., Do, H. M., Marks, M. P. 2013; 72 (6): 237-237

    Abstract

    : The safety of flow-diverting stents for the treatment of ruptured intracranial aneurysms is unknown.: A 35-year-old woman with a ruptured dissecting aneurysm of the intradural right vertebral artery and incorporating the right posterior inferior cerebellar artery was treated with a Pipeline Embolization Device (PED). Five days after reconstruction of the diseased right vertebral segment, she was treated for vasospasm, and retraction of the PED was observed, leaving her dissecting aneurysm unprotected. A second PED was placed with coverage of the aneurysm, but vasospasm complicated optimal positioning of the device.: In addition to the potential risks of dual antiplatelet therapy in these patients, this case illustrates 2 pitfalls of flow-diverting devices in vessels in vasospasm: delayed retraction of the device and difficulty positioning the device for deployment in the setting of vasospasm.: ANR, aneurysmPED, Pipeline Embolization DevicePICA, posterior inferior cerebellar arterySAH, subarachnoid hemorrhage.

    View details for DOI 10.1227/NEU.0b013e31827fc9be

    View details for Web of Science ID 000319535100029

  • Spinal pilocytic astrocytoma in an elderly patient. World neurosurgery Harraher, C. D., Vogel, H., Steinberg, G. K. 2013; 79 (5-6): 799 E7-9

    Abstract

    Astrocytomas are the most common intramedullary spinal cord tumor in pediatric and adolescent patients and the incidence decreases with age. There are very few cases of spinal pilocytic astrocytomas (World Health Organization grade 1) reported after the fourth decade. We report the oldest known case of a pathologically confirmed spinal pilocytic astrocytoma.A 78-year-old woman presented with 12 months of bilateral lower extremity numbness. Magnetic resonance imaging revealed cord edema extending from C6 to T4. There was a 12-mm enhancing intramedullary lesion at the C7-T1 level with an associated cyst. Several years prior, she had seen a neurologist for lower extremity numbness and was diagnosed with peripheral neuropathy.She underwent C7-T1 laminectomy with partial resection of the spinal cord tumor and drainage of the cyst. Pathologic examination demonstrated a mildly cellular proliferation of astrocytes set in an eosinophilic fibrillar background. There were numerous Rosenthal fibers and prominent vasculature. There were no malignant features. The pathologic diagnosis was consistent with pilocytic astrocytoma, World Health Organization grade 1. The patient returned to her baseline function after several weeks and the imaging remained stable at the 4-month follow-up.Spinal pilocytic astrocytomas constitute 90% of intramedullary spinal cord tumors in patients younger than 10 years and 60% of those in adolescent patients. There are very few reported cases in patients older than 50 years. Our patient had an indolent course, cervical-thoracic location, imaging characteristics, and pathology that all support a diagnosis of pilocytic astrocytoma. This case highlights that low-grade lesions can occur in elderly patients and an aggressive approach may not be indicated.

    View details for DOI 10.1016/j.wneu.2011.10.033

    View details for PubMedID 22120566

  • Spinal Pilocytic Astrocytoma in an Elderly Patient WORLD NEUROSURGERY Harraher, C. D., Vogel, H., Steinberg, G. K. 2013; 79 (5-6)

    Abstract

    Astrocytomas are the most common intramedullary spinal cord tumor in pediatric and adolescent patients and the incidence decreases with age. There are very few cases of spinal pilocytic astrocytomas (World Health Organization grade 1) reported after the fourth decade. We report the oldest known case of a pathologically confirmed spinal pilocytic astrocytoma.A 78-year-old woman presented with 12 months of bilateral lower extremity numbness. Magnetic resonance imaging revealed cord edema extending from C6 to T4. There was a 12-mm enhancing intramedullary lesion at the C7-T1 level with an associated cyst. Several years prior, she had seen a neurologist for lower extremity numbness and was diagnosed with peripheral neuropathy.She underwent C7-T1 laminectomy with partial resection of the spinal cord tumor and drainage of the cyst. Pathologic examination demonstrated a mildly cellular proliferation of astrocytes set in an eosinophilic fibrillar background. There were numerous Rosenthal fibers and prominent vasculature. There were no malignant features. The pathologic diagnosis was consistent with pilocytic astrocytoma, World Health Organization grade 1. The patient returned to her baseline function after several weeks and the imaging remained stable at the 4-month follow-up.Spinal pilocytic astrocytomas constitute 90% of intramedullary spinal cord tumors in patients younger than 10 years and 60% of those in adolescent patients. There are very few reported cases in patients older than 50 years. Our patient had an indolent course, cervical-thoracic location, imaging characteristics, and pathology that all support a diagnosis of pilocytic astrocytoma. This case highlights that low-grade lesions can occur in elderly patients and an aggressive approach may not be indicated.

    View details for DOI 10.1016/j.wneu.2011.10.033

    View details for Web of Science ID 000320923300051

    View details for PubMedID 22120566

  • Clip reconstruction of midbasilar aneurysms. World neurosurgery Cook, D. J., Mukerji, N., Steinberg, G. K. 2013; 79 (5-6): 675-677

    View details for DOI 10.1016/j.wneu.2012.10.052

    View details for PubMedID 23111225

  • Derivation of Injury-Responsive Dendritic Cells for Acute Brain Targeting and Therapeutic Protein Delivery in the Stroke-Injured Rat PLOS ONE Manley, N. C., Caso, J. R., Works, M. G., Cutler, A. B., Zemlyak, I., Sun, G., Munhoz, C. D., Chang, S., Sorrells, S. F., Ermini, F. V., Decker, J. H., Bertrand, A. A., Dinkel, K. M., Steinberg, G. K., Sapolsky, R. M. 2013; 8 (4)

    Abstract

    Research with experimental stroke models has identified a wide range of therapeutic proteins that can prevent the brain damage caused by this form of acute neurological injury. Despite this, we do not yet have safe and effective ways to deliver therapeutic proteins to the injured brain, and this remains a major obstacle for clinical translation. Current targeted strategies typically involve invasive neurosurgery, whereas systemic approaches produce the undesirable outcome of non-specific protein delivery to the entire brain, rather than solely to the injury site. As a potential way to address this, we developed a protein delivery system modeled after the endogenous immune cell response to brain injury. Using ex-vivo-engineered dendritic cells (DCs), we find that these cells can transiently home to brain injury in a rat model of stroke with both temporal and spatial selectivity. We present a standardized method to derive injury-responsive DCs from bone marrow and show that injury targeting is dependent on culture conditions that maintain an immature DC phenotype. Further, we find evidence that when loaded with therapeutic cargo, cultured DCs can suppress initial neuron death caused by an ischemic injury. These results demonstrate a non-invasive method to target ischemic brain injury and may ultimately provide a way to selectively deliver therapeutic compounds to the injured brain.

    View details for DOI 10.1371/journal.pone.0061789

    View details for Web of Science ID 000317893400111

    View details for PubMedID 23613937

    View details for PubMedCentralID PMC3627911

  • Immune response profiling identifies autoantibodies specific to Moyamoya patients ORPHANET JOURNAL OF RARE DISEASES Sigdel, T. K., Shoemaker, L. D., Chen, R., Li, L., Butte, A. J., Sarwal, M. M., Steinberg, G. K. 2013; 8

    Abstract

    Moyamoya Disease is a rare, devastating cerebrovascular disorder characterized by stenosis/occlusion of supraclinoid internal carotid arteries and development of fragile collateral vessels. Moyamoya Disease is typically diagnosed by angiography after clinical presentation of cerebral hemorrhage or ischemia. Despite unclear etiology, previous reports suggest there may be an immunological component.To explore the role of autoimmunity in moyamoya disease, we used high-density protein arrays to profile IgG autoantibodies from the sera of angiographically-diagnosed Moyamoya Disease patients and compared these to healthy controls. Protein array data analysis followed by bioinformatics analysis yielded a number of auto-antibodies which were further validated by ELISA for an independent group of MMD patients (n?=?59) and control patients with other cerebrovascular diseases including carotid occlusion, carotid stenosis and arteriovenous malformation.We identified 165 significantly (p?

    View details for DOI 10.1186/1750-1172-8-45

    View details for Web of Science ID 000318759100001

    View details for PubMedID 23518061

    View details for PubMedCentralID PMC3648437

  • Case Series: Intraoperative Neurophysiologic Monitoring (IONM) Changes during Presumably "Non-Critical" Periods of Surgery Lee, L., Cho, S., Viet Nguyen, Ferreira, R., Taricco, L., Steinberg, G., Dodd, R., Ryu, S., Lopez, J. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • In reply. The genetics of moyamoya disease: recent insights into the pathogenesis of the disease. Neurosurgery Achrol, A. S., Khan, N., Steinberg, G. K. 2013; 72 (2): E321-2

    View details for DOI 10.1227/NEU.0b013e31827bc1c1

    View details for PubMedID 23149962

  • Revascularization in Patients with Moyamoya Decreases Abnormally High Posterior Circulation Arterial Flows Measured by Quantitative Magnetic Resonance Angiography Navarro, R., Lober, R., Feroze, A., Khan, N., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Monocyte-derived Macrophages Can Reduce Damage After Experimental Ischemic Stroke Nishiyama, Y., Arac, A., Bliss, T. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Meningeal Mast Cells Can Exacerbate Stroke Pathology In Mice Arac, A., Grimbaldeston, M. A., Nepomuceno, A. R., Olayiwola, O., Pereira, M. P., Vogel, H., Tsai, M., Galli, S. J., Bliss, T. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Increaed GABA(A) Mediated Synaptic Activity and Structural Remodeling in Peri-infarct Cortex Layer 5 in the Post-stroke Rodent Brain. Hiu, T., Bliss, T. M., Farzampour, Z., Paz, J. T., Olson, A., Micheva, K. D., Wang, E. H., Wang, G., Manley, N., Nishiyama, Y., Arac, A., O'Rourke, N., Huguenard, J. R., Smith, S. J., Steinberg, G. K., Tran, K. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Human Neural Stem Cells Enhance Synaptic Structural Remodeling in the Ischemic Brain. Hiu, T., Bliss, T. M., Manley, N., Wang, E. H., Wang, G., Micheva, K. D., Olson, A., Smith, S. J., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Optogenetic Stimulation of Human Neural Stem Cell Grafts In Ischemic Brain Daadi, M., Lee, S., Bajar, B., Lo, M., Ramakrishnan, C., Sun, G., Deisseroth, K., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2013
  • Imaging neural stem cell graft-induced structural repair in stroke. Cell transplantation Daadi, M. M., Hu, S., Klausner, J., Li, Z., Sofilos, M., Sun, G., Wu, J. C., Steinberg, G. K. 2013; 22 (5): 881-892

    Abstract

    Stem cell therapy ameliorates motor deficits in experimental stroke model. Multimodal molecular imaging enables real time longitudinal monitoring of infarct location, size and transplant survival. In the present study, we used magnetic resonance imaging (MRI) and positron emission tomography (PET) to track the infarct evolution, tissue repair and the fate of grafted cells. We genetically engineered embryonic stem cell -derived neural stem cells (NSCs) with a triple fusion reporter gene to express monomeric red fluorescence protein and herpes simplex virus truncated thymidine kinase for multimodal molecular imaging and SPIO labeled for MRI. The infarct size, as well as fate and function of grafted cells were tracked in real time for 3 months using MRI and PET. We report that grafted NSCs reduced the infarct size in animals with less then 1 cm³ initial infarct in a dose-dependent manner, while larger stroke was not amenable to such beneficial effects. PET imaging revealed increased metabolic activity in grafted animals and visualized functioning grafted cells in vivo. Immunohistopathological analysis demonstrated that, after 3-month survival period grafted NSCs dispersed in the stroke-lesioned parenchyma and differentiated into neurons, astrocytes and oligodendrocytes. Longitudinal multimodal imaging provides insights into time course dose-dependant interactions between NSC grafts and structural changes in infracted tissue.

    View details for PubMedID 23044338

  • The Role of Radiosurgery for the Treatment of Cerebral Cavernous Malformations HANDBOOK OF RADIOSURGERY IN CNS DISEASE Gooderham, P. A., Steinberg, G. K., Lim, M., Hsu, W., Rigamonti, D., Kleinberg, L. R. 2013: 147?52
  • Combined endovascular and microsurgical management of complex cerebral aneurysms FRONTIERS IN NEUROLOGY Choudhri, O., Mukerji, N., Steinberg, G. K. 2013; 4

    Abstract

    Cerebral aneurysms are associated with a 50% mortality rate after rupture and patients can suffer significant morbidity during subsequent treatment. Neurosurgical management of both ruptured and unruptured aneurysms has evolved over the years. The historical practice of using microsurgical clipping to treat aneurysms has benefited in the last two decades from tremendous improvement in endovascular technology. Microsurgery and endovascular therapies are often viewed as competing treatments but it is important to recognize their individual limitations. Some aneurysms are considered complex, due to several factors such as aneurysm anatomy and a patient's clinical condition. A complex aneurysm often cannot be completely excluded with a single approach and its successful treatment requires a combination of microsurgical and endovascular techniques. Planning such an approach relies on understanding aneurysm anatomy and thus should routinely include 3D angiographic imaging. In patients with ruptured aneurysms, endovascular coiling is a well-tolerated early treatment and residual aneurysms can be treated with intervals of definitive clipping. Microsurgical clipping also can be used to reconstruct the neck of a complex aneurysm, allowing successful placement of coils across a narrow neck. Endovascular techniques are assisted by balloons, which can be used in coiling and testing parent vessel occlusion before sacrifice. In some cases microsurgical bypasses can provide alternate flow for planned vessel sacrifice. We present current paradigms for combining endovascular and microsurgical approaches to treat complex aneurysms and share our experience in 67 such cases. A dual microsurgical-endovascular approach addresses the challenge of intracranial aneurysms. This combination can be performed safely and produces excellent rates of aneurysm obliteration. Hybrid angiographic operating-room suites can foster seamless and efficient complementary application of these two modalities.

    View details for DOI 10.3389/fneur.2013.00108

    View details for Web of Science ID 000209629000107

    View details for PubMedCentralID PMC3737456

  • Aberrant expression of lymphatic-associated proteins in human brain arteriovenous malformations Shoemaker, L., Fuentes, L., Santiago, S., Steinberg, G., Chang, S. SPRINGER. 2013: 269?70
  • Imaging Neural Stem Cell Graft-Induced Structural Repair in Stroke CELL TRANSPLANTATION Daadi, M. M., Hu, S., Klausner, J., Li, Z., Sofilos, M., Sun, G., Wu, J. C., Steinberg, G. K. 2013; 22 (5): 881-892

    Abstract

    Stem cell therapy ameliorates motor deficits in experimental stroke model. Multimodal molecular imaging enables real time longitudinal monitoring of infarct location, size and transplant survival. In the present study, we used magnetic resonance imaging (MRI) and positron emission tomography (PET) to track the infarct evolution, tissue repair and the fate of grafted cells. We genetically engineered embryonic stem cell -derived neural stem cells (NSCs) with a triple fusion reporter gene to express monomeric red fluorescence protein and herpes simplex virus truncated thymidine kinase for multimodal molecular imaging and SPIO labeled for MRI. The infarct size, as well as fate and function of grafted cells were tracked in real time for 3 months using MRI and PET. We report that grafted NSCs reduced the infarct size in animals with less then 1 cm³ initial infarct in a dose-dependent manner, while larger stroke was not amenable to such beneficial effects. PET imaging revealed increased metabolic activity in grafted animals and visualized functioning grafted cells in vivo. Immunohistopathological analysis demonstrated that, after 3-month survival period grafted NSCs dispersed in the stroke-lesioned parenchyma and differentiated into neurons, astrocytes and oligodendrocytes. Longitudinal multimodal imaging provides insights into time course dose-dependant interactions between NSC grafts and structural changes in infracted tissue.

    View details for DOI 10.3727/096368912X656144

    View details for Web of Science ID 000318585300010

  • Combined endovascular and microsurgical management of complex cerebral aneurysms. Frontiers in neurology Choudhri, O., Mukerji, N., Steinberg, G. K. 2013; 4: 108-?

    Abstract

    Cerebral aneurysms are associated with a 50% mortality rate after rupture and patients can suffer significant morbidity during subsequent treatment. Neurosurgical management of both ruptured and unruptured aneurysms has evolved over the years. The historical practice of using microsurgical clipping to treat aneurysms has benefited in the last two decades from tremendous improvement in endovascular technology. Microsurgery and endovascular therapies are often viewed as competing treatments but it is important to recognize their individual limitations. Some aneurysms are considered complex, due to several factors such as aneurysm anatomy and a patient's clinical condition. A complex aneurysm often cannot be completely excluded with a single approach and its successful treatment requires a combination of microsurgical and endovascular techniques. Planning such an approach relies on understanding aneurysm anatomy and thus should routinely include 3D angiographic imaging. In patients with ruptured aneurysms, endovascular coiling is a well-tolerated early treatment and residual aneurysms can be treated with intervals of definitive clipping. Microsurgical clipping also can be used to reconstruct the neck of a complex aneurysm, allowing successful placement of coils across a narrow neck. Endovascular techniques are assisted by balloons, which can be used in coiling and testing parent vessel occlusion before sacrifice. In some cases microsurgical bypasses can provide alternate flow for planned vessel sacrifice. We present current paradigms for combining endovascular and microsurgical approaches to treat complex aneurysms and share our experience in 67 such cases. A dual microsurgical-endovascular approach addresses the challenge of intracranial aneurysms. This combination can be performed safely and produces excellent rates of aneurysm obliteration. Hybrid angiographic operating-room suites can foster seamless and efficient complementary application of these two modalities.

    View details for DOI 10.3389/fneur.2013.00108

    View details for PubMedID 23964263

    View details for PubMedCentralID PMC3737456

  • Moyamoya Disease Can Masquerade as Multiple Sclerosis NEUROLOGIST Dorfman, L. J., Fischbein, N. J., Woodard, J. I., Choudhri, O., Bell-Stephens, T. E., Steinberg, G. K. 2012; 18 (6): 398-403

    Abstract

    Moyamoya disease (MM) is a rare disorder of the cerebral arterial circulation, whereas multiple sclerosis (MS) is a relatively common immune-mediated attack on central myelin. Despite the differences in pathogenesis, the 2 disorders share some clinical features which can lead to diagnostic confusion: both can affect young adults, cause intermittent neurological symptoms, and show multifocal abnormalities on brain imaging.To emphasize the need for early consideration of MM in the differential diagnosis of MS-spectrum disorders.Chart reviews and individual case analyses.We present detailed descriptions of 3 patients with MM, and summary data on 8 additional cases, in which there was diagnostic confusion with MS, with delays in treatment ranging from 2 months to 19 years (median=4 y).MM can be misdiagnosed as MS, leading to delay in correct treatment. We highlight the clinical and radiologic features which allow differentiation of these conditions early in the course, when treatment can have maximum benefit.

    View details for DOI 10.1097/NRL.0b013e31826a99a1

    View details for Web of Science ID 000310628800012

    View details for PubMedID 23114675

  • Cerebral proliferative angiopathy JOURNAL OF NEUROINTERVENTIONAL SURGERY Marks, M. P., Steinberg, G. K. 2012; 4 (5)

    Abstract

    Cerebral proliferative angiopathy is a rare lesion marked by diffuse intravascular shunting, which should be differentiated from brain arteriovenous malformations. A patient is presented with cerebral proliferative angiopathy and documented progressive development of hypervascular shunting involving extensive portions of the left hemisphere. The patient had angiographic and laboratory evidence of angiogenesis and a progressive neurologic deterioration which corresponded to the development of her lesion. This is the first case which documents the progressive proliferative changes seen with this abnormality.

    View details for DOI 10.1136/neurintsurg-2011-010027

    View details for PubMedID 21990497

  • Sex Differences in Clinical Presentation and Treatment Outcomes in Moyamoya Disease NEUROSURGERY Khan, N., Achrol, A. S., Guzman, R., Burns, T. C., Dodd, R., Bell-Stephens, T., Steinberg, G. K. 2012; 71 (3): 587-593

    Abstract

    Moyamoya (MM) disease is an idiopathic steno-occlusive angiopathy occurring more frequently in females.To evaluate sex differences in preoperative symptoms and treatment outcomes after revascularization surgery.We analyzed 430 MM disease patients undergoing 717 revascularization procedures spanning 19 years (1991-2010) and compared gender differences in preoperative symptoms and long-term outcomes after surgical revascularization.A total of 307 female and 123 male patients (ratio, 2.5:1) with a mean age of 31.0 ± 16.7 years and adults-to-children ratio of 2.5:1 underwent 717 revascularization procedures. Female patients were more likely to experience preoperative transient ischemic attacks (odds ratio: 2.1, P = .001) and less likely to receive a diagnosis of unilateral MM disease (odds ratio: 0.6, P = .04). No association was observed between sex and risk of preoperative ischemic or hemorrhagic stroke. There was no difference in neurological outcome because both male and female patients experienced significant improvement in the modified Rankin Scale score after surgery (P < .0001). On Kaplan-Meier survival analysis, 5-year cumulative risk of adverse postoperative events despite successful revascularization was 11.4% in female vs 5.3% in male patients (P = .05). In multivariate Cox proportional hazards analysis, female sex trended toward an association with adverse postoperative events (hazard ratio: 1.9, P = .14).Female patients are more susceptible to the development of preoperative transient ischemic attack and may be at higher risk of adverse postoperative events despite successful revascularization. There is, however, no sex difference in neurological outcome because patients of both sexes experience significant improvement in neurological status with low risk of the development of future ischemic events after surgical revascularization.

    View details for DOI 10.1227/NEU.0b013e3182600b3c

    View details for Web of Science ID 000308074400016

    View details for PubMedID 22718024

  • A Simplified Method for Administration of Intra-Arterial Nicardipine for Vasospasm With Cervical Catheter Infusion NEUROSURGERY Pandey, P., Steinberg, G. K., Dodd, R., Do, H. M., Marks, M. P. 2012; 71: 77-85

    Abstract

    Cerebral vasospasm is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Nicardipine has previously been used to treat vasospasm through superselective intracranial microcatheter injections.To evaluate a simple method of treatment of vasospasm with slow infusion of nicardipine from a cervical catheter.Twenty-seven patients with symptomatic vasospasm were treated over 4 years with cervical catheter infusions. Nicardipine was infused at 20 mg/h for 30 to 60 minutes. Angioplasty was used in severe cases at the operator's discretion. Outcome at discharge and follow-up was evaluated with Glasgow Outcome Scale.Twenty-seven patients (17 women, 12 men) received intra-arterial therapy for vasospasm. Vasospasm treatment was done at a mean post-hemorrhage date of 7.2 days (range, 4-15 days). They underwent 48 sessions of treatment (mean, 1.8 per patient) in 72 separate arterial territories. Twelve patients underwent multiple treatments. The mean dose used per session was 19.2 mg (range, 5-50 mg). Four patients underwent angioplasty for severe vasospasm. Twenty-two patients (81.5%) had clinical improvement after the infusion. Angiographic improvement was seen in 86.1% of the vessels analyzed, which had moderate or severe spasm before infusion. Overall, 17 patients (62.9%) had good outcome (Glasgow Outcome Scale score, 4 and 5) at discharge, 11 had poor outcome, and 1 patient died. Follow-up was available in 19 patients, and 18 were doing well (Glasgow Outcome Scale score, 4 and 5).Intra-arterial nicardipine is an effective and safe treatment for cerebral vasospasm. In most patients, infusion can be performed from the cervical catheter, with microcatheter infusion and angioplasty reserved for the more severe and resistant cases.

    View details for DOI 10.1227/NEU.0b013e3182426257

    View details for PubMedID 22105209

  • Tracking Stem Cells for Cellular Therapy in Stroke CURRENT PHARMACEUTICAL DESIGN Manley, N. C., Steinberg, G. K. 2012; 18 (25): 3685-3693

    Abstract

    Stem cell transplantation has emerged as a promising treatment strategy for stroke. The development of effective ways to monitor transplanted stem cells is essential to understand how stem cell transplantation enhances stroke recovery and ultimately will be an indispensable tool for advancing stem cell therapy to the clinic. In this review, we describe existing methods of tracking transplanted stem cells in vivo, including optical imaging, magnetic resonance imaging (MRI), and positron emission tomography (PET), with emphasis on the benefits and drawbacks of each imaging approach. Key considerations such as the potential impact of each tracking system on stem cell function, as well as its relative applicability to humans are discussed. Finally, we describe multi-modal imaging strategies as a more comprehensive method to track transplanted stem cells in the stroke-injured brain.

    View details for Web of Science ID 000307869600010

    View details for PubMedID 22571604

  • Dopaminergic Neurons from Midbrain-Specified Human Embryonic Stem Cell-Derived Neural Stem Cells Engrafted in a Monkey Model of Parkinson's Disease PLOS ONE Daadi, M. M., Grueter, B. A., Malenka, R. C., Redmond, D. E., Steinberg, G. K. 2012; 7 (7)

    Abstract

    The use of human embryonic stem cells (hESCs) to repair diseased or injured brain is promising technology with significant humanitarian, societal and economic impact. Parkinson's disease (PD) is a neurological disorder characterized by the loss of midbrain dopaminergic (DA) neurons. The generation of this cell type will fulfill a currently unmet therapeutic need. We report on the isolation and perpetuation of a midbrain-specified self-renewable human neural stem cell line (hNSCs) from hESCs. These hNSCs grew as a monolayer and uniformly expressed the neural precursor markers nestin, vimentin and a radial glial phenotype. We describe a process to direct the differentiation of these hNSCs towards the DA lineage. Glial conditioned media acted synergistically with fibroblastic growth factor and leukemia inhibitory factor to induce the expression of the DA marker, tyrosine hydroxylase (TH), in the hNSC progeny. The glial-derived neurotrophic factor did not fully mimic the effects of conditioned media. The hNSCs expressed the midbrain-specific transcription factors Nurr1 and Pitx3. The inductive effects did not modify the level of the glutamic acid decarboxylase (GAD) transcript, a marker for GABAergic neurons, while the TH transcript increased 10-fold. Immunocytochemical analysis demonstrated that the TH-expressing cells did not co-localize with GAD. The transplantation of these DA-induced hNSCs into the non-human primate MPTP model of PD demonstrated that the cells maintain their DA-induced phenotype, extend neurite outgrowths and express synaptic markers.

    View details for Web of Science ID 000306507000069

    View details for PubMedID 22815935

    View details for PubMedCentralID PMC3398927

  • Distinctive Effects of T Cell Subsets in Neuronal Injury Induced by Cocultured Splenocytes In Vitro and by In Vivo Stroke in Mice STROKE Gu, L., Xiong, X., Zhang, H., Xu, B., Steinberg, G. K., Zhao, H. 2012; 43 (7): 1941-1946

    Abstract

    T cells and their subsets modulate ischemic brain injury. We studied the effects of the absence of T cell subsets on brain infarction after in vivo stroke and then used an in vitro coculture system of splenocytes and neurons to further identify the roles of T cell subsets in neuronal death.Stroke was induced by middle cerebral artery suture occlusion in mice and infarct sizes were measured 2 days poststroke. Splenocytes were cocultured with neurons, and neuronal survival was measured 3 days later.A deficiency of both T and B cells (severe combined immunodeficiency) and the paucity of CD4 or CD8 T cells equally resulted in smaller infarct sizes as measured 2 days poststroke. Although a functional deficiency of regulatory T cells had no effect, impaired Th1 immunity reduced infarction and impaired Th2 immunity aggravated brain injury, which may be due to an inhibited and enhanced inflammatory response in mice deficient in Th1 and Th2 immunity, respectively. In the in vitro coculture system, wild-type splenocytes resulted in dose-dependent neuronal death. The neurotoxicity of splenocytes from these immunodeficient mice was consistent with their effects on stroke in vivo, except for the mice with the paucity of CD4 or CD8 T cells, which did not alter the ratio of neuronal death.T cell subsets play critical roles in brain injury induced by stroke. The detrimental versus beneficial effects of Th1 cells and Th2 cells both in vivo and in vitro reveal differential therapeutic target strategies for stroke treatment.

    View details for DOI 10.1161/STROKEAHA.112.656611

    View details for Web of Science ID 000305882000044

    View details for PubMedID 22678086

    View details for PubMedCentralID PMC3506376

  • The predictive value of serum myeloperoxidase for vasospasm in patients with aneurysmal subarachnoid hemorrhage NEUROSURGICAL REVIEW Lim, M., Bower, R. S., Wang, Y., Sims, L., Bower, M. R., Camara-Quintana, J., Li, G., Cheshier, S., Harsh, G. R., Steinberg, G. K., Guccione, S. 2012; 35 (3): 413-419

    Abstract

    Vasospasm is a major contributor to morbidity and mortality in aneurysmal subarachnoid hemorrhage (SAH), with inflammation playing a key role in its pathophysiology. Myeloperoxidase (MPO), an inflammatory marker, was examined as a potential marker of vasospasm in patients with SAH. Daily serum samples from patients with aneurysmal SAH were assayed for MPO, and transcranial Doppler (TCDs) and neurological exams were assessed to determine vasospasm. Suspected vasospasm was confirmed by angiography. Peak MPO levels were then compared with timing of onset of vasospasm, based on clinical exams, TCDs and cerebral angiography. Patients with vasospasm had a mean MPO level of 115.5 ng/ml, compared to 59.4 ng/ml in those without vasospasm, 42.0 ng/ml in those with unruptured aneurysms, and 4.3 ng/ml in normal controls. In patients who experienced vasospasm, MPO was elevated above the threshold on the day of, or at any point prior to, vasospasm in 10 of 15 events (66.7%), and on the day of, or within 2 days prior to, vasospasm in 8 of 15 events (53.3%). Elevated serum MPO correlates with clinically evident vasospasm following aneurysmal SAH. The potential utility of MPO as a marker of vasospasm is discussed.

    View details for DOI 10.1007/s10143-012-0375-4

    View details for Web of Science ID 000305230000023

    View details for PubMedID 22370810

  • Lithium Treatment Reduces Brain Injury Induced by Focal Ischemia with Partial Reperfusion and the Protective Mechanisms Dispute the Importance of Akt Activity AGING AND DISEASE Takahashi, T., Steinberg, G. K., Zhao, H. 2012; 3 (3): 226-233

    Abstract

    Lithium is a mood stabilizer shown to have neuroprotective effects against several chronic and acute neuronal injuries, including stroke. However, it is unknown whether lithium treatment protects against brain injury post-stroke in a rat model of permanent distal middle cerebral artery occlusion (MCAo) combined with transient bilateral common carotid artery occlusion (CCAo), a model that mimics human stroke with partial reperfusion. In addition, whether lithium treatment alters Akt activity as measured by the kinase activity assay has not been reported, although it is known to inhibit GSK3? activity. After stroke, Akt activity contributes to neuronal survival while GSK3? activity causes neuronal death. We report that a bolus of lithium injection at stroke onset robustly reduced infarct size measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining at 48 h post-stroke and inhibited cell death in the ischemic penumbra, but not in the ischemic core, as shown by TUNEL staining performed 24 h post-stroke. However, lithium treatment did not alter the reduction in Akt activity as measured by Akt kinase assay. We further showed that lithium did not alter phosphorylated GSK3? protein levels, or the degradation of ?-catenin, a substrate of GSK3?, which is consistent with previous findings that long-term treatment is required for lithium to alter GSK3? phosphorylation. In summary, we show innovative data that lithium protects against stroke in a focal ischemia model with partial reperfusion, however, our results dispute the importance of Akt activity in the protective effects of lithium.

    View details for Web of Science ID 000208951000001

    View details for PubMedCentralID PMC3375079

  • PHOSPHORYLATED MITOGEN-ACTIVATED PROTEIN KINASE/EXTRACELLULAR SIGNAL-REGULATED KINASE 1/2 MAY NOT ALWAYS REPRESENT ITS KINASE ACTIVITY IN A RAT MODEL OF FOCAL CEREBRAL ISCHEMIA WITH OR WITHOUT ISCHEMIC PRECONDITIONING NEUROSCIENCE Takahashi, T., Steinberg, G. K., Zhao, H. 2012; 209: 155-160

    Abstract

    The extracellular signal-regulated kinase (ERK) 1/2 protein requires a dual phosphorylation at conserved threonine and tyrosine residues to be fully activated under normal physiological conditions. Thus, ERK1/2 kinase activity is often defined by the quantity of phosphorylated kinase. However, this may not accurately represent its true activity under certain pathological conditions. We investigated whether ERK1/2 kinase activity is proportional to its phosphorylation state in a rat focal ischemia model with and without rapid ischemic preconditioning. We showed that phosphorylated-ERK1/2 protein levels were increased 2.6±0.07-fold, and ERK1/2 kinase activity was increased 10.6±1.9-fold in animals receiving ischemic preconditioning alone without test ischemia compared with sham group (P<0.05, n=6/group), suggesting that phosphorylated-ERK1/2 protein levels represent its kinase activity under these conditions. However, preconditioning plus test ischemia robustly blocked ERK1/2 kinase activity, whereas it increased phosphorylated-ERK1/2 protein levels beyond those receiving test ischemia alone, suggesting that phosphorylated-ERK1/2 protein levels were not representative of actual kinase activity in this pathological condition. In conclusion, protein phosphorylation levels of ERK1/2 do not always correspond to kinase activity, thus, measuring the true kinase activity is essential.

    View details for DOI 10.1016/j.neuroscience.2012.02.005

    View details for Web of Science ID 000303306600017

    View details for PubMedID 22366512

    View details for PubMedCentralID PMC3322316

  • The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Willingham, S. B., Volkmer, J., Gentles, A. J., Sahoo, D., Dalerba, P., Mitra, S. S., Wang, J., Contreras-Trujillo, H., Martin, R., Cohen, J. D., Lovelace, P., Scheeren, F. A., Chao, M. P., Weiskopf, K., Tang, C., Volkmer, A. K., Naik, T. J., Storm, T. A., Mosley, A. R., Edris, B., Schmid, S. M., Sun, C. K., Chua, M., Murillo, O., Rajendran, P., Cha, A. C., Chin, R. K., Kim, D., Adorno, M., Raveh, T., Tseng, D., Jaiswal, S., Enger, P. O., Steinberg, G. K., Li, G., So, S. K., Majeti, R., Harsh, G. R., van de Rijn, M., Teng, N. N., Sunwoo, J. B., Alizadeh, A. A., Clarke, M. F., Weissman, I. L. 2012; 109 (17): 6662-6667

    Abstract

    CD47, a "don't eat me" signal for phagocytic cells, is expressed on the surface of all human solid tumor cells. Analysis of patient tumor and matched adjacent normal (nontumor) tissue revealed that CD47 is overexpressed on cancer cells. CD47 mRNA expression levels correlated with a decreased probability of survival for multiple types of cancer. CD47 is a ligand for SIRP?, a protein expressed on macrophages and dendritic cells. In vitro, blockade of CD47 signaling using targeted monoclonal antibodies enabled macrophage phagocytosis of tumor cells that were otherwise protected. Administration of anti-CD47 antibodies inhibited tumor growth in orthotopic immunodeficient mouse xenotransplantation models established with patient tumor cells and increased the survival of the mice over time. Anti-CD47 antibody therapy initiated on larger tumors inhibited tumor growth and prevented or treated metastasis, but initiation of the therapy on smaller tumors was potentially curative. The safety and efficacy of targeting CD47 was further tested and validated in immune competent hosts using an orthotopic mouse breast cancer model. These results suggest all human solid tumor cells require CD47 expression to suppress phagocytic innate immune surveillance and elimination. These data, taken together with similar findings with other human neoplasms, show that CD47 is a commonly expressed molecule on all cancers, its function to block phagocytosis is known, and blockade of its function leads to tumor cell phagocytosis and elimination. CD47 is therefore a validated target for cancer therapies.

    View details for DOI 10.1073/pnas.1121623109

    View details for PubMedID 22451913

  • Prokineticin 2 is an endangering mediator of cerebral ischemic injury PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Cheng, M. Y., Lee, A. G., Culbertson, C., Sun, G., Talati, R. K., Manley, N. C., Li, X., Zhao, H., Lyons, D. M., Zhou, Q., Steinberg, G. K., Sapolsky, R. M. 2012; 109 (14): 5475-5480

    Abstract

    Stroke causes brain dysfunction and neuron death, and the lack of effective therapies heightens the need for new therapeutic targets. Here we identify prokineticin 2 (PK2) as a mediator for cerebral ischemic injury. PK2 is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Multiple biological roles for PK2 have been discovered, including circadian rhythms, angiogenesis, and neurogenesis. However, the role of PK2 in neuropathology is unknown. Using primary cortical cultures, we found that PK2 mRNA is up-regulated by several pathological stressors, including hypoxia, reactive oxygen species, and excitotoxic glutamate. Glutamate-induced PK2 expression is dependent on NMDA receptor activation and extracellular calcium. Enriched neuronal culture studies revealed that neurons are the principal source of glutamate-induced PK2. Using in vivo models of stroke, we found that PK2 mRNA is induced in the ischemic cortex and striatum. Central delivery of PK2 worsens infarct volume, whereas PK2 receptor antagonist decreases infarct volume and central inflammation while improving functional outcome. Direct central inhibition of PK2 using RNAi also reduces infarct volume. These findings indicate that PK2 can be activated by pathological stimuli such as hypoxia-ischemia and excitotoxic glutamate and identify PK2 as a deleterious mediator for cerebral ischemia.

    View details for DOI 10.1073/pnas.1113363109

    View details for Web of Science ID 000302294700073

    View details for PubMedID 22431614

    View details for PubMedCentralID PMC3325724

  • Neuroradiologic Correlates of Cognitive Impairment in Adult Moyamoya Disease AMERICAN JOURNAL OF NEURORADIOLOGY Mogensen, M. A., Karzmark, P., Zeifert, P. D., Rosenberg, J., Marks, M., Steinberg, G. K., Dorfman, L. J. 2012; 33 (4): 721-725

    Abstract

    MMD has been shown to result in impairment of executive functioning in adults. The purpose of this study was to correlate presurgical neuropsychological assessments with the severity of primary MMD as measured by CBF and CVR and with secondary damage from MMD as estimated by cortical stroke and WMD.A retrospective analysis of 31 adult patients with MMD was performed. Xe-CT was used to obtain CBF and CVR, and MRI was reviewed to grade cortical stroke and WMD. Two tests of executive functioning (FAS and TMT-B) were correlated with imaging findings. A multiple regression analysis was performed.There was a significant overall positive relationship between mean CBF and FAS (P = .038) and TMT-B scores (P = .014). A significant negative relationship was present between the WMD score and the FAS (P = .009) and TMT-B scores (P = .015). Per-region analysis demonstrated that FAS and TMT-B scores were significantly decreased by the presence of a posterior stroke (P < .0001 and P = .001) or WMD (P = .006 and P = .004). All patients with posterior parieto-occipital WMD or stroke also had secondary disease in the anterior regions.Impaired executive functioning in adults with MMD is most strongly associated secondary damage in the form of WMD or cortical stroke. The effect is most profound with parieto-occipital lobe involvement, likely a reflection of overall disease severity. Increasing global WMD burden may be a better indicator of cognitive decline than cortical infarction. Patients with higher baseline CBF seem to have better cognitive functioning.

    View details for DOI 10.3174/ajnr.A2852

    View details for Web of Science ID 000302842900024

    View details for PubMedID 22173751

  • Moyamoya Disease Can Masquerade as Multiple Sclerosis Woodard, J., Fischbein, N., Choudhry, O., Bell-Stephens, T., Steinberg, G., Dorfman, L. LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Isolated Loss of Focal Motor Evoked Potentials during Intracranial Aneurysm Clipping as an Early Predictor of Reversible Ischemia: Case Report 64th Annual Meeting of the American-Academy-of-Neurology (AAN) Lee, L., Steinberg, G., Jones, E., Lopez, J. LIPPINCOTT WILLIAMS & WILKINS. 2012
  • Neurocognitive Impairment in Adults With Moyamoya Disease Without Stroke NEUROSURGERY Karzmark, P., Zeifert, P. D., Bell-Stephens, T. E., Steinberg, G. K., Dorfman, L. J. 2012; 70 (3): 634-638

    Abstract

    Adults with moyamoya disease (MMD) have been shown to manifest cognitive impairment, but it is unclear whether this is the result of ischemic stroke.To determine whether adults with MMD but without stroke have cognitive impairment.We performed detailed neuropsychological assessments in 30 adults with angiographically confirmed MMD without magnetic resonance imaging (MRI) evidence of stroke.Twenty patients (67%) exhibited small T2 hyperintensities in the cerebral subcortical white matter on brain MRI but no evidence of gray matter damage. Significant cognitive impairment, defined as half of test scores ? 1 SD below the normal mean, was present in 7 patients (23%). Executive functioning, mental efficiency, and word finding were the ability areas most frequently impaired, whereas memory was relatively intact. Clinically significant emotional distress (depression and/or anxiety) was present in 11 patients (37%). Comparable cognitive findings were also observed in the subset of 10 patients (33%) with completely normal static brain MRI.Cognitive impairment in MMD can occur in the absence of ischemic stroke as manifested on MRI.

    View details for DOI 10.1227/NEU.0b013e3182320d1a

    View details for Web of Science ID 000300781700020

    View details for PubMedID 21849919

  • Clinical Neuroproteomics and Biomarkers: From Basic Research to Clinical Decision Making NEUROSURGERY Shoemaker, L. D., Achrol, A. S., Sethu, P., Steinberg, G. K., Chang, S. D. 2012; 70 (3): 518-525

    Abstract

    Clinical neuroproteomics aims to advance our understanding of disease and injury affecting the central and peripheral nervous systems through the study of protein expression and the discovery of protein biomarkers to facilitate diagnosis and treatment. The general premise of the biomarker field is that in vivo factors present in either tissue or circulating biofluids, reflect pathological changes, and can be identified and analyzed. This approach offers an opportunity to illuminate changes occurring at both the population and patient levels toward the realization of personalized medicine. This review is intended to provide research-driven clinicians with an overview of protein biomarkers of disease and injury for clinical use and to highlight methodology and potential pitfalls. We examine the neuroproteomic biomarker field and discuss the hallmarks and the challenges of clinically relevant biomarker discovery relating to central nervous system pathology. We discuss the issues in the maturation of potential biomarkers from discovery to Food and Drug Administration approval and review several platforms for protein biomarker discovery, including protein microarray and mass spectrometry-based proteomics. We describe the application of microfluidic technologies to the evolution of a robust clinical test. Finally, we highlight several biomarkers currently in use for cancer, ischemia, and injury in the central nervous system. Future efforts using these technologies will result in the maturation of existing and the identification of de novo biomarkers that could guide clinical decision making and advance diagnostic and therapeutic options for the treatment of neurological disease and injury.

    View details for DOI 10.1227/NEU.0b013e3182333a26

    View details for Web of Science ID 000300781700008

    View details for PubMedID 21866062

  • Reflections on the Benefits and Pitfalls of Ultra-Early Aneurysm Treatment After Subarachnoid Hemorrhage WORLD NEUROSURGERY Gooderham, P. A., Steinberg, G. K. 2012; 77 (2): 261-262

    View details for DOI 10.1016/j.wneu.2011.10.049

    View details for Web of Science ID 000303233800013

    View details for PubMedID 22120550

  • RE: "Effective Surgical Revascularization Improves Cerebral Hemodynamics and Resolves Headache in Pediatric Moyamoya Disease" World neurosurgery Chao, K. n., Steinberg, G. K. 2012

    View details for PubMedID 23159646

  • Lithium treatment reduces brain injury induced by focal ischemia with partial reperfusion and the protective mechanisms dispute the importance of akt activity. Aging and disease Takahashi, T. n., Steinberg, G. K., Zhao, H. n. 2012; 3 (3): 226?33

    Abstract

    Lithium is a mood stabilizer shown to have neuroprotective effects against several chronic and acute neuronal injuries, including stroke. However, it is unknown whether lithium treatment protects against brain injury post-stroke in a rat model of permanent distal middle cerebral artery occlusion (MCAo) combined with transient bilateral common carotid artery occlusion (CCAo), a model that mimics human stroke with partial reperfusion. In addition, whether lithium treatment alters Akt activity as measured by the kinase activity assay has not been reported, although it is known to inhibit GSK3? activity. After stroke, Akt activity contributes to neuronal survival while GSK3? activity causes neuronal death. We report that a bolus of lithium injection at stroke onset robustly reduced infarct size measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining at 48 h post-stroke and inhibited cell death in the ischemic penumbra, but not in the ischemic core, as shown by TUNEL staining performed 24 h post-stroke. However, lithium treatment did not alter the reduction in Akt activity as measured by Akt kinase assay. We further showed that lithium did not alter phosphorylated GSK3? protein levels, or the degradation of ?-catenin, a substrate of GSK3?, which is consistent with previous findings that long-term treatment is required for lithium to alter GSK3? phosphorylation. In summary, we show innovative data that lithium protects against stroke in a focal ischemia model with partial reperfusion, however, our results dispute the importance of Akt activity in the protective effects of lithium.

    View details for PubMedID 22724081

  • Proteomic Biomarker Discovery in Cerebrospinal Fluid for Cerebral Vasospasm Following Subarachnoid Hemorrhage JOURNAL OF STROKE & CEREBROVASCULAR DISEASES Lad, S. P., Hegen, H., Gupta, G., Deisenhammer, F., Steinberg, G. K. 2012; 21 (1): 30-41

    Abstract

    Currently, there are no established biomarkers for diagnosing preclinical vasospasm or monitoring its progression. Two areas of extensive biomarker research are neuroimaging and biochemical markers in body fluids, such as cerebrospinal fluid (CSF). We performed a review of studies conducted over the past 2 decades summarizing the science to date and the evolution of CSF biomarkers in subarachnoid hemorrhage (SAH). A Medline search performed using the search terms "subarachnoid hemorrhage marker AND cerebrospinal fluid," limited to the period January 1, 1990 to June 1, 2009, returned 62 references. Abstracts that did not deal primarily with SAH and potential markers in the CSF of humans were excluded, resulting in 27 abstracts. Only articles providing sufficient information for a substantiated analysis were selected. In addition, articles identified in reference lists of individual articles were selected if considered appropriate. Evidence was classified as class I-IV and recommendations were classified as category A-C according to European Federation of Neurological Societies guidelines. We evaluated CSF markers in SAH patients and divided them into 3 categories: A, markers with auspicious value; B, candidate markers; and C, noncandidate markers. Category A markers included tumor necrosis factor (TNF)-?, soluble tumor necrosis factor receptor I (sTNFR-I), and interleukin (IL)-1 receptor antagonist (IL-1ra), as well as the neurofilament proteins NFL and NfH. Category B markers included apolipoprotein E (ApoE), F2-isoprostane (F2-IsoP), NOx, and the indicators for thrombin activity membrane-bound tissue factor (mTF) and thrombin-antithrombin III complex (TAT) for neurologic outcome prediction, as well as E-selectin, lactate, alpha-II spectrin breakdown products (SBDPs), asymmetric dimethyl-L-arginine (ADMA), and monocyte chemoattractant protein-1 (MCP-1) for vasospasm prognostication. Category C markers included S100B, platelet-derived growth factor (PDGF), YKL-40, chitotriosidase, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-8. Cytokines and their receptors, as well as neuronal intracellular proteins, seem to be potential markers for outcome determination in patients after SAH.

    View details for DOI 10.1016/j.jstrokecerebrovasdis.2010.04.004

    View details for Web of Science ID 000299146100006

    View details for PubMedID 20851633

  • Gene Expression Profiling of Blood in Brain Arteriovenous Malformation Patients TRANSLATIONAL STROKE RESEARCH Weinsheimer, S. M., Xu, H., Achrol, A. S., Stamova, B., McCulloch, C. E., Pawlikowska, L., Tian, Y., Ko, N. U., Lawton, M. T., Steinberg, G. K., Chang, S. D., Jickling, G., Ander, B. P., Kim, H., Sharp, F. R., Young, W. L. 2011; 2 (4): 575-587

    Abstract

    Brain arteriovenous malformations (BAVMs) are an important cause of intracranial hemorrhage (ICH) in young adults. Gene expression profiling of blood has led to the identification of stroke biomarkers, and may help identify BAVM biomarkers and illuminate BAVM pathogenesis. It is unknown whether blood gene expression profiles differ between 1) BAVM patients and healthy controls, or 2) unruptured and ruptured BAVM patients at presentation. We characterized blood transcriptional profiles in 60 subjects (20 unruptured BAVM, 20 ruptured BAVM, and 20 healthy controls) using Affymetrix whole genome expression arrays. Expression differences between groups were tested by ANOVA, adjusting for potential confounders. Genes with absolute fold change ? 1.2 (false discovery rate corrected p ? 0.1) were selected as differentially expressed and evaluated for over-representation in KEGG biological pathways (p ? 0.05). Twenty-nine genes were differentially expressed between unruptured BAVM patients and controls, including 13 which may be predictive of BAVM. Patients with ruptured BAVM compared to unruptured BAVM differed in expression of 1490 genes, with over-representation of genes in 8 pathways including MAPK, VEGF, Wnt signaling and several inflammatory pathways. These results suggest clues to the pathogenesis of BAVM and/or BAVM rupture and point to potential biomarkers or new treatment targets.

    View details for DOI 10.1007/s12975-011-0103-3

    View details for Web of Science ID 000304163700015

    View details for PubMedID 22184505

    View details for PubMedCentralID PMC3241209

  • Results of the Prospective, Randomized, Multicenter Clinical Trial Evaluating a Biosynthesized Cellulose Graft for Repair of Dural Defects NEUROSURGERY Rosen, C. L., Steinberg, G. K., DeMonte, F., Delashaw, J. B., Lewis, S. B., Shaffrey, M. E., Aziz, K., Hantel, J., Marciano, F. F. 2011; 69 (5): 1093-1103

    Abstract

    After intradural cranial surgery, a dural substitute is often required for dural closure. Although preferred, limitations of autograft include local availability and additional surgical site morbidity. Thus, allografts, xenografts, and synthetics are frequently used.To report 6-month results of a randomized, controlled trial of a biosynthesized cellulose (BSC) composed duraplasty device compared with commercially available dural replacements.A total of 99 patients (62 BSC; 37 control) were treated on protocol, using a 2:1 (BSC:control) blocked randomization schedule. Physical examinations were performed pre- and postoperatively within 10 days and at 1, 3, and 6 months. Magnetic resonance imaging was performed preoperatively and at 6 months. The primary study endpoint was the absence of pseudomeningocele and extracerebral fluid collection confirmed radiographically and the absence of cerebrospinal fluid fistula at 6 months.At 6 months, the primary hypothesis, noninferiority of the BSC implant compared with the control group, was confirmed (P = .0206). Overall success was achieved by 96.6% of BSC and 97.1% of control patients. No significant difference was revealed between treatment groups for surgical site infection (P = 1.0000) or wound healing assessment (P ? .3685) outcomes, or radiologic endpoints (P ? .4061). Device strength and seal quality favored BSC.This randomized, controlled trial establishes BSC as noninferior to commercially available dural replacement devices. BSC offers a hypothetical advantage concerning prion and other infectious agent exposure; superior handling qualities are evident. Longer term data are necessary to identify limitations of BSC and its potential equivalence to the gold standard of pericranium.

    View details for DOI 10.1227/NEU.0b013e3182284aca

    View details for Web of Science ID 000295835300034

    View details for PubMedID 21670715

  • Neurosurgical Advances in the Treatment of Moyamoya Disease STROKE Pandey, P., Steinberg, G. K. 2011; 42 (11): 3304-3310

    Abstract

    Moyamoya disease is characterized by chronic stenoocclusive vasculopathy involving the distal supraclinoid internal carotid arteries and presents with ischemic or hemorrhagic symptoms. We review advances in the understanding and management of moyamoya disease.Cerebral revascularization, either direct or indirect, is the cornerstone of treatment for moyamoya disease. Recent advances have been made in understanding the molecular biology and pathophysiology of moyamoya disease, and new genetic mutations and deletions have been identified. Imaging for moyamoya disease is also rapidly improving with new sequences of MRI and better methods of assessing ischemia and cerebrovascular reserve. Positron emission tomography has emerged as an important tool to measure cerebrovascular reserve. Novel surgical techniques assess patency and ischemia during superficial temporal to middle cerebral artery bypass, including indocyanine green videoangiography to evaluate anastomosis patency, and various methods to monitor intraoperative blood flow. Newer methods of indirect revascularization have been described with placement of more tissues supplied by the external carotid artery on the brain surface. Postoperative hyperperfusion to the chronically ischemic brain tissue is a recently identified causative factor of complications. Interestingly, complications from hyperperfusion mimic those caused by ischemia, although they have different treatments, making the role of postoperative blood flow assessment important in distinguishing between the two. Awareness has also increased that even asymptomatic patients can experience significant cognitive decline attributable to chronic ischemia. Whether this reverts after successful revascularization requires investigation.Surgical revascularization with direct, indirect, and combined methods remains the preferred procedure for patients with moyamoya disease.

    View details for DOI 10.1161/STROKEAHA.110.598565

    View details for Web of Science ID 000296574500292

    View details for PubMedID 21980214

  • The CCR2/CCL2 Interaction Mediates the Transendothelial Recruitment of Intravascularly Delivered Neural Stem Cells to the Ischemic Brain STROKE Andres, R. H., Choi, R., Pendharkar, A. V., Gaeta, X., Wang, N., Nathan, J. K., Chua, J. Y., Lee, S. W., Palmer, T. D., Steinberg, G. K., Guzman, R. 2011; 42 (10): 2923-U387

    Abstract

    The inflammatory response is a critical component of ischemic stroke. In addition to its physiological role, the mechanisms behind transendothelial recruitment of immune cells also offer a unique therapeutic opportunity for translational stem cell therapies. Recent reports have demonstrated homing of neural stem cells (NSC) into the injured brain areas after intravascular delivery. However, the mechanisms underlying the process of transendothelial recruitment remain largely unknown. Here we describe the critical role of the chemokine CCL2 and its receptor CCR2 in targeted homing of NSC after ischemia.Twenty-four hours after induction of stroke using the hypoxia-ischemia model in mice CCR2+/+ and CCR2-/- reporter NSC were intra-arterially delivered. Histology and bioluminescence imaging were used to investigate NSC homing to the ischemic brain. Functional outcome was assessed with the horizontal ladder test.Using NSC isolated from CCR2+/+ and CCR2-/- mice, we show that receptor deficiency significantly impaired transendothelial diapedesis specifically in response to CCL2. Accordingly, wild-type NSC injected into CCL2-/- mice exhibited significantly decreased homing. Bioluminescence imaging showed robust recruitment of CCR2+/+ cells within 6 hours after transplantation in contrast to CCR2-/- cells. Mice receiving CCR2+/+ grafts after ischemic injury showed a significantly improved recovery of neurological deficits as compared to animals with transplantation of CCR2-/- NSC.The CCL2/CCR2 interaction is critical for transendothelial recruitment of intravascularly delivered NSC in response to ischemic injury. This finding could have significant implications in advancing minimally invasive intravascular therapeutics for regenerative medicine or cell-based drug delivery systems for central nervous system diseases.

    View details for DOI 10.1161/STROKEAHA.110.606368

    View details for PubMedID 21836091

  • Systemic augmentation of alpha B-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Arac, A., Brownell, S. E., Rothbard, J. B., Chen, C., Ko, R. M., Pereira, M. P., Albers, G. W., Steinman, L., Steinberg, G. K. 2011; 108 (32): 13287-13292

    Abstract

    Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of ?B-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab(-/-) mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

    View details for DOI 10.1073/pnas.1107368108

    View details for Web of Science ID 000293691400065

    View details for PubMedID 21828004

    View details for PubMedCentralID PMC3156222

  • Outcome of repeat revascularization surgery for moyamoya disease after an unsuccessful indirect revascularization Clinical article JOURNAL OF NEUROSURGERY Pandey, P., Steinberg, G. K. 2011; 115 (2): 328-336

    Abstract

    Revascularization for moyamoya disease, either by direct anastomosis or indirect procedures, is an accepted and effective form of treatment for prevention of future ischemic events. Indirect procedures do not provide sufficient collateral vessels in a subset of patients, who then have persistent or new symptoms. Repeat revascularization procedures may be recommended for these patients.Sixteen patients underwent repeat revascularization after undergoing an indirect procedure in the same hemisphere. These patients were included in the study, and a retrospective review of their clinical details, neuroimaging results, surgical details, and outcome was performed. Direct revascularization was the procedure of choice; however, in patients with no acceptable recipient vessel (> 0.6 mm) the authors added a second indirect procedure for further revascularization.Over the last 19 years, 16 patients (8 male and 8 female patients, age range 5-48 years, mean 16.7 years, 10 pediatric and 6 adult patients) underwent repeat revascularization for moyamoya disease. Initially all patients presented with ischemic symptoms (4 transient ischemic attacks [TIAs] and 12 strokes; 2 patients had bilateral symptoms). Angiography revealed that 13 patients had bilateral disease, and 3 had unilateral disease. Initial surgery was bilateral encephaloduroarteriosynangiosis (EDAS) in 9, unilateral EDAS alone in 3, unilateral EDAS with contralateral superficial temporal artery-middle cerebral artery (STA-MCA) bypass in 2, bilateral encephalomyosynangiosis (EMS) in 1, and unilateral EMS in 1. Thirteen of the 16 patients continued to have TIAs in the hemisphere ipsilateral to surgery, whereas 1 patient had seizures and cognitive deficit, 1 had asymptomatic infarct on MR imaging, and 1 had visual symptoms. Poor revascularization was seen on angiography studies in all patients. The median duration between the surgeries was 24 months (3 months-10 years). Repeat revascularization was performed in 23 hemispheres (16 patients). Direct revascularization was performed in 14 hemispheres (60.9%): STA-MCA bypass in 10, external carotid artery-MCA vein bypass in 2, occipital artery (OA)-MCA in 1, and OA-posterior cerebral artery in 1 hemisphere. Indirect revascularization was performed for patients without an acceptable recipient vessel, and was done in 9 hemispheres. The procedures included EMS (4 hemispheres), repeat EDAS (2), and omental transposition (3). There was 1 postoperative death in a patient undergoing a high-flow vein graft implantation. None of the other patients experienced any neurological worsening after surgery. Follow-up was available in all patients, ranging from 3 to 144 months (mean 34 months, median 12 months). Of the 15 patients who survived repeat revascularization surgery, 12 (80%) were free from any TIA, stroke, or any other neurological symptoms. Two patients had occasional TIAs, less frequent than before, whereas 1 patient had frequent TIAs and underwent revision of the revascularization. Angiographic studies were available in 11 patients, and showed improved flow in the hemispheres in 10 patients. Follow-up MR imaging performed at 6 months did not reveal a new infarct in any patient.Repeat revascularization procedures are effective for patients who are clinically symptomatic and have inadequate collateral vessels following indirect procedures. Although direct procedures are preferred, the choice of procedure depends on the operative findings and the status of donor and recipient vessels.

    View details for DOI 10.3171/2011.3.JNS101908

    View details for Web of Science ID 000293145100029

    View details for PubMedID 21529138

  • Loss of BRCC3 Deubiquitinating Enzyme Leads to Abnormal Angiogenesis and Is Associated with Syndromic Moyamoya AMERICAN JOURNAL OF HUMAN GENETICS Miskinyte, S., Butler, M. G., Herve, D., Sarret, C., Nicolino, M., Petralia, J. D., Bergametti, F., Arnould, M., Pham, V. N., Gore, A. V., Spengos, K., Gaza, S., Woimant, F., Steinberg, G. K., Weinstein, B. M., Tournier-Lasserve, E. 2011; 88 (6): 718-728

    Abstract

    Moyamoya is a cerebrovascular angiopathy characterized by a progressive stenosis of the terminal part of the intracranial carotid arteries and the compensatory development of abnormal and fragile collateral vessels, also called moyamoya vessels, leading to ischemic and hemorrhagic stroke. Moyamoya angiopathy can either be the sole manifestation of the disease (moyamoya disease) or be associated with various conditions, including neurofibromatosis, Down syndrome, TAAD (autosomal-dominant thoracic aortic aneurysm), and radiotherapy of head tumors (moyamoya syndromes). Its prevalence is ten times higher in Japan than in Europe, and an estimated 6%-12% of moyamoya disease is familial in Japan. The pathophysiological mechanisms of this condition remain obscure. Here, we report on three unrelated families affected with an X-linked moyamoya syndrome characterized by the association of a moyamoya angiopathy, short stature, and a stereotyped facial dysmorphism. Other symptoms include an hypergonadotropic hypogonadism, hypertension, dilated cardiomyopathy, premature coronary heart disease, premature hair graying, and early bilateral acquired cataract. We show that this syndromic moyamoya is caused by Xq28 deletions removing MTCP1/MTCP1NB and BRCC3. We also show that brcc3 morphant zebrafish display angiogenesis defects that are rescued by endothelium-specific expression of brcc3. Altogether, these data strongly suggest that BRCC3, a deubiquitinating enzyme that is part of the cellular BRCA1 and BRISC complexes, is an important player in angiogenesis and that BRCC3 loss-of-function mutations are associated with moyamoya angiopathy.

    View details for DOI 10.1016/j.ajhg.2011.04.017

    View details for Web of Science ID 000291768500004

    View details for PubMedID 21596366

    View details for PubMedCentralID PMC3113251

  • Intraoperative Angiography for Cranial Dural Arteriovenous Fistula AMERICAN JOURNAL OF NEURORADIOLOGY Pandey, P., Steinberg, G. K., Westbroek, E. M., Dodd, R., Do, H. M., Marks, M. P. 2011; 32 (6): 1091-1095

    Abstract

    IA is a valuable adjunct during surgery for a variety of neurovascular diseases; however, there are no reported series describing IA for DAVFs. This study was undertaken to evaluate the safety and efficacy of IA for DAVFs.A retrospective review of DAVF surgical cases during a 20-year period was conducted, and cases with IA were evaluated. Clinical details, surgical and angiographic findings, and postoperative outcomes were reviewed. The incidence of residual fistula on IAs, the utility of the surgical procedure, and the incidence of false-negative findings on IA were also determined.IA was performed in 29 patients (31 DAVFs) for DAVFs. The distribution of the fistulas was the following: transverse-sigmoid (n = 9), tentorial (n = 6), torcular (n = 3), cavernous sinus (n = 4), SSS (n = 4), foramen magnum (n = 3), and temporal-middle fossa (n = 2). Twelve patients had undergone prior embolization, while 6 patients had unsuccessful embolization procedures. Thirty-eight surgeries were performed for DAVF in 29 patients, and IA was performed in 34 surgeries. Forty-four angiographic procedures were performed in the 34 surgeries. Nine patients underwent multiple angiographies. In 11 patients (37.9%), IA revealed residual fistula after the surgeon determined that no lesion remained. This led to further exploration at the same sitting in 10 patients, while in 1 patient, further surgery was performed at a later date. False-negative findings on IA occurred in 3 patients (10.7%).IA is an important adjunct in surgery for DAVF. In this series, it resulted in further surgical treatment in 37.9% of patients. However, there was a 10% false-negative rate, which justified subsequent postoperative angiography.

    View details for DOI 10.3174/ajnr.A2443

    View details for Web of Science ID 000292066600024

    View details for PubMedID 21622580

  • Endovascular Stenting of Venous Sinus Stenosis for Idiopathic Intracranial Hypertension WORLD NEUROSURGERY Pandey, P., Steinberg, G. K. 2011; 75 (5-6): 594?95
  • Stem cells and stroke: opportunities, challenges and strategies EXPERT OPINION ON BIOLOGICAL THERAPY Burns, T. C., Steinberg, G. K. 2011; 11 (4): 447-461

    Abstract

    Stroke remains the leading cause of disability in the Western world. Despite decades of work, no clinically effective therapies exist to facilitate recovery from stroke. Stem cells may have the potential to minimize injury and promote recovery after stroke. AREAS COVERED: Transplanted stem cells have been shown in animal models to migrate to the injured region, secrete neurotrophic compounds, promote revascularization, enhance plasticity and regulate the inflammatory response, thereby minimizing injury. Endogenous neural stem cells also have a remarkable propensity to respond to injury. Under select conditions, subventricular zone progenitors may be mobilized to replace lost neurons. In response to focal infarcts, neuroblasts play important trophic roles to minimize neural injury. Importantly, these endogenous repair mechanisms may be experimentally augmented, leading to robust improvements in function. Ongoing clinical studies are now assessing the safety and feasibility of cell-based therapies for stroke. EXPERT OPINION: We outline the unique challenges and potential pitfalls in the clinical translation of stem cell research for stroke. We then detail what we believe to be the specific basic science and clinical strategies needed to overcome these challenges, fill remaining gaps in knowledge and facilitate development of clinically viable stem cell-based therapies for stroke.

    View details for DOI 10.1517/14712598.2011.552883

    View details for Web of Science ID 000288221600002

    View details for PubMedID 21323594

    View details for PubMedCentralID PMC3087443

  • Long-term behavioral assessment of function in an experimental model for ischemic stroke JOURNAL OF NEUROSCIENCE METHODS Encarnacion, A., Horie, N., Keren-Gill, H., Bliss, T. M., Steinberg, G. K., Shamloo, M. 2011; 196 (2): 247-257

    Abstract

    Middle cerebral artery occlusion (MCAO) in rats is a well-studied experimental model for ischemic stroke leading to brain infarction and functional deficits. Many preclinical studies have focused on a small time window after the ischemic episode to evaluate functional outcome for screening therapeutic candidates. Short evaluation periods following injury have led to significant setbacks due to lack of information on the delayed effects of treatments, as well as short-lived and reversible neuroprotection, so called false-positive results. In this report, we evaluated long-term functional deficit for 90 days after MCAO in two rat strains with two durations of ischemic insult, in order to identify the best experimental paradigm to assess injury and subsequent recovery. Behavioral outcomes were measured pre-MCAO followed by weekly assessment post-stroke. Behavioral tests included the 18-point composite neurological score, 28-point neuroscore, rearing test, vibrissae-evoked forelimb placing test, foot fault test and the CatWalk. Brain lesions were assessed to correlate injury to behavior outcomes at the end of study. Our results indicate that infarction volume in Sprague-Dawley rats was dependent on occlusion duration. In contrast, the infarction volume in Wistar rats did not correlate with the duration of ischemic episode. Functional outcomes were not dependent on occlusion time in either strain; however, measurable deficits were detectable long-term in limb asymmetry, 18- and 28-point neuroscores, forelimb placing, paw swing speed, and gait coordination. In conclusion, these behavioral assays, in combination with an extended long-term assessment period, can be used for evaluating therapeutic candidates in preclinical models of ischemic stroke.

    View details for DOI 10.1016/j.jneumeth.2011.01.010

    View details for Web of Science ID 000290781200003

    View details for PubMedID 21256866

    View details for PubMedCentralID PMC3539723

  • An Insult-Inducible Vector System Activated by Hypoxia and Oxidative Stress for Neuronal Gene Therapy TRANSLATIONAL STROKE RESEARCH Cheng, M. Y., Lee, I., Jin, M., Sun, G., Zhao, H., Steinberg, G. K., Sapolsky, R. M. 2011; 2 (1): 92-100

    Abstract

    Gene therapy has demonstrated the protective potential of a variety of genes against stroke. However, conventional gene therapy vectors are limited due to the inability to temporally control their expression, which can sometimes lead to deleterious side effects. Thus, an inducible vector that can be temporally controlled and activated by the insult itself would be advantageous. Using hypoxia responsive elements (HRE) and antioxidant responsive elements (ARE), we have constructed an insult-inducible vector activated by hypoxia and reactive oxygen species (ROS). In COS7 cells, the inducible ARE-HRE-luciferase vectors are highly activated by oxygen deprivation, hydrogen peroxide treatment, and the ROS-induced transcription factor NF-E2-related factor 2 (Nrf2). Using a defective herpes virus, the neuroprotective potential of this inducible vector was tested by over-expressing the transcription factor Nrf2. In primary cortical cultures, expression of the inducible ARE-HRE-Nrf2 protects against oxygen glucose deprivation, similar to that afforded by the constitutively expressed Nrf2. This ARE+HRE vector system is advantageous in that it allows the expression of a transgene to be activated not only during hypoxia but also maintained after reperfusion, thus prolonging the transgene expression during an ischemic insult. This insult-inducible vector system will be a valuable gene therapy tool for activating therapeutic/protective genes in cerebrovascular diseases.

    View details for DOI 10.1007/s12975-010-0060-2

    View details for Web of Science ID 000304162800012

    View details for PubMedID 21603078

    View details for PubMedCentralID PMC3097421

  • Surgical Management Of Cavernous Malformation Of Brainstem, Thalamus And Basal Ganglia- A Series Of 176 Patients Pandey, P., Westbroeck, E. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: E91
  • RNAi-mediated Knockdown of Injury-induced Prokineticin 2 And Its Effects On Neuron Death International Stroke Conference Cheng, M. Y., Culbertson, C., Lee, A. G., Manley, N., Sun, G., Steinberg, G. K., Sapolsky, R. M. LIPPINCOTT WILLIAMS & WILKINS. 2011: E141?E141
  • Glycyrrhizin Protects Against Focal Ischemia and Attenuates Peripheral Immunosuppression in Rats International Stroke Conference Xiong, X., Gu, L., Li, L., Lee, J., Li, M., Xu, L., Giffard, R., Krams, S. M., Steinberg, G. K., Zhao, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: E67?E68
  • Moderate Hypothermia Attenuates Peripheral Immunodepression Caused by Stroke in Rats International Stroke Conference Gu, L., Xiong, X., Ito, T., Lee, J., Krams, S., Steinberg, G. K., Zhao, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: E302?E303
  • Angiographic Staging Of 215 Moyamoya Patients: Defining A New Modified Staging And Correlating Results To Patient Demographics And Clinical Findings International Stroke Conference Khan, N., Marks, M. P., Petralia, J., Tunovic, E., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: E201?E201
  • Transplanted Stem Cell-Secreted Vascular Endothelial Growth Factor Effects Poststroke Recovery, Inflammation, and Vascular Repair STEM CELLS Horie, N., Pereira, M. P., Niizuma, K., Sun, G., Keren-Gill, H., Encarnacion, A., Shamloo, M., Hamilton, S. A., Jiang, K., Huhn, S., Palmer, T. D., Bliss, T. M., Steinberg, G. K. 2011; 29 (2): 274-285

    Abstract

    Cell transplantation offers a novel therapeutic strategy for stroke; however, how transplanted cells function in vivo is poorly understood. We show for the first time that after subacute transplantation into the ischemic brain of human central nervous system stem cells grown as neurospheres (hCNS-SCns), the stem cell-secreted factor, human vascular endothelial growth factor (hVEGF), is necessary for cell-induced functional recovery. We correlate this functional recovery to hVEGF-induced effects on the host brain including multiple facets of vascular repair and its unexpected suppression of the inflammatory response. We found that transplanted hCNS-SCns affected multiple parameters in the brain with different kinetics: early improvement in blood-brain barrier integrity and suppression of inflammation was followed by a delayed spatiotemporal regulated increase in neovascularization. These events coincided with a bimodal pattern of functional recovery, with, an early recovery independent of neovascularization, and a delayed hVEGF-dependent recovery coincident with neovascularization. Therefore, cell transplantation therapy offers an exciting multimodal strategy for brain repair in stroke and potentially other disorders with a vascular or inflammatory component.

    View details for DOI 10.1002/stem.584

    View details for Web of Science ID 000287698600011

    View details for PubMedID 21732485

  • Failure of Primary Percutaneous Angioplasty and Stenting in the Prevention of Ischemia in Moyamoya Angiopathy CEREBROVASCULAR DISEASES Khan, N., Dodd, R., Marks, M. P., Bell-Stephens, T., Vavao, J., Steinberg, G. K. 2011; 31 (2): 147-153

    Abstract

    Moyamoya disease (MMD) is an idiopathic progressive arteriopathy affecting the proximal intracranial vasculature. To date only 4 case reports on intracranial angioplasty or stenting as treatment of this disease exist. We present 5 adult patients with MMD who failed angioplasty and/or stenting who remained symptomatic despite endovascular treatment or presented with recurrent symptoms and recurrence of stenosis/occlusion on angiography requiring subsequent extracranial-intracranial revascularization.Five adult MMD patients who underwent endovascular treatment with angioplasty or stenting were referred for further evaluation and treatment from outside hospitals. Data were collected from clinical referral notes and angiograms or reports. All patients underwent repeat 6-vessel cerebral angiography to assess the extent of disease and results of prior endovascular treatment.Six endovascular procedures were performed in all 5 patients. Internal carotid artery (ICA) balloon angioplasty and Wingspan stenting was performed in 2 patients (3 arteries). One patient had ICA-M1 angioplasty without stenting. Two patients had M1 angioplasty and Wingspan stenting. All patients developed repeat transient ischemic attacks following treatment attributable to the vascular territories of endovascular treatment. Repeat endovascular treatment was performed in 3 patients at a mean of 4 months (range = 2-6). Two went on to a third endovascular treatment due to progression of disease in the angioplastied/stented vessel. The average time of symptom recurrence after initial endovascular therapy was 1.8 months (0-4 months). Follow-up angiography when referred to our institution demonstrated 70-90% instent restenosis of the stented vessel in 3 and occlusion in 1 patient. Due to persistence of symptoms cerebral revascularization was performed in all patients.MMD is a progressive angiopathy. Angioplasty and stenting may temporarily improve the cerebral blood flow and decrease cerebral ischemic events but do not appear to be durable nor provide long-term prevention against future ischemic events.

    View details for DOI 10.1159/000320253

    View details for PubMedID 21135550

  • Optogenetic Stimulation of Neural Stem Cell Grafts in Experimental Stroke Model 11th International Neural Transplantation and Repair Meeting/18th Annual Meeting of the American-Society-for-Neural-Therapy-and-Repair Daadi, M. M., Goshen, I., Klausner, J. Q., Lee-Messer, C., Sun, G., Deisseroth, K., Steinberg, G. K. COGNIZANT COMMUNICATION CORP. 2011: 551?51
  • Limited Therapeutic Time Windows of Mild-to-Moderate Hypothermia in a Focal Ischemia Model in Rat. Stroke research and treatment Zhao, H., Steinberg, G. 2011; 2011: 131834-?

    Abstract

    Although many studies have shown the great potential of induced hypothermia in stroke treatment, we recognize that there are limitations to the protective effects of hypothermia even in the laboratory. Here, we review our experiments on the protective effects of mild-to-moderate hypothermia in rats. Focal ischemia was induced by bilateral common carotid artery (CCA) occlusion for 1 to 2 hours combined with permanent or transient middle cerebral artery (MCA) occlusion. We compared the effects of mild (33°C) and moderate (30°C) hypothermia, evaluated therapeutic time windows, and studied the underlying mechanisms. On review, our findings revealed that the protective effects of induced mild hypothermia (33°C) were limited, and the therapeutic time window of even moderate hypothermia (30°C) was very short in our specific models, although this limitation might be due to the relatively brief periods of hypothermia used. In addition, we found that hypothermia reduced brain injury by preserving Akt activity, PTEN phosphorylation and ?PKC activity, while inhibiting ROS production, and ?PKC activity.

    View details for DOI 10.4061/2011/131834

    View details for PubMedID 21876846

    View details for PubMedCentralID PMC3159378

  • Patients with moyamoya disease presenting with movement disorder Report of 4 cases JOURNAL OF NEUROSURGERY-PEDIATRICS Pandey, P., Bell-Stephens, T., Steinberg, G. K. 2010; 6 (6): 559-566

    Abstract

    Moyamoya disease is a rare cerebrovascular disease characterized by idiopathic bilateral stenosis or occlusion of bilateral internal carotid arteries and the development of characteristic leptomeningeal collateral vessels at the base of the brain. Typical presentations include transient ischemic attacks or stroke, and hemorrhage. Presentation with movement disorders is extremely rare, especially in the pediatric population. The authors describe the cases of 4 children with moyamoya disease who presented with movement disorders. Among 446 patients (118 pediatric) with moyamoya disease surgically treated by the senior author, 4 pediatric patients had presented with movement disorders. The clinical records, imaging studies, surgical details, and postoperative clinical and imaging data were retrospectively reviewed. The initial presenting symptom was movement disorder in all 4 patients: chorea in 2, hemiballismus in 1, and involuntary limb shaking in 1. All the patients had watershed infarcts involving the frontal subcortical region on MR imaging. Additionally, 1 patient had a ganglionic infarct. Single-photon emission computed tomography studies showed frontoparietal cortical and subcortical hypoperfusion in all patients. Three patients had bilateral disease, whereas 1 had unilateral disease. All the patients underwent superficial temporal artery-middle cerebral artery bypass. Postoperatively, all 4 patients had complete improvement in their symptoms. The SPECT scans revealed normal perfusion in 3 patients and a small residual perfusion deficit in 1. Movement disorders are a rare presenting feature of moyamoya disease. Hypoperfusion of the frontal cortical and subcortical region was seen in all patients, and the symptomatology was attributed to ischemic dysfunction and imbalance in the cortical-subcortical-ganglionic-thalamic-cortical circuitry. Combined revascularization with superficial temporal artery-middle cerebral artery bypass and encephaloduroarteriosynangiosis leads to excellent results.

    View details for DOI 10.3171/2010.9.PEDS10192

    View details for PubMedID 21121731

  • The Akt Pathway Is Involved in Rapid Ischemic Tolerance in Focal Ischemia in Rats TRANSLATIONAL STROKE RESEARCH Gao, X., Zhang, H., Steinberg, G., Zhao, H. 2010; 1 (3): 202-209

    Abstract

    Although the protective mechanisms of delayed ischemic preconditioning have received extensive studies, few have addressed the mechanisms associated with rapid ischemic postconditioning. We investigated whether ischemic tolerance induced by rapid preconditioning is regulated by the Akt survival signaling pathway. Stroke was generated by permanent occlusion of the left distal middle cerebral artery (MCA) plus 30 min or 1 h occlusion of the bilateral common carotid artery (CCA) in male rats. Rapid preconditioning performed 1h before stroke onset reduced infarct size by 69% in rats with 30 min CCA occlusion, but by only 19% with 1 h occlusion. After control ischemia with 30 min CCA occlusion, Western Blot showed that P-Akt was transiently increased while Akt kinase assay showed that Akt activity was decreased. Although preconditioning did not change P-Akt levels at 1h and 5h compared with control ischemia, it attenuated reduction in Akt activity at 5h in the penumbra. However, preconditioning did not change the levels of P-PDK1, P-PTEN, and P-GSK3? in the Akt pathway, all of which were decreased after stroke. At last, the PI3K kinase inhibitor, LY294002, completely reversed the protection from ischemic preconditioning. In conclusion, Akt contributes to the protection of rapid preconditionin against stroke.

    View details for DOI 10.1007/s12975-010-0017-5

    View details for Web of Science ID 000208326700008

    View details for PubMedID 21804899

    View details for PubMedCentralID PMC3144475

  • Moyamoya in a Child Treated With Interferon for Recurrent Osteosarcoma JOURNAL OF PEDIATRIC HEMATOLOGY ONCOLOGY Buchbinder, D., Steinberg, G., Linetsky, M., Casillas, J. 2010; 32 (6): 476-478

    Abstract

    Moyamoya is a cerebral vasculopathy of unknown etiology rarely described as a late effect after the treatment of childhood cancer. We describe a 12-year-old female who developed moyamoya after the completion of systemic chemotherapy, surgery, and adjuvant interferon alpha for osteosarcoma with pulmonary metastases. Given the importance of characterizing late effects after the treatment of childhood cancer, the potential role of interferon alpha in the development of moyamoya is discussed.

    View details for DOI 10.1097/MPH.0b013e3181e5e1db

    View details for Web of Science ID 000280666100007

    View details for PubMedID 20562650

  • Direct Bypass Techniques for the Treatment of Pediatric Moyamoya Disease NEUROSURGERY CLINICS OF NORTH AMERICA Guzman, R., Steinberg, G. 2010; 21 (3): 565-?

    Abstract

    Moyamoya is an increasingly recognized cause of stroke in children and adults. Identification of the disease early in its course with prompt institution of therapy is critical to providing the best outcome for patients. Revascularization surgery seems to be effective in preventing stroke in moyamoya, with direct techniques providing durable protection when performed at experienced centers.

    View details for DOI 10.1016/j.nec.2010.03.013

    View details for Web of Science ID 000279583700014

    View details for PubMedID 20561504

  • Study of Systemic Cooling in Acute Spinal Cord Injury NEUROSURGERY Creasey, G., Steinberg, G. K. 2010; 66 (6)
  • Optimizing the success of cell transplantation therapy for stroke (vol 37, pg 275, 2010) NEUROBIOLOGY OF DISEASE Bliss, T. M., Andres, R. H., Steinberg, G. K. 2010; 38 (3): 495
  • Majewski Osteodysplastic Primordial Dwarfism Type II (MOPD II): Expanding the Vascular Phenotype AMERICAN JOURNAL OF MEDICAL GENETICS PART A Bober, M. B., Khan, N., Kaplan, J., Lewis, K., Feinstein, J. A., Scott, C. I., Steinberg, G. K. 2010; 152A (4): 960-965

    Abstract

    Majewski Osteodysplastic Primordial Dwarfism, Type II (MOPD II) is a rare, autosomal recessive disorder. Features include severe intrauterine growth retardation (IUGR), poor postnatal growth (adult stature approximately 100 cm), severe microcephaly, skeletal dysplasia, characteristic facial features, and normal or near normal intelligence. An Institutional Review Board (IRB) approved registry was created and currently follows 25 patients with a diagnosis of MOPD II. Based on previous studies, a neurovascular screening program was implemented and 13 (52%) of these patients have been found to have cerebral neurovascular abnormalities including moyamoya angiopathy and/or intracranial aneurysms. The typical moyamoya pathogenesis begins with vessel narrowing in the supraclinoid internal carotid artery, anterior cerebral (A1) or middle cerebral (M1) artery segments. The narrowing may predominate initially on one side, progresses to bilateral stenosis, with subsequent occlusion of the vessels and collateral formation. We present four patients who, on neurovascular screening, were found to have cerebrovascular changes. Two were asymptomatic, one presented with a severe headache and projectile vomiting related to a ruptured aneurysm, and one presented after an apparent decline in cognitive functioning. Analysis of the registry suggests screening for moyamoya disease be performed at the time of MOPD II diagnosis and at least every 12-18 months using MRA or computerized tomographic angiography (CTA). We believe this is imperative. If diagnosed early enough, re-vascularization and aneurysm treatment in skilled hands can be performed safely and prevent or minimize long-term sequelae in this population. Emergent evaluation is also needed when other neurologic or cardiac symptoms are present.

    View details for DOI 10.1002/ajmg.a.33252

    View details for Web of Science ID 000276754000025

    View details for PubMedID 20358609

  • Management of Pediatric Intracranial Arteriovenous Malformations: Experience With Multimodality Therapy Darsaut, T. E., Guzman, R., Marcellus, M. L., Edwards, M. S., Tian, L., Do, H. M., Chang, S. D., Levy, R. P., Adler, J. R., Marks, M. P., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: E220
  • Transplantation of Human Neural Stem Cells Improves Axonal Plasticity and Attenuates Impairment of Axonal Transport in the Post-ischemic Microenvironment Andres, R. H., Zhan, K., Sun, G., Schaar, B. T., McMillan, E., Svendsen, C. N., Bliss, T. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: E209
  • Inheritance Pattern of Familial Moyamoya Disease in North America: Autosomal Dominant With Incomplete Penetrance Achrol, A. S., Varga, M., Salari, K., Guzman, R., Bell-Stephens, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: E218?E219
  • Gender Differences in Clinical Presentation and Treatment Outcomes in Moyamoya Disease International Stroke Conference Khan, N., Achrol, A. S., Guzman, R., Dodd, R., Bell-Stephens, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2010: E264?E264
  • Intraoperative Neurophysiologic Monitoring in the Endovascular and Surgical Treatment of Pediatric Arteriovenous Malformations Nguyen, V., Cho, S., Chang, S., Steinberg, G., Alto, P., Marks, M., Do, H., Lopez, J. LIPPINCOTT WILLIAMS & WILKINS. 2010: A501
  • Human Neural Stem Cell Grafts Modify Microglial Response and Enhance Axonal Sprouting in Neonatal Hypoxic-Ischemic Brain Injury STROKE Daadi, M. M., Davis, A. S., Arac, A., Li, Z., Maag, A., Bhatnagar, R., Jiang, K., Sun, G., Wu, J. C., Steinberg, G. K. 2010; 41 (3): 516-523

    Abstract

    Hypoxic-ischemic (HI) brain injury in newborn infants represents a major cause of cerebral palsy, development delay, and epilepsy. Stem cell-based therapy has the potential to rescue and replace the ischemic tissue caused by HI and to restore function. However, the mechanisms by which stem cell transplants induce functional recovery are yet to be elucidated. In the present study, we sought to investigate the efficacy of human neural stem cells derived from human embryonic stem cells in a rat model of neonatal HI and the mechanisms enhancing brain repair.The human neural stem cells were genetically engineered for in vivo molecular imaging and for postmortem histological tracking. Twenty-four hours after the induction of HI, animals were grafted with human neural stem cells into the forebrain. Motor behavioral tests were performed the fourth week after transplantation. We used immunocytochemistry and neuroanatomical tracing to analyze neural differentiation, axonal sprouting, and microglia response. Treatment-induced changes in gene expression were investigated by microarray and quantitative polymerase chain reaction.Bioluminescence imaging permitted real time longitudinal tracking of grafted human neural stem cells. HI transplanted animals significantly improved in their use of the contralateral impeded forelimb and in the Rotorod test. The grafts showed good survival, dispersion, and differentiation. We observed an increase of uniformly distributed microglia cells in the grafted side. Anterograde neuroanatomical tracing demonstrated significant contralesional sprouting. Microarray analysis revealed upregulation of genes involved in neurogenesis, gliogenesis, and neurotrophic support.These results suggest that human neural stem cell transplants enhance endogenous brain repair through multiple modalities in response to HI.

    View details for DOI 10.1161/STROKEAHA.109.573691

    View details for Web of Science ID 000274799600019

    View details for PubMedID 20075340

  • Optimizing the success of cell transplantation therapy for stroke NEUROBIOLOGY OF DISEASE Bliss, T. M., Andres, R. H., Steinberg, G. K. 2010; 37 (2): 275-283

    Abstract

    Stem cell transplantation has evolved as a promising experimental treatment approach for stroke. In this review, we address the major hurdles for successful translation from basic research into clinical applications and discuss possible strategies to overcome these issues. We summarize the results from present pre-clinical and clinical studies and focus on specific areas of current controversy and research: (i) the therapeutic time window for cell transplantation; (ii) the selection of patients likely to benefit from such a therapy; (iii) the optimal route of cell delivery to the ischemic brain; (iv) the most suitable cell types and sources; (v) the potential mechanisms of functional recovery after cell transplantation; and (vi) the development of imaging techniques to monitor cell therapy.

    View details for DOI 10.1016/j.nbd.2009.10.003

    View details for Web of Science ID 000274224400006

    View details for PubMedID 19822211

    View details for PubMedCentralID PMC2818270

  • In vivo neural stem cell imaging: current modalities and future directions REGENERATIVE MEDICINE Gera, A., Steinberg, G. K., Guzman, R. 2010; 5 (1): 73-86

    Abstract

    Neural stem cells have been proposed as a promising therapy for treating a wide variety of neuropathologies. While several studies have demonstrated the therapeutic benefits of neural stem cells, the exact mechanism remains elusive. In order to facilitate research efforts to understand these mechanisms, and before neural stem cell-based therapies can be utilized in a clinical context, we must develop means of monitoring these cells in vivo. However, because of tissue depth and the blood-brain barrier, in vivo imaging of neural stem cells in the brain has unique challenges that do not apply to stem cells for other purposes. In this paper, we review contemporary methods for in vivo neural stem cell imaging, including MRI, PET and optical imaging techniques.

    View details for DOI 10.2217/RME.09.79

    View details for Web of Science ID 000273623600013

    View details for PubMedID 20017696

  • Moyamoya Disease in North America MOYAMOYA DISEASE UPDATE Guzman, R., Khan, N., Steinberg, G. K., Cho, B. K., Tominaga, T. 2010: 353?60
  • Human Neural Stem Cells Repair Damaged Stroke Tissue. A Magnetic Resonance Imaging Study Daadi, M. M., Klausner, J., Bhatnagar, R., Sun, G., Rutt, B., Steinberg, G. K. COGNIZANT COMMUNICATION CORP. 2010: 336
  • Clinical outcome after 450 revascularization procedures for moyamoya disease JOURNAL OF NEUROSURGERY Guzman, R., Lee, M., Achrol, A., Bell-Stephens, T., Kelly, M., Do, H. M., Marks, M. P., Steinberg, G. K. 2009; 111 (5): 927-935

    Abstract

    Moyamoya disease (MMD) is a rare cerebrovascular disease mainly described in the Asian literature. To address a lack of data on clinical characteristics and long-term outcomes in the treatment of MMD in North America, the authors analyzed their experience at Stanford University Medical Center. They report on a consecutive series of patients treated for MMD and detail their demographics, clinical characteristics, and long-term surgical outcomes.Data obtained in consecutive series of 329 patients with MMD treated microsurgically by the senior author (G.K.S.) between 1991 and 2008 were analyzed. Demographic, clinical, and surgical data were prospectively gathered and neurological outcomes assessed in postoperative follow-up using the modified Rankin Scale. Association of demographic, clinical, and surgical data with postoperative outcome was assessed by chi-square, uni- and multivariate logistic regression, and Kaplan-Meier survival analyses.The authors treated a total of 233 adult patients undergoing 389 procedures (mean age 39.5 years) and 96 pediatric patients undergoing 168 procedures (mean age 10.1 years). Direct revascularization technique was used in 95.1% of adults and 76.2% of pediatric patients. In 264 patients undergoing 450 procedures (mean follow-up 4.9 years), the surgical morbidity rate was 3.5% and the mortality rate was 0.7% per treated hemisphere. The cumulative 5-year risk of perioperative or subsequent stroke or death was 5.5%. Of the 171 patients presenting with a transient ischemic attack, 91.8% were free of transient ischemic attacks at 1 year or later. Overall, there was a significant improvement in quality of life in the cohort as measured using the modified Rankin Scale (p < 0.0001).Revascularization surgery in patients with MMD carries a low risk, is effective at preventing future ischemic events, and improves quality of life. Patients in whom symptomatic MMD is diagnosed should be offered revascularization surgery.

    View details for DOI 10.3171/2009.4.JNS081649

    View details for PubMedID 19463046

  • Efficacy of endovascular stenting in dural venous sinus stenosis for the treatment of idiopathic intracranial hypertension NEUROSURGICAL FOCUS Arac, A., Lee, M., Steinberg, G. K., Marcellus, M., Marks, M. P. 2009; 27 (5)

    Abstract

    Multiple pathophysiological mechanisms have been proposed for the increased intracranial pressure observed in idiopathic intracranial hypertension (IIH). The condition is well characterized, with intractable headaches, visual obscurations, and papilledema as dominant features, mainly affecting obese women. With the advent of MR venography and increased use of cerebral angiography, there has been recent emphasis on the significant number of patients with IIH found to have associated nonthrombotic dural venous sinus stenosis. This has led to a renewed interest in endovascular stenting as a treatment for IIH. However, the assumption that venous stenosis leads to a high pressure gradient that decreases CSF resorption through arachnoid villi requires further evidence. In this paper, the authors analyze the published results to date of dural venous sinus stenting in patients with IIH. They also present a case from their institution for illustration. The pathophysiological mechanism in IIH requires further elucidation, but venous sinus stenosis with subsequent intracranial hypertension appears to be an important mechanism in at least a subgroup of patients with IIH. Among these patients, 78% had complete relief or improvement of their main presenting symptoms after endovascular stenting. Resolution or improvement in papilledema was seen in 85.1% of patients. Endovascular stenting should be considered whenever venous sinus stenosis is diagnosed in patients with IIH.

    View details for DOI 10.3171/2009.9.FOCUS09165

    View details for PubMedID 19877792

  • Kinase activities of JNK and ERK do not match their phosphorylation levels after preconditioning in focal ischemia in rats 24th International Symposium on Cerebral Blood Flow and Metabolism/9th International Conference on Quantification of Brain Function with PET Takahashi, T., Gao, X., Steinberg, G., Zhao, H. NATURE PUBLISHING GROUP. 2009: S161?S162
  • Characterization of the immune response in peripheral organs after cerebral ischemia in mice Arac, A., Bliss, T. M., Steinberg, G. K. NATURE PUBLISHING GROUP. 2009: S93?S94
  • Canonical Wnt signaling promotes neurogenesis in the adult murine brain and reduces apoptotic cell death following focal cerebral ischemia Iordanova, I., Guzman, R., Fuerer, C., Nusse, R., Steinberg, G. NATURE PUBLISHING GROUP. 2009: S550
  • The protective effect of early hypothermia on PTEN phosphorylation correlates with free radical inhibition in rat stroke JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Lee, S. M., Zhao, H., Maier, C. M., Steinberg, G. K. 2009; 29 (9): 1589-1600

    Abstract

    We recently showed that intraischemic moderate hypothermia (30 degrees C) reduces ischemic damage through the Akt pathway after permanent distal middle cerebral artery occlusion in rats. The only Akt pathway component preserved by hypothermia is phosphorylated phosphatase and tensin homolog deleted on chromosome 10 (p-PTEN), which suggests that p-PTEN may have a central role in neuroprotection. Reactive oxygen species (ROS) are critically involved in mediating ischemic damage after stroke by interacting with signaling molecules, including Akt, PTEN, and delta-protein kinase C (PKC). We investigated the protective mechanisms of moderate hypothermia on these signaling proteins after transient focal ischemia in rats. Early moderate hypothermia (3 h) was administered 15 mins before reperfusion, and delayed moderate hypothermia (3 h) was applied 15 mins after reperfusion. Our results indicate that early hypothermia reduced infarction, whereas delayed hypothermia did not. However, both early and delayed hypothermia maintained levels of Mn-SOD (superoxide dismutase) and phosphorylated Akt and blocked delta-PKC cleavage, suggesting that these factors may not be critical to the protection of hypothermia. Nevertheless, early hypothermia preserved p-PTEN levels after reperfusion, whereas delayed hypothermia did not. Furthermore, ROS inhibition maintained levels of p-PTEN after stroke. Together, these findings suggest that phosphorylation levels of PTEN are closely associated with the protective effect of early hypothermia against stroke.

    View details for DOI 10.1038/jcbfm.2009.81

    View details for Web of Science ID 000269447600010

    View details for PubMedID 19553907

    View details for PubMedCentralID PMC3221613

  • The impact of hypopituitarism on function and performance in subjects with recent history of traumatic brain injury and aneurysmal subarachnoid haemorrhage. Brain injury Srinivasan, L., Roberts, B., Bushnik, T., Englander, J., Spain, D. A., Steinberg, G. K., Ren, L., Sandel, M. E., Al-Lawati, Z., Teraoka, J., Hoffman, A. R., Katznelson, L. 2009; 23 (7): 639-648

    Abstract

    To correlate deficient pituitary function with life satisfaction and functional performance in subjects with a recent history of traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH).Cross-sectional study.Eighteen subjects with TBI and 16 subjects with SAH underwent pituitary hormonal and functional assessments 5-12 months following the event. Adrenal reserve was assessed with a 1 mcg cosyntropin stimulation test and growth hormone deficiency (GHD) was diagnosed by insufficient GH response to GHRH-Arginine stimulation. Assessments of life satisfaction and performance-function included the Satisfaction with Life Scale (SWLS), Craig Handicap Assessment and Reporting Technique (CHART) and the Mayo Portland Adaptability Inventory-4 (MPAI-4).Hypopituitarism was present in 20 (58.8%) subjects, including 50% with adrenal insufficiency. Hypothyroidism correlated with worse performance on SWLS and CHART measures. GHD was associated with poorer performance on CHART and MPAI-4 scale.In this series of subjects with history of TBI and SAH, hypothyroidism and GHD were associated with diminished life satisfaction and performance-function on multiple assessments. Further studies are necessary to determine the appropriate testing of adrenal reserve in this population and to determine the benefit of pituitary hormone replacement therapy on function following brain injury.

    View details for DOI 10.1080/02699050902970778

    View details for PubMedID 19557567

  • Molecular and Magnetic Resonance Imaging of Human Embryonic Stem Cell-Derived Neural Stem Cell Grafts in Ischemic Rat Brain MOLECULAR THERAPY Daadi, M. M., Li, Z., Arac, A., Grueter, B. A., Sofilos, M., Malenka, R. C., Wu, J. C., Steinberg, G. K. 2009; 17 (7): 1282-1291

    Abstract

    Real-time imaging of transplanted stem cells is essential for understanding their interactions in vivo with host environments, for tracking cell fate and function and for successful delivery and safety monitoring in the clinical setting. In this study, we used bioluminescence (BLI) and magnetic resonance imaging (MRI) to visualize the fate of grafted human embryonic stem cell (hESC)-derived human neural stem cells (hNSCs) in stroke-damaged rat brain. The hNSCs were genetically engineered with a lentiviral vector carrying a double fusion (DF) reporter gene that stably expressed enhanced green fluorescence protein (eGFP) and firefly luciferase (fLuc) reporter genes. The hNSCs were self-renewable, multipotent, and expressed markers for neural stem cells. Cell survival was tracked noninvasively by MRI and BLI for 2 months after transplantation and confirmed histologically. Electrophysiological recording from grafted GFP(+) cells and immuno-electronmicroscopy demonstrated connectivity. Grafted hNSCs differentiated into neurons, into oligodendrocytes in stroke regions undergoing remyelination and into astrocytes extending processes toward stroke-damaged vasculatures. Our data suggest that the combination of BLI and MRI modalities provides reliable real-time monitoring of cell fate.

    View details for DOI 10.1038/mt.2009.104

    View details for Web of Science ID 000267785800021

    View details for PubMedID 19436269

    View details for PubMedCentralID PMC2835224

  • Assessment of outcome following decompressive craniectomy for malignant middle cerebral artery infarction in patients older than 60 years of age NEUROSURGICAL FOCUS Arac, A., Blanchard, V., Lee, M., Steinberg, G. K. 2009; 26 (6)

    Abstract

    Decompressive surgery can be life saving after malignant cerebral infarction. However, severe residual disability occurs in a significant number of surviving patients. Most discussion about the benefits of surgery is based on studies performed in patients who are < or = 60 years of age. Less is known about the benefits of the procedure in the elderly population. The authors undertook a review of the literature on decompressive craniectomy for malignant cerebral infarction and compared the mortality and outcome data published in patients older and younger than 60 years of age. The authors discuss their analysis, with specific reference to the limitations of the studies analyzed, the outcome measures used, and the special considerations required when discussing stroke recovery in the elderly.Studies on decompressive craniectomy for malignant middle cerebral artery infarction reported in the English literature were analyzed. A cutoff point for age of > 60 or < or = 60 years was set, and the study population was segregated. No studies specifically analyzed patients > 60 years old. A total of 19 studies was identified, 10 of which included patients who were > 60 years of age. A comparison between the 2 age groups was made within the 10 studies and also among all the patients in the 19 studies. Mortality rates and outcome scores were assessed for each study, and a Barthel Index (BI) score of < 60 or a modified Rankin Scale (mRS) score of > 3 was considered to represent a poor outcome. Rates were compared using the Fisher exact test, and p values < 0.05 were considered statistically significant.Nineteen studies were found, which included 273 patients undergoing decompressive craniectomy for malignant cerebral infarcts. Ten of these studies included 73 patients (26.7%) who were > 60 years of age. The mean follow-up times ranged from 5.75 to 12.3 months in the > 60-years group and 4.2 to 28 months in the < or = 60-years group. The mortality rate was significantly higher, at 51.3% in the > 60-years group (37 of 72 patients) compared with 20.8% (41 of 197 patients) in the < or = 60-years group (p < 0.0001). Similarly, patients who survived in the > 60-years group had significantly higher rates of poor outcomes, at 81.8% (27 of 33), compared with 33.1% (47 of 142) in the < or = 60-year-old group (p < 0.0001). The BI was the most commonly used primary outcome measure (15 out of 19 studies), followed by the mRS score, which was used in 4 studies.The mortality rate and functional outcome, as measured by the BI and mRS, were significantly worse in patients > 60 years of age following decompressive craniectomy for malignant infarction. Age is an important factor to consider in patient selection for surgery. However, cautious interpretation of the results is required because the outcome scores that were used only measure physical disability, whereas other factors, including psychosocial, financial, and caregiver burden, should be considered in addition to age alone.

    View details for DOI 10.3171/2009.3.FOCUS0958

    View details for Web of Science ID 000266501400003

    View details for PubMedID 19485716

  • The evolution of cerebral revascularization surgery NEUROSURGICAL FOCUS Hayden, M. G., Lee, M., Guzman, R., Steinberg, G. K. 2009; 26 (5)

    Abstract

    Among the relatively few surgeons to be awarded the Nobel Prize was Alexis Carrel, a French surgeon and pioneer in revascularization surgery at the turn of the 20th century. The authors trace the humble beginnings of cerebral revascularization surgery through to the major developments that helped shape the modern practice of cerebral bypass surgery. They discuss the cornerstone studies in the development of this technique, including the Extracranial/Intracranial Bypass Study initiated in 1977. Recent innovations, including modern techniques to monitor cerebral blood flow, microanastomosis techniques, and ongoing trials that play an important role in the evolution of this field are also evaluated.

    View details for DOI 10.3171/2009.3.FOCUS0931

    View details for Web of Science ID 000265656800017

    View details for PubMedID 19408995

  • Intraoperative hypothermia during vascular neurosurgical procedures NEUROSURGICAL FOCUS Choi, R., Andres, R. H., Steinberg, G. K., Guzman, R. 2009; 26 (5)

    Abstract

    Increasing evidence in animal models and clinical trials for stroke, hypoxic encephalopathy for children, and traumatic brain injury have shown that mild hypothermia may attenuate ischemic damage and improve neurological outcome. However, it is less clear if mild intraoperative hypothermia during vascular neurosurgical procedures results in improved outcomes for patients. This review examines the scientific evidence behind hypothermia as a treatment and discusses factors that may be important for the use of this adjuvant technique, including cooling temperature, duration of hypothermia, and rate of rewarming.

    View details for DOI 10.3171/2009.3.FOCUS0927

    View details for Web of Science ID 000265656800024

    View details for PubMedID 19409003

  • Pathogenesis and radiobiology of brain arteriovenous malformations: implications for risk stratification in natural history and posttreatment course NEUROSURGICAL FOCUS Achrol, A. S., Guzman, R., Varga, M., Adler, J. R., Steinberg, G. K., Chang, S. D. 2009; 26 (5)

    Abstract

    Brain arteriovenous malformations (BAVMs) are an important cause of intracerebral hemorrhage (ICH) in young adults. Biological predictors of future ICH risk are lacking, and controversy exists over previous studies of natural history risk among predominantly ruptured BAVM cohorts. Recent studies have suggested that the majority of BAVMs are now diagnosed as unruptured lesions, and that the risk according to natural history among these lesions may be less than previously assumed. In the first part of this review, the authors discuss available data on the natural history of BAVMs and highlight the need for future studies that aim to develop surrogate biomarkers of disease progression that accurately predict future risk of ICH in BAVMs. The etiology of BAVM remains unknown. Recent studies have suggested a role for genetic factors in the pathogenesis of sporadic BAVM, which is further supported by reports of familial occurrence of BAVM and association with known systemic genetic disorders (such as Osler-Weber-Rendu disease, Sturge-Weber disease, and Wyburn-Mason syndrome). Molecular characterization of BAVM tissue demonstrates a highly angiogenic milieu with evidence of increased endothelial cell turnover. Taken together with a number of reports of de novo BAVM formation, radiographic growth after initial BAVM diagnosis, and regrowth after successful treatment of BAVM, these findings challenge the long-held assumption that BAVMs are static lesions of congenital origin. In the second part of this review, the authors discuss available data on the origins of BAVM and offer insights into future investigations into genetics and endothelial progenitor cell involvement in the pathogenesis of BAVM. Current treatment options for BAVM focus on removal or obliteration of the lesion in an attempt to protect against future ICH risk, including microsurgical resection, endovascular embolization, and stereotactic radiosurgery (SRS). In the third part of this review, the authors discuss available data on SRS in BAVMs and highlight the need for future studies on the radiobiology of BAVMs, especially in regard to biomarker detection for tracking SRS response during the latency period. Insights from future investigations in BAVM may not only prove important for the development of novel therapies and relevant biomarkers for BAVM, but could also potentially benefit a variety of other disorders involving new vessel formation in the CNS, including stroke, tumors, moyamoya disease, and other cerebrovascular malformations.

    View details for DOI 10.3171/2009.2.FOCUS0926

    View details for Web of Science ID 000265656800009

    View details for PubMedID 19409010

  • Pathophysiology and genetic factors in moyamoya disease NEUROSURGICAL FOCUS Achrol, A. S., Guzman, R., Lee, M., Steinberg, G. K. 2009; 26 (4)

    Abstract

    Moyamoya disease is an uncommon cerebrovascular condition characterized by progressive stenosis of the bilateral internal carotid arteries with compensatory formation of an abnormal network of perforating blood vessels providing collateral circulation. The etiology and pathogenesis of moyamoya disease remain unclear. Evidence from histological studies, proteomics, and endothelial progenitor cell analyses suggests new theories underlying the cause of vascular anomalies, including moyamoya disease. Familial moyamoya disease has been noted in as many as 15% of patients, indicating an autosomal dominant inheritance pattern with incomplete penetrance. Genetic analyses in familial moyamoya disease and genome-wide association studies represent promising strategies for elucidating the pathophysiology of this condition. In this review, the authors discuss recent studies that have investigated possible mechanisms underlying the etiology of moyamoya disease, including stem cell involvement and genetic factors. They also discuss future research directions that promise not only to offer new insights into the origin of moyamoya disease but to enhance our understanding of new vessel formation in the CNS as it relates to stroke, vascular anomalies, and tumor growth.

    View details for DOI 10.3171/2009.1.FOCUS08302

    View details for Web of Science ID 000265656400004

    View details for PubMedID 19335130

  • Prokineticin 2 Exacerbates Cerebral Ischemic Injury In Rats American-Association-International-Stroke Conference 2009 Cheng, M. Y., Lee, A. G., Sun, G., Zhao, H., Zhou, Q., Steinberg, G., Sapolsky, R. LIPPINCOTT WILLIAMS & WILKINS. 2009: E213?E213
  • Grafts of Human Embryonic Stem Cell-Derived Neural Stem Cells Promote Neuroanatomical Rewiring And Connectivity With Host In Hypoxia Ischemia Model of Neonates American-Association-International-Stroke Conference 2009 Daadi, M. M., Arac, A., Davis, A., Maag, A., Batnagar, R., Choi, M., Sun, G., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: E169?E169
  • Therapeutic Homing of Neurosphere-Derived Multipotent Precursors After Intracarotid Delivery in Stroke is Dependent on the MCP-1/CCR2 Interaction. American-Association-International-Stroke Conference 2009 Andres, R. H., Choi, R., Gaeta, X., Wang, N., Cote, J., Lee, S. W., Palmer, T. D., Guzman, R., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: E171?E171
  • Quantitative hemodynamic studies in moyamoya disease NEUROSURGICAL FOCUS Lee, M., Zaharchuk, G., Guzman, R., Achrol, A., Bell-Stephens, T., Steinberg, G. K. 2009; 26 (4)

    Abstract

    Moyamoya disease is characterized by a chronic stenoocclusive vasculopathy affecting the terminal internal carotid arteries. The clinical presentation and outcome of moyamoya disease remain varied based on angiographic studies alone, and much work has been done to study cerebral hemodynamics in this group of patients. The ability to measure cerebral blood flow (CBF) accurately continues to improve with time, and with it a better understanding of the pathophysiological mechanisms in patients with moyamoya disease. The main imaging techniques used to evaluate cerebral hemodynamics include PET, SPECT, xenon-enhanced CT, dynamic perfusion CT, MR imaging with dynamic susceptibility contrast and with arterial spin labeling, and Doppler ultrasonography. More invasive techniques include intraoperative ultrasonography. The authors review the current knowledge of CBF in this group of patients and the role each main quantitative method has played in evaluating them, both in the disease state and after surgical intervention.

    View details for DOI 10.3171/2009.1.FOCUS08300

    View details for Web of Science ID 000265656400005

    View details for PubMedID 19335131

    View details for PubMedCentralID PMC2905646

  • Biallelic somatic and germline mutations in cerebral cavernous malformations (CCMs): evidence for a two-hit mechanism of CCM pathogenesis HUMAN MOLECULAR GENETICS Akers, A. L., Johnson, E., Steinberg, G. K., Zabramski, J. M., Marchuk, D. A. 2009; 18 (5): 919-930

    Abstract

    Cerebral cavernous malformations (CCMs) are vascular anomalies of the central nervous system, comprising dilated blood-filled capillaries lacking structural support. The lesions are prone to rupture, resulting in seizures or hemorrhagic stroke. CCM can occur sporadically, manifesting as solitary lesions, but also in families, where multiple lesions generally occur. Familial cases follow autosomal-dominant inheritance due to mutations in one of three genes, CCM1/KRIT1, CCM2/malcavernin or CCM3/PDCD10. The difference in lesion burden between familial and sporadic CCM, combined with limited molecular data, suggests that CCM pathogenesis may follow a two-hit molecular mechanism, similar to that seen for tumor suppressor genes. In this study, we investigate the two-hit hypothesis for CCM pathogenesis. Through repeated cycles of amplification, subcloning and sequencing of multiple clones per amplicon, we identify somatic mutations that are otherwise invisible by direct sequencing of the bulk amplicon. Biallelic germline and somatic mutations were identified in CCM lesions from all three forms of inherited CCMs. The somatic mutations are found only in a subset of the endothelial cells lining the cavernous vessels and not in interstitial lesion cells. These data suggest that CCM lesion genesis requires complete loss of function for one of the CCM genes. Although widely expressed in the different cell types of the brain, these data also suggest a unique role for the CCM proteins in endothelial cell biology.

    View details for DOI 10.1093/hmg/ddn430

    View details for Web of Science ID 000263409100011

    View details for PubMedID 19088123

    View details for PubMedCentralID PMC2640209

  • Manufacturing neurons from human embryonic stem cells: biological and regulatory aspects to develop a safe cellular product for stroke cell therapy REGENERATIVE MEDICINE Daadi, M. M., Steinberg, G. K. 2009; 4 (2): 251-263

    Abstract

    Demographic trends, particularly those related to longer life expectancy, suggest that the demand for tissue and organ transplants will further increase since many disorders result from degeneration, injury or organ failure. The most urgent problem in transplantation medicine is the shortage or lack of suitable donor organs and tissue, leading to ethical and societal problems such as organ trafficking. The discovery of stem cells in the inner cell mass of developing embryos and in adult tissue has revolutionized the medical field by introducing new therapeutic dimensions to consider for previously untreatable diseases and injuries. The unlimited self-renewal ability and pluripotent capacity to become any cell type of the organism make human embryonic stem cells (hESCs) a compelling source of cells to study tissue histogenesis and to apply in a wide array of tissue engineering, cell transplantation therapy and drug discovery applications. In this article, we will focus on hESCs and address the derivation of therapeutic neural stem cell lines from hESCs, as well as the biological and regulatory aspects to developing a safe cellular product for stroke cell therapy.

    View details for DOI 10.2217/17460751.4.2.251

    View details for Web of Science ID 000264857700014

    View details for PubMedID 19317644

  • Netrin-4 enhances angiogenesis and neurologic outcome after cerebral ischemia JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Hoang, S., Liauw, J., Choi, M., Choi, M., Guzman, R. G., Steinberg, G. K. 2009; 29 (2): 385-397

    Abstract

    Functional recovery after cerebral ischemia is mediated by the regeneration of vascular networks and the restoration of synaptic architecture. Netrins have been implicated in neuronal pathfinding and angiogenesis. In this study, we investigated the expression of Netrin-4 and its putative receptors, deleted in colorectal cancer (DCC), Unc5A, and Unc5B after distal middle cerebral artery occlusion in mice. Netrin-4 protein was also administered intracerebroventricularly to examine its effect on angiogenesis and behavioral recovery. Netrin-4 protein was highly upregulated in the ischemic core as soon as 1 day after cerebral ischemia, with subsequent downregulation after 1 week. Its expression was limited to the area of blood-brain barrier damage and was seen on both blood vessels and astrocytic foot processes. Although there was not a significant upregulation of the putative Netrin-4 receptor Unc5A and Unc5B, there was a significant increase in expression of the DCC receptor on neuronal processes in the peri-infarct cortex. Intracerebroventricular administration of Netrin-4 into the ischemic brain increased blood vessel density, endothelial proliferation, and improved behavioral recovery at 1 week after stroke, but did not have an effect on blood-brain barrier permeability or infarct size. These findings suggest that Netrin-4 may improve poststroke functional recovery by enhancing blood vessel proliferation.

    View details for DOI 10.1038/jcbfm.2008.128

    View details for Web of Science ID 000263119900018

    View details for PubMedID 18985053

  • Activating delta PKC antagonizes the protective effect of ERK1/2 inhibition against stroke in rats BRAIN RESEARCH Castaneda, D., Zhao, H., Mochly-Rosen, D., Steinberg, G. K. 2009; 1251: 256-261

    Abstract

    Two pathways that have been shown to mediate cerebral ischemic damage are the MEK/ERK cascade and the pro-apoptotic deltaPKC pathway. We investigated the relationship between these pathways in a rat model of focal ischemia by observing and modifying the activation state of each pathway. The ERK1/2 inhibitor, U0126, injected at ischemia onset, attenuated the increase in phosphorylated ERK1/2 (P-ERK1/2) after reperfusion. The deltaPKC inhibitor, deltaV1-1, delivered at reperfusion, did not significantly change P-ERK1/2 levels. In contrast, the deltaPKC activator, psi deltaRACK, injected at reperfusion, reduced ERK1/2 phosphorylation measured 4 h after reperfusion. Additionally, U0126 pretreatment at ischemia onset reduced infarct size compared with vehicle, but U0126 injected at the onset of reperfusion had no protection. Finally, combination of U0126 injection at ischemia onset plus deltaV1-1 injection at reperfusion further reduced infarct size, while combination of U0126 delivered at ischemia onset with psi deltaRACK injected at reperfusion increased infarct size compared with U0126 alone. In conclusion, we find that inhibiting both the MEK/ERK and the deltaPKC pathways offers greater protection than either alone, indicating they likely act independently.

    View details for DOI 10.1016/j.brainres.2008.11.051

    View details for PubMedID 19063870

  • Positron Emission Tomography Imaging of Poststroke Angiogenesis STROKE Cai, W., Guzman, R., Hsu, A. R., Wang, H., Chen, K., Sun, G., Gera, A., Choi, R., Bliss, T., He, L., Li, Z., Maag, A. D., Hori, N., Zhao, H., Moseley, M., Steinberg, G. K., Chen, X. 2009; 40 (1): 270-277

    Abstract

    Vascular endothelial growth factor (VEGF) and VEGF receptors (VEGFRs) play important roles during neurovascular repair after stroke. In this study, we imaged VEGFR expression with positron emission tomography (PET) to noninvasively analyze poststroke angiogenesis.Female Sprague-Dawley rats after distal middle cerebral artery occlusion surgery were subjected to weekly MRI, (18)F-FDG PET, and (64)Cu-DOTA-VEGF(121) PET scans. Several control experiments were performed to confirm the VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone. VEGFR, BrdU, lectin staining, and (125)I-VEGF(165) autoradiography on stroke brain tissue slices were performed to validate the in vivo findings.T2-weighed MRI correlated with the "cold spot" on (18)F-FDG PET for rats undergoing distal middle cerebral artery occlusion surgery. The (64)Cu-DOTA-VEGF(121) uptake in the stroke border zone peaked at approximately 10 days after surgery, indicating neovascularization as confirmed by histology (VEGFR-2, BrdU, and lectin staining). VEGFR specificity of (64)Cu-DOTA-VEGF(121) uptake was confirmed by significantly lower uptake of (64)Cu-DOTA-VEGF(mutant) in vivo and intense (125)I-VEGF(165) uptake ex vivo in the stroke border zone. No appreciable uptake of (64)Cu-DOTA-VEGF(121) was observed in the brain of sham-operated rats.For the first time to our knowledge, we successfully evaluated the VEGFR expression kinetics noninvasively in a rat stroke model. In vivo imaging of VEGFR expression could become a significant clinical tool to plan and monitor therapies aimed at improving poststroke angiogenesis.

    View details for DOI 10.1161/STROKEAHA.108.517474

    View details for PubMedID 18948613

  • Axonal Sprouting and Immune-Mediated Effects of Grafted Human Embryonic Stem Cell-Derived Neural Stem Cells in Pediatric Hypoxic-Ischemic Brain Injury Model Daadi, M. M., Arac, A., Li, Z., Sun, G., Wu, J. C., Steinberg, G. K. COGNIZANT COMMUNICATION CORP. 2009: 212
  • The impact of hypopituitarism on function and performance in subjects with recent history of traumatic brain injury and aneurysmal subarachnoid haemorrhage BRAIN INJURY Srinivasan, L., Roberts, B., Bushnik, T., Englander, J., Spain, D. A., Steinberg, G. K., Ren, L., Sandel, M. E., Al-Lawati, Z., Teraoka, J., Hoffman, A. R., Katznelson, L. 2009; 23 (7-8): 639-648

    Abstract

    To correlate deficient pituitary function with life satisfaction and functional performance in subjects with a recent history of traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH).Cross-sectional study.Eighteen subjects with TBI and 16 subjects with SAH underwent pituitary hormonal and functional assessments 5-12 months following the event. Adrenal reserve was assessed with a 1 mcg cosyntropin stimulation test and growth hormone deficiency (GHD) was diagnosed by insufficient GH response to GHRH-Arginine stimulation. Assessments of life satisfaction and performance-function included the Satisfaction with Life Scale (SWLS), Craig Handicap Assessment and Reporting Technique (CHART) and the Mayo Portland Adaptability Inventory-4 (MPAI-4).Hypopituitarism was present in 20 (58.8%) subjects, including 50% with adrenal insufficiency. Hypothyroidism correlated with worse performance on SWLS and CHART measures. GHD was associated with poorer performance on CHART and MPAI-4 scale.In this series of subjects with history of TBI and SAH, hypothyroidism and GHD were associated with diminished life satisfaction and performance-function on multiple assessments. Further studies are necessary to determine the appropriate testing of adrenal reserve in this population and to determine the benefit of pituitary hormone replacement therapy on function following brain injury.

    View details for DOI 10.1080/02699050902970778

    View details for Web of Science ID 000267370600008

  • POSITRON EMISSION TOMOGRAPHY IMAGING OF VEGF RECEPTOR EXPRESSION IN POST-STROKE ANGIOGENESIS 21st American Peptide Symposium Cai, W., Guzman, R., Hsu, A., Wang, H., Steinberg, G., Chen, X. JOHN WILEY & SONS INC. 2009: 373?73
  • Effects of Creatine on Survival, Migration, and Differentiation of Neural Stem Cells 16th Annual Meeting of the American-Society-for-Neural-Therapy-and-Repair Andres, R. H., PENDHARKAR, A. V., Guzman, R., De, A., Bliss, T. M., McMillan, E., Svendsen, C. N., Gambhir, S. S., Widmer, H. R., Wallimann, T., Steinberg, G. K. COGNIZANT COMMUNICATION CORP. 2009: 208?
  • Who's in Favor of Translational Cell Therapy for Stroke: STEPS Forward Please? CELL TRANSPLANTATION Chopp, M., Steinberg, G. K., Kondziolka, D., Lu, M., Bliss, T. M., Li, Y., Hess, D. C., Borlongan, C. V. 2009; 18 (7): 691-693

    Abstract

    A consortium of translational stem cell and stroke experts from multiple academic institutes and biotechnology companies, under the guidance of the government (FDA/NIH), is missing. Here, we build a case for the establishment of this consortium if cell therapy for stroke is to advance from the laboratory to the clinic.

    View details for DOI 10.3727/096368909X470883

    View details for Web of Science ID 000271253200002

    View details for PubMedID 19796499

  • Subarachnoid hemorrhage. Handbook of clinical neurology Kelly, M. E., Dodd, R., Steinberg, G. K. 2009; 93: 791-808

    View details for DOI 10.1016/S0072-9752(08)93039-6

    View details for PubMedID 18804680

  • Functional Engraftment of the Medial Ganglionic Eminence Cells in Experimental Stroke Model CELL TRANSPLANTATION Daadi, M. M., Lee, S. H., Arac, A., Grueter, B. A., Bhatnagar, R., Maag, A., Schaar, B., Malenka, R. C., Palmer, T. D., Steinberg, G. K. 2009; 18 (7): 815-826

    Abstract

    Currently there are no effective treatments targeting residual anatomical and behavioral deficits resulting from stroke. Evidence suggests that cell transplantation therapy may enhance functional recovery after stroke through multiple mechanisms. We used a syngeneic model of neural transplantation to explore graft-host communications that enhance cellular engraftment.The medial ganglionic eminence (MGE) cells were derived from 15-day-old transgenic rat embryos carrying green fluorescent protein (GFP), a marker, to easily track the transplanted cells. Adult rats were subjected to transient intraluminal occlusion of the medial cerebral artery. Two weeks after stroke, the grafts were deposited into four sites, along the rostro-caudal axis and medially to the stroke in the penumbra zone. Control groups included vehicle and fibroblast transplants. Animals were subjected to motor behavioral tests at 4 week posttransplant survival time. Morphological analysis demonstrated that the grafted MGE cells differentiated into multiple neuronal subtypes, established synaptic contact with host cells, increased the expression of synaptic markers, and enhanced axonal reorganization in the injured area. Initial patch-clamp recording demonstrated that the MGE cells received postsynaptic currents from host cells. Behavioral analysis showed reduced motor deficits in the rotarod and elevated body swing tests. These findings suggest that graft-host interactions influence the fate of grafted neural precursors and that functional recovery could be mediated by neurotrophic support, new synaptic circuit elaboration, and enhancement of the stroke-induced neuroplasticity.

    View details for DOI 10.3727/096368909X470829

    View details for Web of Science ID 000271253200013

    View details for PubMedID 19500468

  • Potential of adult neural stem cells in stroke therapy REGENERATIVE MEDICINE Andres, R. H., Choi, R., Steinberg, G. K., Guzman, R. 2008; 3 (6): 893-905

    Abstract

    Despite state-of-the-art therapy, clinical outcome after stroke remains poor, with many patients left permanently disabled and dependent on care. Stem cell therapy has evolved as a promising new therapeutic avenue for the treatment of stroke in experimental studies, and recent clinical trials have proven its feasibility and safety in patients. Replacement of damaged cells and restoration of function can be accomplished by transplantation of different cell types, such as embryonic, fetal or adult stem cells, human fetal tissue and genetically engineered cell lines. Adult neural stem cells offer the advantage of avoiding the ethical problems associated with embryonic or fetal stem cells and can be harvested as autologous grafts from the individual patients. Furthermore, stimulation of endogenous adult stem cell-mediated repair mechanisms in the brain might offer new avenues for stroke therapy without the necessity of transplantation. However, important scientific issues need to be addressed to advance our understanding of the molecular mechanisms underlying the critical steps in cell-based repair to allow the introduction of these experimental techniques into clinical practice. This review describes up-to-date experimental concepts using adult neural stem cells for the treatment of stroke.

    View details for DOI 10.2217/17460751.3.6.893

    View details for Web of Science ID 000261008000016

    View details for PubMedID 18947311

  • Thrombospondins 1 and 2 are necessary for synaptic plasticity and functional recovery after stroke JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Liauw, J., Hoang, S., Choi, M., Eroglu, C., Choi, M., Sun, G., Percy, M., Wildman-Tobriner, B., Bliss, T., Guzman, R. G., Barres, B. A., Steinberg, G. K. 2008; 28 (10): 1722-1732

    Abstract

    Thrombospondins 1 and 2 (TSP-1/2) belong to a family of extracellular glycoproteins with angiostatic and synaptogenic properties. Although TSP-1/2 have been postulated to drive the resolution of postischemic angiogenesis, their role in synaptic and functional recovery is unknown. We investigated whether TSP-1/2 are necessary for synaptic and motor recovery after stroke. Focal ischemia was induced in 8- to 12-week-old wild-type (WT) and TSP-1/2 knockout (KO) mice by unilateral occlusion of the distal middle cerebral artery and the common carotid artery (CCA). Thrombospondins 1 and 2 increased after stroke, with both TSP-1 and TSP-2 colocalizing mostly to astrocytes. Wild-type and TSP-1/2 KO mice were compared in angiogenesis, synaptic density, axonal sprouting, infarct size, and functional recovery at different time points after stroke. Using the tongue protrusion test of motor function, we observed that TSP-1/2 KO mice exhibited significant deficit in their ability to recover function (P<0.05) compared with WT mice. No differences were found in infarct size and blood vessel density between the two groups after stroke. However, TSP-1/2 KO mice exhibited significant synaptic density and axonal sprouting deficits. Deficiency of TSP-1/2 leads to impaired recovery after stroke mainly due to the role of these proteins in synapse formation and axonal outgrowth.

    View details for DOI 10.1038/jcbfm.2008.65

    View details for Web of Science ID 000259445100009

    View details for PubMedID 18594557

  • epsilon PKC confers acute tolerance to cerebral ischemic reperfusion injury NEUROSCIENCE LETTERS Bright, R., Sun, G., Yenari, M. A., Steinberg, G. K., Mochly-Rosen, D. 2008; 441 (1): 120-124

    Abstract

    In response to mild ischemic stress, the brain elicits endogenous survival mechanisms to protect cells against a subsequent lethal ischemic stress, referred to as ischemic tolerance. The molecular signals that mediate this protection are thought to involve the expression and activation of multiple kinases, including protein kinase C (PKC). Here we demonstrate that epsilonPKC mediates cerebral ischemic tolerance in vivo. Systemic delivery of psiepsilonRACK, an epsilonPKC-selective peptide activator, confers neuroprotection against a subsequent cerebral ischemic event when delivered immediately prior to stroke. In addition, activation of epsilonPKC by psiepsilonRACK treatment decreases vascular tone in vivo, as demonstrated by a reduction in microvascular cerebral blood flow. Here we demonstrate the role of acute and transient epsilonPKC in early cerebral tolerance in vivo and suggest that extra-parenchymal mechanisms, such as vasoconstriction, may contribute to the conferred protection.

    View details for DOI 10.1016/j.neulet.2008.05.080

    View details for PubMedID 18586397

  • FasL shedding is reduced by hypothermia in experimental stroke JOURNAL OF NEUROCHEMISTRY Liu, L., Kim, J. Y., Koike, M. A., Yoon, Y. J., Tang, X. N., Ma, H., Lee, H., Steinberg, G. K., Lee, J. E., Yenari, M. A. 2008; 106 (2): 541-550

    Abstract

    Protection by mild hypothermia has previously been associated with better mitochondrial preservation and suppression of the intrinsic apoptotic pathway. It is also known that the brain may undergo apoptotic death via extrinsic, or receptor-mediated pathways, such as that triggered by Fas/FasL. Male Sprague-Dawley rats subjected to 2 h middle cerebral artery occlusion with 2 h intraischemic mild hypothermia (33 degrees C) were assayed for Fas, FasL and caspase-8 expression. Ischemia increased Fas, but decreased FasL by approximately 50-60% at 6 and 24 h post-insult. Mild hypothermia significantly reduced expression of Fas and processed caspase-8 both by approximately 50%, but prevented ischemia-induced FasL decreases. Fractionation revealed that soluble/shed FasL (sFasL) was decreased by hypothermia, while membrane-bound FasL (mFasL) increased. To more directly assess the significance of the Fas/FasL pathway in ischemic stroke, primary neuron cultures were exposed to oxygen glucose deprivation. Since FasL is cleaved by matrix metalloproteinases (MMPs), and mild hypothermia decreases MMP expression, treatment with a pan-MMP inhibitor also decreased sFasL. Thus, mild hypothermia is associated with reduced Fas expression and caspase-8 activation. Hypothermia prevented total FasL decreases, and most of it remained membrane-bound. These findings reveal new observations regarding the effect of mild hypothermia on the Fas/FasL and MMP systems.

    View details for DOI 10.1111/j.1471-4159.2008.05411.x

    View details for Web of Science ID 000257708000005

    View details for PubMedID 18410517

    View details for PubMedCentralID PMC2735469

  • Multimodality treatment of posterior fossa arteriovenous malformations JOURNAL OF NEUROSURGERY Kelly, M. E., Guzman, R., Sinclair, J., Bell-Stephens, T. E., Bower, R., Hamilton, S., Marks, M. P., Do, H. M., Chang, S. D., Adler, J. R., Levy, R. P., Steinberg, G. K. 2008; 108 (6): 1152-1161

    Abstract

    Posterior fossa arteriovenous malformations (AVMs) are relatively uncommon and often difficult to treat. The authors present their experience with multimodality treatment of 76 posterior fossa AVMs, with an emphasis on Spetzler-Martin Grades III-V AVMs.Seventy-six patients with posterior fossa AVMs treated with radiosurgery, surgery, and endovascular techniques were analyzed.Between 1982 and 2006, 36 patients with cerebellar AVMs, 33 with brainstem AVMs, and 7 with combined cerebellar-brainstem AVMs were treated. Natural history data were calculated for all 76 patients. The risk of hemorrhage from presentation until initial treatment was 8.4% per year, and it was 9.6% per year after treatment and before obliteration. Forty-eight patients had Grades III-V AVMs with a mean follow-up of 4.8 years (range 0.1-18.4 years, median 3.1 years). Fifty-two percent of patients with Grades III-V AVMs had complete obliteration at the last follow-up visit. Three (21.4%) of 14 patients were cured with a single radiosurgery treatment, and 4 (28.6%) of 14 with 1 or 2 radiosurgery treatments. Twenty-one (61.8%) of 34 patients were cured with multimodality treatment. The mean Glasgow Outcome Scale (GOS) score after treatment was 3.8. Multivariate analysis performed in the 48 patients with Grades III-V AVMs showed radiosurgery alone to be a negative predictor of cure (p = 0.0047). Radiosurgery treatment alone was not a positive predictor of excellent clinical outcome (GOS Score 5; p > 0.05). Nine (18.8%) of 48 patients had major neurological complications related to treatment.Single-treatment radiosurgery has a low cure rate for posterior fossa Spetzler-Martin Grades III-V AVMs. Multimodality therapy nearly tripled this cure rate, with an acceptable risk of complications and excellent or good clinical outcomes in 81% of patients. Radiosurgery alone should be used for intrinsic brainstem AVMs, and multimodality treatment should be considered for all other posterior fossa AVMs.

    View details for DOI 10.3171/JNS/2008/108/6/1152

    View details for PubMedID 18518720

  • Multimodality treatment of posterior fossa arteriovenous malformations - Response JOURNAL OF NEUROSURGERY Kelly, M. E., Guzman, R., Marks, M. P., Do, H. M., Chang, S. D., Adler, J. R., Steinberg, G. K. 2008; 108 (6): 1150-1151
  • Dual roles of the MAPK/ERK1/2 cell signaling pathway after stroke JOURNAL OF NEUROSCIENCE RESEARCH Sawe, N., Steinberg, G., Zhao, H. 2008; 86 (8): 1659-1669

    Abstract

    Extracellular signal-regulated kinase 1/2 (ERK1/2), one of the best-characterized members of the mitogen-activated protein kinase (MAPK) family, mediates a range of activity from metabolism, motility, and inflammation to cell death and survival. It is phosphorylated and activated through a three-tiered MEK mode via cell surface receptors stimulated by growth factors or cytokines. The phosphorylated ERK1/2 level is usually increased after cerebral ischemia/reperfusion, but whether an increase in ERK1/2 phosphorylation is protective or detrimental is highly debatable. Much of the support for ERK1/2's role as a neuroprotectant against stroke stems from its apparent involvement in the beneficial effects of growth factors, estrogen, preconditioning, and hypothermia on the ischemic brain. Conversely, evidence supporting the detrimental effects of ERK1/2 activity is derived from its activation promoting inflammation and oxidative stress and its inhibition reducing ischemic damage. The dual potential of ERK1/2 actions in the ischemic brain is likely related to its responses to a diverse array of agonists and cell surface receptors. Plausibly, the ERK1/2 activity generated by cytokines and free radicals or other inflammatory factors after stroke may worsen ischemic damage, whereas the ERK1/2 activity produced by exogenous growth factors, estrogen, and preconditioning favors neuroprotection. Future experiments should be conducted to optimize the protective effect of ERK1/2 while blocking its detrimental actions.

    View details for DOI 10.1002/jnr.21604

    View details for Web of Science ID 000256646400001

    View details for PubMedID 18189318

  • The Akt signaling pathway contributes to postconditioning's protection against stroke; the protection is associated with the MAPK and PKC pathways JOURNAL OF NEUROCHEMISTRY Gao, X., Zhang, H., Takahashi, T., Hsieh, J., Liao, J., Steinberg, G. K., Zhao, H. 2008; 105 (3): 943-955

    Abstract

    We previously reported that ischemic postconditioning with a series of mechanical interruptions of reperfusion reduced infarct volume 2 days after focal ischemia in rats. Here, we extend this data by examining long-term protection and exploring underlying mechanisms involving the Akt, mitogen-activated protein kinase (MAPK) and protein kinase C (PKC) signaling pathways. Post-conditioning reduced infarct and improved behavioral function assessed 30 days after stroke. Additionally, postconditioning increased levels of phosphorylated Akt (Ser473) as measured by western blot and Akt activity as measured by an in vitro kinase assay. Inhibiting Akt activity by a phosphoinositide 3-kinase inhibitor, LY294002, enlarged infarct in postconditioned rats. Postconditioning did not affect protein levels of phosphorylated-phosphatase and tensin homologue deleted on chromosome 10 or -phosphoinositide-dependent protein kinase-1 (molecules upstream of Akt) but did inhibit an increase in phosphorylated-glycogen synthase kinase 3beta, an Akt effector. In addition, postconditioning blocked beta-catenin phosphorylation subsequent to glycogen synthase kinase, but had no effect on total or non-phosphorylated active beta-catenin protein levels. Furthermore, postconditioning inhibited increases in the amount of phosphorylated-c-Jun N-terminal kinase and extracellular signal-regulated kinase 1/2 in the MAPK pathway. Finally, postconditioning blocked death-promoting deltaPKC cleavage and attenuated reduction in phosphorylation of survival-promoting epsilonPKC. In conclusion, our data suggest that postconditioning provides long-term protection against stroke in rats. Additionally, we found that Akt activity contributes to postconditioning's protection; furthermore, increases in epsilonPKC activity, a survival-promoting pathway, and reductions in MAPK and deltaPKC activity; two putative death-promoting pathways correlate with postconditioning's protection.

    View details for DOI 10.1111/j.1471-4159.2008.05218.x

    View details for Web of Science ID 000255139200034

    View details for PubMedID 18182053

    View details for PubMedCentralID PMC2746404

  • Potential of stem/progenitor cells in treating stroke: the missing steps in translating cell therapy from laboratory to clinic REGENERATIVE MEDICINE Borlongan, C. V., Chopp, M., Steinberg, G. K., Bliss, T. M., Li, Y., Lu, M., Hess, D. C., Kondziolka, D. 2008; 3 (3): 249-250

    View details for DOI 10.2217/17460751.3.3.249

    View details for Web of Science ID 000257995200001

    View details for PubMedID 18462048

  • Effect of moyamoya disease on neuropsychological functioning in adults NEUROSURGERY Karzmark, P., Zeifert, P. D., Tan, S., Dorfman, L. J., Bell-Stephens, T. E., Steinberg, G. K. 2008; 62 (5): 1048-1051

    Abstract

    Moyamoya disease is a cerebrovascular disorder characterized by progressive occlusion of vessels comprising the circle of Willis, resulting in formation of collaterals that have a cloudy appearance on angiography. Neuropsychological research on the cognitive effects of the disorder in adults has been limited in scope and generalizability; only a few case studies have been published. The current study was intended to more comprehensively document the nature of cognitive impairment in moyamoya disease by assessing a large number of adult cases with a neuropsychological assessment test battery.Thirty-six adult patients with neurodiagnostically confirmed moyamoya disease were given presurgical neuropsychological assessments.Mean group performances were within normal limits for all measures assessed. The highest rate of impairment was for measures of executive functioning. The lowest rates occurred with memory and perception measures. Cognitive impairment was present in 11 (31%) of the patients; it was judged to be moderate to severe in four patients (11%). Five patients reported a mild level of depression, and two patients reported a moderate level.The present findings suggest that moyamoya disease diagnosed in adults can impair cognition but that the effect is not as severe as in pediatric cases. Executive functioning is most affected. Memory and, to a large extent, intellect are spared. The current pattern of results suggests brain region-behavior correlations that deserve further study.

    View details for DOI 10.1227/01.NEU.0000312712.55567.E6

    View details for Web of Science ID 000257218500011

    View details for PubMedID 18580802

  • Intracarotid injection of fluorescence activated cell-sorted CD49d-positive neural stem cells improves targeted cell delivery and behavior after stroke in a mouse stroke model STROKE Guzman, R., De Los Angeles, A., Cheshier, S., Choi, R., Hoang, S., Liauw, J., Schaar, B., Steinberg, G. 2008; 39 (4): 1300-1306

    Abstract

    Intravascular delivery of neural stem cells (NSCs) after stroke has been limited by the low efficiency of transendothelial migration. Vascular cell adhesion molecule-1 is an endothelial adhesion molecule known to be upregulated early after stroke and is responsible for the firm adhesion of inflammatory cells expressing the surface integrin, CD49d. We hypothesize that enriching for NSCs that express CD49d and injecting them into the carotid artery would improve targeted cell delivery to the injured brain.Mouse NSCs were analyzed for the expression of CD49d by fluorescence activated cell sorting. A CD49d-enriched (CD49d(+)) (>95%) and -depleted (CD49d(-); <5%) NSC population was obtained by cell sorting. C57/Bl6 mice underwent left-sided hypoxia-ischemia surgery and were assigned to receive 3 x 10(5) CD49d(+), CD49d(-) NSCs, or vehicle injection into the left common carotid artery 48 hours after stroke. Behavioral recovery was measured using a rotarod for 2 weeks after cell injection.Fluorescence activated cell sorting analysis revealed 25% CD49d(+) NSCs. In a static adhesion assay, NSCs adhered to vascular cell adhesion molecule-1 in a dose-dependent manner. Significantly more NSCs were found in the cortex, the hippocampus, and the subventricular zone in the ischemic hemisphere in animals receiving CD49d(+) NSCs as compared with CD49d(-) NSCs (P<0.05). Animals treated with CD49d(+) cells showed a significantly better behavioral recovery as compared with CD49d(-) and vehicle-treated animals.We show that enrichment of NSCs by fluorescence activated cell sorting for the surface integrin, CD49d, and intracarotid delivery promotes cell homing to the area of stroke in mice and improves behavioral recovery.

    View details for DOI 10.1161/STROKEAHA.107.500470

    View details for Web of Science ID 000254632900038

    View details for PubMedID 18309158

  • Hypothermia blacks beta-catenin degradation after focal ischemia in rats BRAIN RESEARCH Zhang, H., Ren, C., Gao, X., Takahashi, T., Sapolsky, R. M., Steinberg, G. K., Zhao, H. 2008; 1198: 182-187

    Abstract

    Dephosphorylated and activated glycogen synthase kinase (GSK) 3beta hyperphosphorylates beta-catenin, leading to its ubiquitin-proteosome-mediated degradation. beta-catenin-knockdown increases while beta-catenin overexpression prevents neuronal death in vitro; in addition, protein levels of beta-catenin are reduced in the brain of Alzheimer's patients. However, whether beta-catenin degradation is involved in stroke-induced brain injury is unknown. Here we studied activities of GSK 3beta and beta-catenin, and the protective effect of moderate hypothermia (30 degrees C) on these activities after focal ischemia in rats. The results of Western blot showed that GSK 3beta was dephosphorylated at 5 and 24 h after stroke in the normothermic (37 degrees C) brain; hypothermia augmented GSK 3beta dephosphorylation. Because hypothermia reduces infarction, these results contradict with previous studies showing that GSK 3beta dephosphorylation worsens neuronal death. Nevertheless, hypothermia blocked degradation of total GSK 3beta protein. Corresponding to GSK 3beta activity in normothermic rats, beta-catenin phosphorylation transiently increased at 5 h in both the ischemic penumbra and core, and the total protein level of beta-catenin degraded after normothermic stroke. Hypothermia did not inhibit beta-catenin phosphorylation, but it blocked beta-catenin degradation in the ischemic penumbra. In conclusion, moderate hypothermia can stabilize beta-catenin, which may contribute to the protective effect of moderate hypothermia.

    View details for DOI 10.1016/j.brainres.2008.01.007

    View details for Web of Science ID 000254106400020

    View details for PubMedID 18241848

    View details for PubMedCentralID PMC2350209

  • Intravascular cell replacement therapy for stroke NEUROSURGICAL FOCUS Guzman, R., Choi, R., Gera, A., Angeles, A. D., Andres, R. H., Steinberg, G. K. 2008; 24 (3-4)

    Abstract

    The use of stem cell transplantation to restore neurological function after stroke is being recognized as a potential novel therapy. Before stem cell transplantation can become widely applicable, however, questions remain about the optimal site of delivery and timing of transplantation. In particular, there seems to be increasing evidence that intravascular cell delivery after stroke is a viable alternative to intracerebral transplantation. In this review, the authors focus on the intravascular delivery of stem cells for stroke treatment with an emphasis on timing, transendothelial migration and possible mechanisms leading to neuroprotection, angiogenesis, immunomodulation, and neural plasticity. They also review current concepts of in vivo imaging and tracking of stem cells after stroke.

    View details for DOI 10.3171/FOC/2008/24/3-4/E14

    View details for Web of Science ID 000256374100015

    View details for PubMedID 18341391

  • Neural progenitor cells transplanted into the uninjured brain undergo targeted migration after stroke onset JOURNAL OF NEUROSCIENCE RESEARCH Guzman, R., Bliss, T., Angeles, A. D., Moseley, M., Palmer, T., Steinberg, G. 2008; 86 (4): 873-882

    Abstract

    Endogenous neural stem cells normally reside in their niche, the subventricular zone, in the uninjured rodent brain. Upon stroke, these cells become more proliferative and migrate away from the subventricular zone into the surrounding parenchyma. It is not known whether this stroke-induced behavior is due to changes in the niche or introduction of attractive cues in the infarct zone, or both. A related question is how transplanted neural stem cells respond to subsequent insults, including whether exogenous stem cells have the plasticity to respond to subsequent injuries after engraftment. We addressed this issue by transplanting neural progenitor cells (NPCs) into the uninjured brain and then subjecting the animal to stroke. We were able to follow the transplanted NPCs in vivo by labeling them with superparamagnetic iron oxide particles and imaging them via high-resolution magnetic resonance imaging (MRI) during engraftment and subsequent to stroke. We find that transplanted NPCs that are latent can be activated in response to stroke and exhibit directional migration into the parenchyma, similar to endogenous neural NPCs, without a niche environment.

    View details for DOI 10.1002/jnr.21542

    View details for Web of Science ID 000253961700013

    View details for PubMedID 17975825

  • Cell replacement therapy for intracerebral hemorrhage NEUROSURGICAL FOCUS Andres, R. H., Guzman, R., Ducray, A. D., Mordasini, P., Gera, A., Barth, A., Widmer, H. R., Steinberg, G. K. 2008; 24 (3-4)

    Abstract

    Intracerebral hemorrhage (ICH), for which no effective treatment strategy is currently available, constitutes one of the most devastating forms of stroke. As a result, developing therapeutic options for ICH is of great interest to the medical community. The 3 potential therapies that have the most promise are cell replacement therapy, enhancing endogenous repair mechanisms, and utilizing various neuroprotective drugs. Replacement of damaged cells and restoration of function can be accomplished by transplantation of cells derived from different sources, such as embryonic or somatic stem cells, umbilical cord blood, and genetically modified cell lines. Early experimental data showing the benefits of cell transplantation on functional recovery after ICH have been promising. Nevertheless, several studies have focused on another therapeutic avenue, investigating novel ways to activate and direct endogenous repair mechanisms in the central nervous system, through exposure to specific neuronal growth factors or by inactivating inhibitory molecules. Lastly, neuroprotective drugs may offer an additional tool for improving neuronal survival in the perihematomal area. However, a number of scientific issues must be addressed before these experimental techniques can be translated into clinical therapy. In this review, the authors outline the recent advances in the basic science of treatment strategies for ICH.

    View details for DOI 10.3171/FOC/2008/24/3-4/E15

    View details for Web of Science ID 000256374100016

    View details for PubMedID 18341392

  • Adherent Self-Renewable Human Embryonic Stem Cell-Derived Neural Stem Cell Line: Functional Engraftment in Experimental Stroke Model PLOS ONE Daadi, M. M., Maag, A., Steinberg, G. K. 2008; 3 (2)

    Abstract

    Human embryonic stem cells (hESCs) offer a virtually unlimited source of neural cells for structural repair in neurological disorders, such as stroke. Neural cells can be derived from hESCs either by direct enrichment, or by isolating specific growth factor-responsive and expandable populations of human neural stem cells (hNSCs). Studies have indicated that the direct enrichment method generates a heterogeneous population of cells that may contain residual undifferentiated stem cells that could lead to tumor formation in vivo.We isolated an expandable and homogenous population of hNSCs (named SD56) from hESCs using a defined media supplemented with epidermal growth factor (EGF), basic fibroblast growth factor (bFGF) and leukemia inhibitory growth factor (LIF). These hNSCs grew as an adherent monolayer culture. They were fully neuralized and uniformly expressed molecular features of NSCs, including nestin, vimentin and radial glial markers. These hNSCs did not express the pluripotency markers Oct4 or Nanog, nor did they express markers for the mesoderm or endoderm lineages. The self-renewal property of the hNSCs was characterized by a predominant symmetrical mode of cell division. The SD56 hNSCs differentiated into neurons, astrocytes and oligodendrocytes throughout multiple passages in vitro, as well as after transplantation. Together, these criteria confirm the definitive NSC identity of the SD56 cell line. Importantly, they exhibited no chromosome abnormalities and did not form tumors after implantation into rat ischemic brains and into naïve nude rat brains and flanks. Furthermore, hNSCs isolated under these conditions migrated toward the ischemia-injured adult brain parenchyma and improved the independent use of the stroke-impaired forelimb two months post-transplantation.The SD56 human neural stem cells derived under the reported conditions are stable, do not form tumors in vivo and enable functional recovery after stroke. These properties indicate that this hNSC line may offer a renewable, homogenous source of neural cells that will be valuable for basic and translational research.

    View details for DOI 10.1371/journal.pone.0001644

    View details for Web of Science ID 000260586400037

    View details for PubMedID 18286199

    View details for PubMedCentralID PMC2238795

  • Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning NEUROSCIENCE Ren, C., Gao, X., Steinberg, G. K., Zhao, H. 2008; 151 (4): 1099-1103

    Abstract

    Remote ischemic preconditioning is an emerging concept for stroke treatment, but its protection against focal stroke has not been established. We tested whether remote preconditioning, performed in the ipsilateral hind limb, protects against focal stroke and explored its protective parameters. Stroke was generated by a permanent occlusion of the left distal middle cerebral artery (MCA) combined with a 30 min occlusion of the bilateral common carotid arteries (CCA) in male rats. Limb preconditioning was generated by 5 or 15 min occlusion followed with the same period of reperfusion of the left hind femoral artery, and repeated for two or three cycles. Infarct was measured 2 days later. The results showed that rapid preconditioning with three cycles of 15 min performed immediately before stroke reduced infarct size from 47.7+/-7.6% of control ischemia to 9.8+/-8.6%; at two cycles of 15 min, infarct was reduced to 24.7+/-7.3%; at two cycles of 5 min, infarct was not reduced. Delayed preconditioning with three cycles of 15 min conducted 2 days before stroke also reduced infarct to 23.0+/-10.9%, but with two cycles of 15 min it offered no protection. The protective effects at these two therapeutic time windows of remote preconditioning are consistent with those of conventional preconditioning, in which the preconditioning ischemia is induced in the brain itself. Unexpectedly, intermediate preconditioning with three cycles of 15 min performed 12 h before stroke also reduced infarct to 24.7+/-4.7%, which contradicts the current dogma for therapeutic time windows for the conventional preconditioning that has no protection at this time point. In conclusion, remote preconditioning performed in one limb protected against ischemic damage after focal cerebral ischemia.

    View details for DOI 10.1016/j.neuroscience.2007.11.056

    View details for Web of Science ID 000253301500016

    View details for PubMedID 18201834

    View details for PubMedCentralID PMC2696348

  • Neurologic complications of arteriovenous malformation embolization using liquid embolic agents AMERICAN JOURNAL OF NEURORADIOLOGY Jayaraman, M. V., Marcellus, M. L., Hamilton, S., Do, H. M., Campbell, D., Chang, S. D., Steinberg, G. K., Marks, M. P. 2008; 29 (2): 242-246

    Abstract

    Embolization of arteriovenous malformations (AVMs) is commonly used to achieve nidal volume reduction before microsurgical resection or stereotactic radiosurgery. The purpose of this study was to examine the overall neurologic complication rate in patients undergoing AVM embolization and analyze the factors that may determine increased risk.We performed a retrospective review of all patients with brain AVMs embolized at 1 center from 1995 through 2005. Demographics, including age, sex, presenting symptoms, and clinical condition, were recorded. Angiographic factors including maximal nidal size, presence of deep venous drainage, and involvement of eloquent cortex were also recorded. For each embolization session, the agent used, number of pedicles embolized, the percentage of nidal obliteration, and any complications were recorded. Complications were classified as the following: none, non-neurologic (mild), transient neurologic deficit, and permanent nondisabling and permanent disabling deficits. The permanent complications were also classified as ischemic or hemorrhagic. Modified Rankin Scale (mRS) scores were collected pre- and postembolization on all patients. Univariate regression analysis of factors associated with the development of any neurologic complication was performed.Four hundred eighty-nine embolization procedures were performed in 192 patients. There were 6 Spetzler-Martin grade I (3.1%), 26 grade II (13.5%), 71 grade III (37.0%), 57 grade IV (29.7%), and 32 grade V (16.7%) AVMs. Permanent nondisabling complications occurred in 5 patients (2.6%) and permanent disabling complications or deaths occurred in 3 (1.6%). In addition, there were non-neurologic complications in 4 patients (2.1%) and transient neurologic deficits in 22 (11.5%). Five of the 8 permanent complications (2.6% overall) were ischemic, and 3 of 8 (1.6% overall) were hemorrhagic. Of the 178 patients who were mRS 0-2 pre-embolization, 4 (2.3%) were dependent or dead (mRS >2) at follow-up. Univariate analysis of risk factors for permanent neurologic deficits following embolization showed that basal ganglia location was weakly associated with a new postembolization neurologic deficit.Embolization of brain AVMs can be performed with a high degree of technical success and a low rate of permanent neurologic complications.

    View details for DOI 10.3174/ajnr.A0793

    View details for Web of Science ID 000253345200013

    View details for PubMedID 17974613

  • Revascularization surgery significantly reduces the incidence of TIA in pediatric patients with Moyamoya disease Guzman, R., Lee, M., Bell-Stephens, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 719
  • Timing of MGE cell transplantation after distal middle cerebral artery occlusion significantly influences the cell-host interaction Shichinohe, H., Daadi, M. M., Horie, N., Palmer, T. D., Bliss, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 534
  • Predictors of retreatment of ruptured intracranial aneurysms: The cerebral aneurysm rupture after treatment study Patil, C. G., Elijovich, L., Steinberg, G. K., Spetzler, R. F., McDougall, C. G., Zabramski, J. M., Gress, D. R., Lawton, M. T., Higashida, R. T., Duckwiler, G. R., Purdy, P. D., Piepgras, D. G., Giannotta, S. L., Johnston, S. LIPPINCOTT WILLIAMS & WILKINS. 2008: 536
  • Intracarotid delivery of CD49d FACS sorted neural stem cells enhances angiogenesis and improves functional outcome after experimental stroke Guzman, R., Angeles, A., Choo, K., Gaeta, X., Cote, J., Cheshier, S., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 540
  • Ischemia-induced angiogenesis is enhanced by hCNS-SCn transplantation Horie, N., Bliss, T., Shichinohe, H., Palmer, T., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2008: 658
  • Dispersion, engraftment and differentiation of a multipotent human embryonic stem cell-derived neural stem line (sd56) in stroked rats Daadi, M., Maag, A., Sun, G., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 661
  • Blockade of stress hormones during cerebral ischemia improves functional recovery and neurogenesis Hoehn, B., Palmer, T., Salposky, R. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 670
  • Moyamoya disease in children - Response NEUROSURGICAL FOCUS Guzman, R., Veeravagu, A., Steinberg, G. K. 2008; 24 (2)
  • An insult-inducible vector system activated by hypoxia inducible factor 1 (hif1) and reactive oxygen species 33rd International Stroke Conference Cheng, M., Jin, M., Lee, I., Zhao, H., Steinberg, G. K., Sapolsky, R. M. LIPPINCOTT WILLIAMS & WILKINS. 2008: 727?28
  • In vivo PET imaging of VEGF-R expression profile after experimental focal stroke. 33rd International Stroke Conference Guzman, R., Cai, W., Chen, K., Hsu, A. R., Bliss, T., Sun, G., Wang, H., He, L., Maag, A., Hori, N., Chen, X., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2008: 667?67
  • Analysis of intraoperative flow measurements in moyamoya patients during revascularization surgery 33rd International Stroke Conference Lee, M., Guzman, R., Bell-Stephens, T., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2008: 720?20
  • Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. 33rd International Stroke Conference Ren, C., Gao, X., Steinberg, G. K., Zhao, H. LIPPINCOTT WILLIAMS & WILKINS. 2008: 664?64
  • Progressive cerebral vascular degeneration with mitochondrial encephalopathy AMERICAN JOURNAL OF MEDICAL GENETICS PART A Longo, N., Schrijver, I., Vogel, H., Pique, L. M., Cowan, T. M., Pasquali, M., Steinberg, G. K., Hedlund, G. L., Ernst, S. L., Gallagher, R. C., Enns, G. M. 2008; 146A (3): 361-367

    Abstract

    MELAS (mitochondrial encephalopathy with lactic acidosis and stroke-like episodes) is a maternally inherited disorder characterized by recurrent cerebral infarctions that do not conform to discreet vascular territories. Here we report on a patient who presented at 7 years of age with loss of consciousness and severe metabolic acidosis following vomiting and dehydration. She developed progressive sensorineural hearing loss, myopathy, ptosis, short stature, and mild developmental delays after normal early development. Biochemical testing identified metabolites characteristic of medium-chain acyl-CoA dehydrogenase (MCAD) deficiency (hexanoylglycine and suberylglycine), but also severe lactic acidemia (10-25 mM) and, in urine, excess of lactic acid, intermediates of the citric cycle, and marked ketonuria, suggesting mitochondrial dysfunction. She progressed rapidly to develop temporary cortical blindness. Brain imaging indicated generalized atrophy, more marked on the left side, in addition to white matter alterations consistent with a mitochondrial disorder. Magnetic resonance angiography indicated occlusion of the left cerebral artery with development of collateral circulation (Moyamoya syndrome). This process worsened over time to involve the other side of the brain. A muscle biopsy indicated the presence of numerous ragged red fibers. Molecular testing confirmed compound heterozygosity for the common mutation in the MCAD gene (985A>G) and a second pathogenic mutation (233T>C). MtDNA testing indicated that the muscle was almost homoplasmic for the 3243A>T mutation in tRNALeu, with a lower mutant load (about 50% heteroplasmy) in blood and skin fibroblasts. These results indicate that mitochondrial disorders may be associated with severe vascular disease resulting in Moyamoya syndrome. The contribution of the concomitant MCAD deficiency to the development of the phenotype in this case is unclear.

    View details for DOI 10.1002/ajmg.a.31841

    View details for Web of Science ID 000253008300014

  • Moyamoya disease in pediatric patients: outcomes of neurosurgical interventions NEUROSURGICAL FOCUS Veeravagu, A., Guzman, R., Patil, C. G., Hou, L. C., Lee, M., Steinberg, G. K. 2008; 24 (2)

    Abstract

    Neurosurgical interventions for moyamoya disease (MMD) in pediatric patients include direct, indirect, and combined revascularization procedures. Each technique has shown efficacy in the treatment of pediatric MMD; however, no single study has demonstrated the superiority of one technique over another. In this review, the authors explore the various studies focused on the use of these techniques for MMD in the pediatric population. They summarize the results of each study to clearly depict the clinical outcomes achieved at each institution that had utilized direct, indirect, or combined techniques. In certain studies, multiple techniques were used, and the clinical or radiological outcomes were compared accordingly. Direct techniques have been shown to aid a reduction in perioperative strokes and provide immediate revascularization to ischemic areas; however, these procedures are technically challenging, and not all pediatric patients are appropriate candidates. Indirect techniques have also shown efficacy in the pediatric population but may require a longer period for revascularization to occur and perfusion deficits to be reversed. The authors concluded that the clinical efficacy of one technique over another is still unclear, as most studies have had small populations and the same outcome measures have not been applied. Authors who compared direct and indirect techniques noted approximately equal clinical outcomes with differences in radiological findings. Additional, larger studies are needed to determine the advantages and disadvantages of the different techniques for the pediatric age group.

    View details for DOI 10.3171/FOC/2008/24/2/E16

    View details for Web of Science ID 000256268400018

    View details for PubMedID 18275292

  • MCP-1 regulates targeted migration of transplanted neural precursor cells after stroke 15th Annual Meeting of the American-Society-for-Neural-Therapy-and-Repair Andres, R. H., Choi, R., Lee, S., Gera, A., Gaeta, X., Guzman, R., Steinberg, G. K. COGNIZANT COMMUNICATION CORP. 2008: 458?59
  • General versus specific actions of mild-moderate hypothermia in attenuating cerebral ischemic damage JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Zhao, H., Steinberg, G. K., Sapolsky, R. M. 2007; 27 (12): 1879-1894

    Abstract

    Mild or moderate hypothermia is generally thought to block all changes in signaling events that are detrimental to ischemic brain, including ATP depletion, glutamate release, Ca(2+) mobilization, anoxic depolarization, free radical generation, inflammation, blood-brain barrier permeability, necrotic, and apoptotic pathways. However, the effects and mechanisms of hypothermia are, in fact, variable. We emphasize that, even in the laboratory, hypothermic protection is limited. In certain models of permanent focal ischemia, hypothermia may not protect at all. In cases where hypothermia reduces infarct, some studies have overemphasized its ability to maintain cerebral blood flow and ATP levels, and to prevent anoxic depolarization, glutamate release during ischemia. Instead, hypothermia may protect against ischemia by regulating cascades that occur after reperfusion, including blood-brain barrier permeability and the changes in gene and protein expressions associated with necrotic and apoptotic pathways. Hypothermia not only blocks multiple damaging cascades after stroke, but also selectively upregulates some protective genes. However, most of these mechanisms are addressed in models with intraischemic hypothermia; much less information is available in models with postischemic hypothermia. Moreover, although it has been confirmed that mild hypothermia is clinically feasible for acute focal stroke treatment, no definite beneficial effect has been reported yet. This lack of clinical protection may result from suboptimal criteria for patient entrance into clinical trials. To facilitate clinical translation, future efforts in the laboratory should focus more on the protective mechanisms of postischemic hypothermia, as well as on the effects of sex, age and rewarming during reperfusion on hypothermic protection.

    View details for Web of Science ID 000250957800001

    View details for PubMedID 17684517

  • Viral caspase inhibitor p35, but not crmA, is neuroprotective in the ischemic penumbra following experimental stroke NEUROSCIENCE Sung, J. H., Zhao, H., Roy, M., Sapolsky, R. M., Steinberg, G. K. 2007; 149 (4): 804-812

    Abstract

    Apoptosis, a predominant cause of neuronal death after stroke, can be executed in a caspase-dependent or apoptosis inducing factor (AIF)-dependent manner. Herpes simplex virus (HSV) vectors expressing caspase inhibitors p35 and crmA have been shown to be neuroprotective against various excitotoxic insults. Here we further evaluated the possible neuroprotective role of p35 and crmA in a rat stroke model. Overexpression of p35, but not crmA, significantly increased neuronal survival. Results of double immunofluorescence staining indicate that compared with neurons infected with crmA or control vectors, p35-infected neurons had less active caspase-3 expression, cytosolic cytochrome c and nuclear AIF translocation.

    View details for DOI 10.1016/j.neuroscience.2007.07.030

    View details for Web of Science ID 000251501700008

    View details for PubMedID 17945431

    View details for PubMedCentralID PMC2144739

  • Conditions of protection by hypothermia and effects on apoptotic pathways in a rat model of permanent middle cerebral artery occlusion JOURNAL OF NEUROSURGERY Zhao, H., Wang, J. Q., Shimohata, T., Sun, G., Yenari, M. A., Sapolsky, R. M., Steinberg, G. K. 2007; 107 (3): 636-641

    Abstract

    Hypothermia is protective in stroke models, but findings from permanent occlusion models are conflicting. In this article the authors induced focal ischemia in rats by permanent distal middle cerebral artery (MCA) occlusion plus transient occlusion of the common carotid arteries (CCAs). This models a scenario in which the MCA remains occluded but partial reperfusion occurs through collateral vessels. The authors also determined whether hypothermia mediates ischemic damage by blocking apoptotic pathways.The left MCA was occluded permanently and the CCAs were reopened after 2 hours, leading to partial reperfusion in rats maintained at 37 degrees C, 33 degrees C (mild hypothermia), or 30 degrees C (moderate hypothermia) for 2 hours during and/or after CCA occlusion (that is, for a total of 2 or 4 hours of hypothermia or normothermia). Infarct size was measured 2 days after the stroke. Immunofluorescence staining and Western blot analysis were used to detect cytochrome c and apoptosis inducing factor (AIF) translocation.Four hours of prolonged mild hypothermia (33 degrees C) reduced the infarct size 22% in the model of permanent MCA occlusion, whereas 2 hours of such mild hypothermia maintained either during CCA occlusion or after CCA release did not attenuate ischemic damage. However, moderate hypothermia (30 degrees C) during CCA occlusion was significantly more protective than 4 hours of 33 degrees C (46% decrease in infarct size). Four hours of mild or moderate hypothermia reduced cytosolic cytochrome c release and both nuclear and cytosolic AIF translocation in the penumbra 2 days after stroke.These findings suggest that hypothermic neuroprotection might be achieved by blocking AIF and cytochrome c-mediated apoptosis.

    View details for Web of Science ID 000249220100022

    View details for PubMedID 17886565

  • Suppression of delta PKC activation after focal cerebral ischemia contributes to the protective effect of hypothermia JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Shimohata, T., Zhao, H., Sung, J. H., Sun, G., Mochly-Rosen, D., Steinberg, G. K. 2007; 27 (8): 1463-1475

    Abstract

    Mild hypothermia is a robust neuroprotective treatment for stroke. Understanding the mechanisms underlying hypothermia's benefits will lead to more effective treatments to prevent stroke damage. Delta protein kinase C (deltaPKC) is a kinase that has been strongly implicated in executing ischemic damage. We investigated the effects of hypothermia on deltaPKC activation, as determined by its subcellular translocation, proteolytic cleavage, and phosphorylation in a focal cerebral ischemia model. The amount of constitutively activated C-terminal catalytic fragment of deltaPKC (CF-deltaPKC) increased after stroke. Both hypothermia (30 degrees C) and the caspase-3-specific inhibitor, Z-DQMD-FMK, blocked the accumulation of activated deltaPKC in the penumbra. Other hallmarks of deltaPKC activation, its translocation to the mitochondria, and nucleus were observed in the penumbra as early as 10 mins after reperfusion. These events were blocked by hypothermia. Hypothermia also blocked CF-deltaPKC increases in the mitochondria and nuclei. Conversely, a specific deltaPKC activator, psideltaRACK, decreased the neuroprotective effect of hypothermia. Finally, deltaPKC activity may lead to mitochondrial injury and cytochrome c release, as the timing of cytochrome c release corresponded to the time course of deltaPKC translocation. Both cytochrome c release and deltaPKC translocation were blocked by hypothermia. In conclusion, hypothermia protects against ischemic damage in part by suppressing deltaPKC activation after stroke.

    View details for DOI 10.1038/sj.jcbfm.9600450

    View details for PubMedID 17293847

  • delta PKC mediates microcerebrovascular dysfunction in acute ischemia and in chronic hypertensive stress in vivo BRAIN RESEARCH Bright, R., Steinberg, G. K., Mochly-Rosen, D. 2007; 1144: 146-155

    Abstract

    Maintaining cerebrovascular function is a priority for reducing damage following acute ischemic events such as stroke, and under chronic stress in diseases such as hypertension. Ischemic episodes lead to endothelial cell damage, deleterious inflammatory responses, and altered neuronal and astrocyte regulation of vascular function. These, in turn, can lead to impaired cerebral blood flow and compromised blood-brain barrier function, promoting microvascular collapse, edema, hemorrhagic transformation, and worsened neurological recovery. Multiple studies demonstrate that protein kinase C (PKC), a widely expressed serine/threonine kinase, is involved in mediating arterial tone and microvascular function. However, there is no clear understanding about the role of individual PKC isozymes. We show that intraperitoneal injection of deltaV1-1-TAT(47-57) (0.2 mg/kg in 1 mL), an isozyme-specific peptide inhibitor of deltaPKC, improved microvascular pathology, increased the number of patent microvessels by 92% compared to control-treated animals, and increased cerebral blood flow by 26% following acute focal ischemia induced by middle cerebral artery occlusion in normotensive rats. In addition, acute delivery of deltaV1-1-TAT(47-57) in hypertensive Dahl rats increased cerebral blood flow by 12%, and sustained delivery deltaV1-1-TAT(47-57) (5 uL/h, 1 mM), reduced infarct size by 25% following an acute stroke induced by MCA occlusion for 90 min. Together, these findings demonstrate that deltaPKC is an important therapeutic target for protection of microvascular structure and function under both acute and chronic conditions of cerebrovascular stress.

    View details for DOI 10.1016/j.brainres.2007.01.113

    View details for PubMedID 17350602

  • Surgical and endovascular management of symptomatic posterior circulation fusiform aneurysms JOURNAL OF NEUROSURGERY Coert, B. A., Chang, S. D., Do, H. M., Marks, M. P., Steinberg, G. K. 2007; 106 (5): 855-865

    Abstract

    Patients with fusiform aneurysms can present with subarachnoid hemorrhage (SAH), mass effect, ischemia, or unrelated symptoms. The absence of an aneurysm neck impedes the direct application of a clip and endovascular coil deployment. To evaluate the effects of their treatments, the authors retrospectively analyzed a consecutive series of patients with posterior circulation fusiform aneurysms treated at Stanford University Medical Center between 1991 and 2005.Forty-nine patients (mean age 53 years, male/female ratio 1.2:1) treated at the authors' medical center form the basis of the analysis. Twenty-nine patients presented with an SAH. The patients presenting without SAH had cranial nerve dysfunction (five patients), symptoms of mass effect (eight patients), ischemia (six patients), or unrelated symptoms (one patient). The aneurysms were located on the vertebral artery (VA) or posterior inferior cerebellar artery (PICA) (21 patients); vertebrobasilar junction (VBJ) or basilar artery (BA) (18 patients); and posterior cerebral artery (PCA) (10 patients). Pretreatment clinical grades were determined using the Hunt and Hess scale; for patients with unruptured aneurysms (Hunt and Hess Grade 0) functional subgrades were added. Outcome was evaluated using the Glasgow Outcome Scale (GOS) score during a mean follow-up period of 33 months. Overall long-term outcome was good (GOS Score 4 or 5) in 59%, poor (GOS Score 2 or 3) in 16%, and fatal (GOS Score 1) in 24% of the patients. In a univariate analysis, poor outcome was predicted by age greater than 55 years, VBJ location, pretreatment Hunt and Hess grade in patients presenting with SAH, and incomplete aneurysm thrombosis after endovascular treatment. In a multivariate analysis, age greater than 55 years was the confounding factor predicting poor outcome. Stratification by aneurysm location removed the effect of age. Of 13 patients with residual aneurysm after treatment, five (38%) subsequently died of SAH (three patients) or progressive mass effect/brainstem ischemia (two patients).Certain posterior circulation aneurysm locations (PCA, VA-PICA, and BA-VBJ) represent separate disease entities affecting patients at different ages with distinct patterns of presentation, treatment options, and outcomes. Favorable overall long-term outcome can be achieved in 90% of patients with PCA aneurysms, in 60% of those with VA-PICA aneurysms, and in 39% of those with BA-VBJ aneurysms when using endovascular and surgical techniques. The natural history of the disease was poor in patients with incomplete aneurysm thrombosis after treatment.

    View details for PubMedID 17542530

  • Morphologic assessment of middle cerebral artery aneurysms for endovascular treatment. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Jayaraman, M. V., Do, H. M., Versnick, E. J., Steinberg, G. K., Marks, M. P. 2007; 16 (2): 52-56

    Abstract

    Aneurysms of the middle cerebral artery (MCA) trifurcation region are underrepresented in large series of endovascularly treated aneurysms. The purpose of our study was to evaluate the incidence of specific morphologic features of MCA bifurcation aneurysms that may affect suitability for endovascular treatment.We evaluated 53 consecutive patients with 58 bifurcation or trifurcation MCA aneurysms seen for angiographic evaluation during a 4-year period at our institution. All angiograms were reviewed for: aneurysm size (largest dimension, dome and neck size), branch vessels originating from the aneurysm sac, straightening of the aneurysm wall to suggest intramural thrombus, calcification in the region of the aneurysm, stenosis of the parent vessel, and presence of daughter sacs.Of 58 aneurysms, 51 (88%) had a dome to neck ratio less than 2:1. Branch vessel incorporation in the aneurysm sac was seen in 23/58 (40%), straightening suggestive of thrombus in 14/58 (24%), calcification in 2/58 (3%), parent vessel stenosis in 1/58 (2%), and daughter sacs in 4/58 (7%).The majority of MCA aneurysms have morphologic features such as a dome to neck ratio less than 2:1 or branch vessel incorporation that may make them unsuitable for endovascular treatment using conventional intra-aneurysmal coiling.

    View details for PubMedID 17689394

  • Cell transplantation therapy for stroke 25th Princeton Conference on Cerebrovascular Disease Bliss, T., Guzman, R., Daadi, M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: 817?26

    Abstract

    No treatment currently exists to restore lost neurological function after stroke. A growing number of studies highlight the potential of stem cell transplantation as a novel therapeutic approach for stroke. In this review we summarize these studies, discuss potential mechanisms of action of the transplanted cells, and emphasize the need to determine parameters that are critical for transplantation success.

    View details for DOI 10.1161/01.STR.0000247888.25985.62

    View details for Web of Science ID 000244122600838

    View details for PubMedID 17261746

  • Non-tumorigenic properties of human embryonic stem cell-derived multipotent neural stem cells in experimental stroke models Daadi, M. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: 468
  • Endogenous thrombospondins 1 and 2 are necessary for synaptic plasticity and spontaneous functional recovery after stroke 32nd International Stroke Conference Liauw, J., Hoang, S., Choi, M., Choi, M., Shen, J., Choo, K., Wildman-Tobriner, B., Percy, M., Guzman, R., Bliss, T., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2007: 466?66
  • Examination of the protective effect of delta PKC inhibitor delta V1-1 on MEK/ERK-mediated pathway in focal ischemia in rats 32nd International Stroke Conference Castaneda, D., Zhao, H., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2007: 558?58
  • Overexpression of a chimeric steroid receptor protects striatal neurons from cerebral ischemia 32nd International Stroke Conference Cheng, M. Y., Sun, G., Zhao, H., Steinberg, G. K., Sapolsky, R. M. LIPPINCOTT WILLIAMS & WILKINS. 2007: 547?47
  • Hemorrhage rate in patients with Spetzler-Martin grades IV and V arteriovenous malformations - Is treatment justified? STROKE Jayaraman, M. V., Marcellus, M. L., Do, H. M., Chang, S. D., Rosenberg, J. K., Steinberg, G. K., Marks, M. P. 2007; 38 (2): 325-329

    Abstract

    We sought to examine the prospective annual risk of hemorrhage in patients harboring Spetzler-Martin grades IV and V arteriovenous malformations (AVMs) before and after initiation of treatment.Medical records of 61 consecutive patients presenting with Spetzler-Martin grades IV and V AVMs were retrospectively reviewed for demographics, angiographic features, presenting symptom(s), and time of all hemorrhage events, before or after treatment initiation. Pretreatment hemorrhage rates (excluding hemorrhages at presentation) and posttreatment rates were subsequently calculated. Modified Rankin Scale (mRS) scores before and after treatment were recorded.The annual pretreatment hemorrhage rate for all patients was 10.4% per year (95% CI, 2.2 to 15.4%), 13.9% (95% CI, 3.5 to 22.1%) in patients with hemorrhagic presentation and 7.3% (2.6 to 14.3%) in patients with nonhemorrhagic presentation. Posttreatment hemorrhage rates were 6.1% per year (95% CI, 2.5 to 13.2%) for all patients, 5.6% (95% CI, 2.1 to 11.8%) for patients presenting with hemorrhage and 6.4% (95% CI, 1.6 to 10.1%) in patients with nonhemorrhagic presentation. A noninferiority test showed that the posttreatment hemorrhage rate was less than or equal to the pretreatment hemorrhage rate (P<0.0001), with some indication that the reduction was greatest in patients with hemorrhagic presentation. Of the 62 patients, 51 (82%) had an mRS score of 0 to 2 before treatment, and 47 (76%) had an mRS score of 0 to 2 at the last follow-up after treatment.The annual rate of hemorrhage in grades IV and V AVMs is higher in this series than reported for all AVMs, which may reflect some referral bias in this single-center study. Nevertheless, initiation of treatment does not appear to increase the rate of subsequent hemorrhage. Treatment for these lesions may be warranted, given their poor natural history.

    View details for DOI 10.1161/01.STR.0000254497.24545.de

    View details for PubMedID 17194881

  • epsilon PKC may contribute to the protective effect of hypothermia in a rat focal cerebral ischemia model STROKE Shimohata, T., Zhao, H., Steinberg, G. K. 2007; 38 (2): 375-380

    Abstract

    Protein kinase C epsilon (epsilonPKC) has been implicated as a neuroprotectant in vitro. We studied epsilonPKC activation (by its localization and proteolysis) in a rodent stroke model and correlated the effects of hypothermia with epsilonPKC activity after cerebral ischemia.Rats were subjected to permanent distal middle cerebral artery occlusion plus 1 hour of bilateral common carotid artery occlusion. Body temperatures were maintained at 37 degrees C or 30 degrees C during common carotid artery occlusion. Brains were harvested at 10 minutes, 4 hours, and 24 hours after common carotid artery release, and the cortex corresponding to the ischemic core and penumbra was dissected. epsilonPKC localization after stroke was assessed by Western blot and immunofluorescence microscopy. A caspase-3 inhibitor was used to test whether epsilonPKC cleavage is caspase dependent.epsilonPKC in the membrane fraction and whole-protein homogenates decreased moderately in the penumbra but decreased markedly in the ischemic core. Hypothermia blocked this decrease in both the ischemic core and penumbra. Confocal microscopy confirmed that neuronal epsilonPKC expression decreased in the ischemic core at 4 hours after reperfusion, and this loss was prevented by hypothermia. Two carboxyl-terminal cleavage products of epsilonPKC with molecular masses of 43 and 35 kDa were detected. Although the protein band of 43 kDa decreased after stroke, the 35-kDa band increased. Such changes were not dependent on caspase-3. However, hypothermia blocked changes in the cleavage form of 35 kDa but not 43 kDa after stroke.Moderate hypothermia preserves epsilonPKC activity after stroke.

    View details for DOI 10.1161/01.STR.0000254616.78387.ee

    View details for Web of Science ID 000244122600044

    View details for PubMedID 17204679

  • Gene therapy using SOD1 protects striatal neurons from experimental stroke NEUROSCIENCE LETTERS Davis, A. S., Zhao, H., Sun, G. H., Sapolsky, R. M., Steinberg, G. K. 2007; 411 (1): 32-36

    Abstract

    Reactive oxygen species contribute to neuronal death following cerebral ischemia. Prior studies using transgenic animals have demonstrated the neuroprotective effect of the antioxidant, copper/zinc superoxide dismutase (SOD1). In this study, we investigated whether SOD1 overexpression using gene therapy techniques in non-transgenic animals would increase neuronal survival. A neurotropic, herpes simplex virus-1 (HSV-1) vector containing the SOD1 gene was injected into the striatum either before or after transient focal cerebral ischemia. Striatal neuron survival at 2 days was improved by 52% when vector was delivered 12-15 h prior to ischemia and by 53% when vector delivery was delayed 2 h following ischemia. These data add to the growing literature, which suggests that an antioxidant approach, perhaps by employing gene therapy techniques, may be beneficial in the treatment of stroke.

    View details for DOI 10.1016/j.neulet.2006.08.089

    View details for Web of Science ID 000243153100007

    View details for PubMedID 17110031

    View details for PubMedCentralID PMC1716259

  • Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke MOLECULAR NEUROBIOLOGY Zhao, H., Sapolsky, R. M., Steinberg, G. K. 2006; 34 (3): 249-269

    Abstract

    In recent years, the phosphoinositide-3-kinase/Akt cell survival signaling pathway has been increasingly researched in the field of stroke. Akt activity is suggested to be upregulated by phosphorylation through the activation of receptor tyrosine kinases by growth factors. Although the upstream signaling components phosphoinositide-dependent protein kinase (PDK)1 and integrinlinked kinase enhance the activity of Akt, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) decreases it. Upon activation, Akt phosphorylates an array of molecules, including glycogen synthase kinase3beta (GSK3beta), forkhead homolog in rhabdomyosarcoma (FKHR), and Bcl-2-associated death protein, thereby blocking mitochondrial cytochrome c release and caspase activity. Generally, the level of Akt phosphorylation at site Ser 473 (P-Akt) transiently increases after focal ischemia, whereas the levels of phosphorylation of PTEN, PDK1, forkhead transcription factor, and GSK3beta decrease. Numerous compounds (such as growth factors, estrogen, free radical scavengers, and other neuroprotectants) reduce ischemic damage, possibly by upregulating P-Akt. However, preconditioning and hypothermia block ischemic damage by inhibiting an increase of P-Akt. Inhibition of the Akt pathway blocks the protective effect of preconditioning and hypothermia, suggesting the Akt pathway contributes to their protective effects and that the P-Akt level does not represent its true kinase activity. Together, attenuation of the Akt pathway dysfunction contributes to neuronal survival after stroke.

    View details for Web of Science ID 000250119900008

    View details for PubMedID 17308356

  • Hypothermia blocks ischemic changes in ubiquitin distribution and levels following stroke NEUROREPORT Liu, J., Zhao, H., Sung, J., Sun, G., Steinberg, G. K. 2006; 17 (16): 1691-1695

    Abstract

    Dysfunction of the ubiquitin-proteasome system has recently been linked to stroke. Ischemia may cause increased protein misfolding and inhibit the proteasome, shifting the balance from free ubiquitin to conjugated ubiquitin. In this study, we examine the effect of hypothermia on the distribution of total and free ubiquitin, as well as the levels of conjugated ubiquitin after experimental stroke using a focal cerebral ischemia model. We show that hypothermia prevents redistribution of ubiquitin following ischemia, largely through preservation of intracellular cytoplasmic free ubiquitin. We also show that hypothermia blocks the increase in conjugated ubiquitin observed after stroke. Our data indicate that hypothermia's neuroprotection is mediated, in part, through preservation of ubiquitin-proteasome system function.

    View details for Web of Science ID 000241961900007

    View details for PubMedID 17047455

  • Interrupting reperfusion as a stroke therapy: ischemic postconditioning reduces infarct size after focal ischemia in rats JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Zhao, H., Sapolsky, R. M., Steinberg, G. K. 2006; 26 (9): 1114-1121

    Abstract

    Cerebral ischemic preconditioning protects against stroke, but is clinically feasible only when the occurrence of stroke is predictable. Reperfusion plays a critical role in cerebral injury after stroke; we tested the hypothesis that interrupting reperfusion lessens ischemic injury. We found for the first time that such postconditioning with a series of mechanical interruptions of reperfusion significantly reduces ischemic damage. Focal ischemia was generated by permanent distal middle cerebral artery (MCA) occlusion plus transient bilateral common carotid artery (CCA) occlusion. After 30 secs of CCA reperfusion, ischemic postconditioning was performed by occluding CCAs for 10 secs, and then allowing for another two cycles of 30 secs of reperfusion and 10 secs of CCA occlusion. Infarct size was measured 2 days later. Cerebral blood flow (CBF) was measured in animals subjected to permanent MCA occlusion plus 15 mins of bilateral CCA occlusion, which demonstrates that postconditioning disturbed the early hyperemia immediately after reperfusion. Postconditioning dose dependently reduced infarct size in animals subjected to permanent MCA occlusion combined with 15, 30, and 60 mins of bilateral CCA occlusion, by reducing infarct size approximately 80%, 51%, and 17%, respectively. In addition, postconditioning blocked terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling-positive staining, a marker of apoptosis, in the penumbra 2 days after stroke. Furthermore, in situ superoxide detection using hydroethidine suggested that postconditioning attenuated superoxide products during early reperfusion after stroke. In conclusion, postconditioning reduced infarct size, most plausibly by blocking apoptosis and free radical generation. With further study it may eventually be clinically applicable for stroke treatment.

    View details for DOI 10.1038/sj.jcbfm.9600348

    View details for Web of Science ID 000240015300002

    View details for PubMedID 16736038

  • Carotid and vertebral rete mirabile in man presenting with intraparenchymal hemorrhage: a case report. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Li, G., Jayaraman, M. V., Lad, S. P., Adler, J., Do, H., Steinberg, G. K. 2006; 15 (5): 228-231

    Abstract

    Carotid and vertebral rete mirabile is an unusual segmental regression of both the cavernous carotid artery and transdural vertebral arteries with a network of collateral vessels seen rarely in human beings. We present a 57-year-old woman with carotid and vertebral rete mirabile who presented with an acute intraparenchymal hemorrhage. The majority of patients present with subarachnoid hemorrhage or ischemic stroke. This is the first case of a non-Asian patient presenting with an intraparenchymal hemorrhage. In this case report, we describe the clinical and angiographic features of this unusual entity.

    View details for PubMedID 17904080

  • Outcomes of surgery for resection of regions of symptomatic radiation injury after stereotactic radiosurgery for arteriovenous malformations NEUROSURGERY Massengale, J. L., Levy, R. P., Marcellus, M., Moes, G., Marks, M. P., Steinberg, G. K. 2006; 59 (3): 553-559

    Abstract

    Although radiation injury after stereotactic radiosurgery (SRS), including radiation necrosis (RN), is often treated with surgical resection, detailed outcome data are lacking after resection of symptomatic radiation-injured regions with imaging characteristics suspicious for RN after SRS for arteriovenous malformations (AVM). We present outcomes in seven such patients.We conducted a retrospective chart review of seven patients with AVMs of Spetzler-Martin Grades II (n = 1), III (n = 2), and IV (n = 4) who underwent helium ion, proton beam, or gamma knife SRS and required resection of RN-suspicious tissue 1 to 24 months after post-SRS symptom onset. Postoperative outcomes included Karnofsky Performance Scale (KPS) score and time to symptomatic improvement.Symptomatic improvement required at least 9 months in the three patients with large regions suspicious for RN (>or=4 cm), whereas of four patients with smaller regions (<4 cm), three showed improvement within 2 months (P < 0.05). The remaining patient, who showed no benefit, underwent resection 2 years after the onset of RN symptoms (compared with

    View details for DOI 10.1227/01.NEU.0000227476.95859.F1

    View details for PubMedID 16955037

  • New vessel formation in the central nervous system during tumor growth, vascular malformations, and Moyamoya CURRENT NEUROVASCULAR RESEARCH Lim, M., Cheshier, S., Steinberg, G. K. 2006; 3 (3): 237-245

    Abstract

    In the normal adult brain, blood vessel formation is tightly down-regulated. However, pathologic processes such as brain tumors can increase the proportion of endothelial cells involved in angiogenesis. When this process is initiated, a complex series of timed events result in new vessel formation. In this review, we will describe the process of angiogenesis in the central nervous system. We will discuss the roles of Vascular Endothelial Growth Factor (VEGF), Fibroblast Growth Factor (FGF), Angiopoietins, Platelet Derived Growth Factor (PDGF), and integrins in angiogenesis. We will also look into their significance in disease processes such as neoplasms, arteriovenous malformations (AVM), and Moyamoya disease.

    View details for Web of Science ID 000240424200008

    View details for PubMedID 16918387

  • Rates of delayed rebleeding from intracranial aneurysms are low after surgical and endovascular treatment STROKE Johnston, S. C., Dowd, C. F., Lawton, M. T., Gress, D. R., Higashida, R. T., Halbach, V. V., Zhao, S., Katsura, K. H., Fong, K. J., Douglas, V. C., Ventura, R., Elkins, J. S., Nguyen-Huynh, M. N., McDougall, C. G., Spetzler, R. F., Zabramski, J. M., Jahnke, H. K., Piepgras, D. G., Nichols, D. A., Gravenhof, D. R., Herzig, D., Mawad, M. E., Meyer, D., Steinberg, G. K., Marks, M. P., Luu, D., Yi, H., Duckwiler, G. R., Martin, N. A., Adapon, H., Giannotta, S. L., Larsen, D. W., Teitelbaum, G. P., Fishback, D., Thomson, E., Samson, D. S., Purdy, P. D., Replogle, R. E., Thomas, J. 2006; 37 (6): 1437-1442

    Abstract

    Although results of the randomized International Subarachnoid Aneurysm Trial suggested that coil embolization was superior to surgical clipping 1 year after treatment, a paucity of data on long-term outcomes has been a major concern.In an ambidirectional cohort study, 9 institutions with expertise in intracranial aneurysm treatment identified all ruptured saccular aneurysms treated 1996 to 1998. After an initial medical record review, all patients meeting entry criteria were contacted by postal questionnaire or telephone. Possible reruptures were adjudicated independently by a neurologist, a neurosurgeon, and a neurointerventional radiologist. Rates of delayed (>1 year) and early rerupture and retreatment were evaluated using Kaplan-Meier survival analysis and the log-rank test.A total of 1010 patients (711 surgically clipped, 299 treated with coil embolization) were included. Patients treated with coil embolization were older, more likely to have smaller aneurysms arising from the posterior circulation, and less likely to have middle cerebral artery aneurysms. Rerupture of the index aneurysm after 1 year occurred in 1 patient treated with coil embolization during 904 person-years of follow-up (annual rate 0.11%) and in no patients treated with surgical clipping during 2666 person-years (P=0.11). Aneurysm retreatment after 1 year was more frequent in patients treated with coil embolization (P<0.0001), but major complications were rare during retreatment.Rerupture of aneurysms treated by either coil embolization or surgical clipping is rare after the first year. Late retreatment is more common after coil embolization than after clipping but complication rates are low. Thus, late events are unlikely to overwhelm differences between procedures at 1-year follow-up.

    View details for DOI 10.1161/01.STR.0000221331.01830.ce

    View details for Web of Science ID 000237925000029

    View details for PubMedID 16627789

  • Transplantation of hNT neurons into the ischemic cortex: Cell survival and effect on sensorimotor behavior JOURNAL OF NEUROSCIENCE RESEARCH Bliss, T. M., Kelly, S., Shah, A. K., Foo, W. C., Kohli, P., Stokes, C., Sun, G. H., Ma, M., Masel, J., Kleppner, S. R., Schallert, T., Palmer, T., Steinberg, G. K. 2006; 83 (6): 1004-1014

    Abstract

    Cell transplantation offers a potential new treatment for stroke. Animal studies using models that produce ischemic damage in both the striatum and the frontal cortex have shown beneficial effects when hNT cells (postmitotic immature neurons) were transplanted into the ischemic striatum. In this study, we investigated the effect of hNT cells in a model of stroke in which the striatum remains intact and damage is restricted to the cortex. hNT cells were transplanted into the ischemic cortex 1 week after stroke induced by distal middle cerebral artery occlusion (dMCAo). The cells exhibited robust survival at 4 weeks posttransplant even at the lesion border. hNT cells did not migrate, but they did extend long neurites into the surrounding parenchyma mainly through the white matter. Neurite extension was predominantly toward the lesion in ischemic animals but was bidirectional in uninjured animals. Extension of neurites through the cortex toward the lesion was also seen when there was some surviving cortical tissue between the graft and the infarct. Prolonged deficits were obtained in four tests of sensory-motor function. hNT-transplanted animals showed a significant improvement in functional recovery on one motor test, but there was no effect on the other three tests relative to control animals. Thus, despite clear evidence of graft survival and neurite extension, the functional benefit of hNT cells after ischemia is not guaranteed. Functional benefit could depend on other variables, such as infarct location, whether the cells mature, the behavioral tests employed, rehabilitation training, or as yet unidentified factors.

    View details for DOI 10.1002/jnr.20800

    View details for Web of Science ID 000237217100008

    View details for PubMedID 16496370

  • Surgical management of posterior fossa arteriovenous malformations. Neurosurgery Sinclair, J., Kelly, M. E., Steinberg, G. K. 2006; 58 (4): ONS-189 201

    Abstract

    Arteriovenous malformations (AVMs) involving the cerebellum and brainstem are relatively rare lesions that most often present clinically as a result of a hemorrhagic episode. Although these AVMs were once thought to have a more aggressive clinical course in comparison with supratentorial AVMs, recent autopsy data suggests that there may be little difference in hemorrhage rates between the two locations. Although current management of these lesions often involves preoperative embolization and stereotactic radiosurgery, surgical resection remains the treatment of choice, conferring immediate protection to the patient from the risk of future hemorrhage.Most symptomatic AVMs that involve the cerebellum and the pial or ependymal surfaces of the brainstem are candidates for surgical resection. Preoperative angiography and magnetic resonance imaging studies are critical to determine suitability for resection and choice of operative exposure. In addition to considering the location of the nidus, arterial supply, and predominant venous drainage, the surgical approach must also be selected with consideration of the small confines of the posterior fossa and eloquence of the brainstem, cranial nerves, and deep cerebellar nuclei.Since the 1980s, progressive advances in preoperative embolization, frameless stereotaxy, and intraoperative electrophysiologic monitoring have significantly improved the number of posterior fossa AVMs amenable to microsurgical resection with minimal morbidity and mortality.Future improvements in endovascular technology and stereotactic radiosurgery will likely continue to increase the number of posterior fossa AVMs that can safely be removed and further improve the clinical outcomes associated with microsurgical resection.

    View details for PubMedID 16582640

  • Transplantation of the medial ganglionic eminence-derived neuronal precursors into ischemic stroke-lesioned rats improves motor behavioral deficits Daadi, M. M., Bliss, T. M., Lee, S. H., Palmer, T. D., Steinberg, G. K. ACADEMIC PRESS INC ELSEVIER SCIENCE. 2006: 565
  • Surgical management of posterior fossa arteriovenous malformations NEUROSURGERY Sinclair, J., Kelly, M. E., Steinberg, G. K. 2006; 58 (4): 189-201
  • Elevated serum levels of VEGF, bFGF, MMP-2, and MMP-9 in patients with Moyamoya disease 31st International Stroke Conference Lim, M., Wang, Y., Bower, R., Cheshier, S., Sims, L., Choi, S., Harsh, G., Steinberg, G., Guccione, S. LIPPINCOTT WILLIAMS & WILKINS. 2006: 701?
  • Hypothermia protects against cerebral ischemia by suppressing delta Pkc activation in rats 31st International Stroke Conference Shimohata, T., Zhao, H., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: 677?77

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