Gary K. Steinberg, MD, PhD

All Publications

• Genome-Wide DNA Methylation Profiling Reveals Low Methylation Variability in Moyamoya Disease. Translational stroke research Tokairin, K., Ito, M., Lee, A. G., Teo, M., He, S., Cheng, M. Y., Steinberg, G. K. 2024

  Abstract

  Moyamoya disease (MMD) is a chronic cerebrovascular disorder that can lead to stroke and neurological dysfunctions. Given the largely sporadic nature and the role of gene-environment interactions in various diseases, we examined epigenetic modifications in MMD. We performed genome-wide DNA methylation using Illumina 850K Methylation EPIC BeadChip, in two racially distinct adult female cohorts: a non-Asian cohort (13 MMD patients and 7 healthy controls) and an Asian cohort (14 MMD patients and 3 healthy controls). An additional external cohort with both sexes (females: 5 MMD patients and 5 healthy controls, males: 5 MMD patients and 5 healthy controls) was included for validation. Our findings revealed strikingly low DNA methylation variability between MMD patients and healthy controls, in both MMD female cohorts. In the non-Asian cohort, only 6 probes showed increased variability versus 647 probes that showed decreased variability. Similarly, in the Asian cohort, the MMD group also displayed a reduced methylation variability across all 2845 probes. Subsequent analysis showed that these differentially variable probes are located on genes involved in key biological processes such as methylation and transcription, DNA repair, cytoskeletal remodeling, natural killer cell signaling, cellular growth, and migration. These findings mark the first observation of low methylation variability in any disease, contrasting with the high variability observed in other disorders. This reduced methylation variability in MMD may hinder patients' adaptability to environmental shifts, such as hemodynamic stress, thereby influencing vascular homeostasis and contributing to MMD pathology. These findings offer new insights into the mechanisms of MMD and potential treatment strategies.

  View details for DOI 10.1007/s12975-024-01299-w

  View details for PubMedID 39356405

• Prevalence of Systemic Hypertension and the Effects of Cerebral Revascularization in Patients With Moyamoya Disease STROKE-VASCULAR AND INTERVENTIONAL NEUROLOGY Lee, H., Ahmed, U., Bell-Stephens, T., Steinberg, G. K. 2024; 4 (3)

  View details for DOI 10.1161/SVIN.123.001176

  View details for Web of Science ID 001215306400022

• Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease. Stroke Tigchelaar, S. S., Wang, A. R., Vaca, S. D., Li, Y., Steinberg, G. K. 2024

  Abstract

  Moyamoya disease (MMD) is a progressive, occlusive disease of the internal carotid arteries and their proximal branches, with the subsequent development of an abnormal vascular network that is rupture-prone. Steno-occlusive changes in the posterior cerebral arteries (PCAs) may contribute to worsened outcomes in patients with MMD; however, there is little information on the incidence and natural history of posterior circulation MMD (PCMMD). We describe clinical PCMMD characteristics in a large cohort of patients with MMD.We retrospectively reviewed patients with MMD treated between 1991 and 2019 at a large academic medical center. Demographics, perioperative outcomes, and radiological phenotypes were recorded for 770 patients. PCA disease was graded as either 0 (no disease), 1 (mild), 2 (moderate), or 3 (severe or occluded) based on cerebral angiography. Patients with angiographically confirmed MMD diagnosis with at least 6 months follow-up and completion of revascularization surgery were included; patients with intracranial atherosclerosis, intracranial dissection, vasculitis, and undefined inflammatory processes were excluded. The presence of stenosis/occlusion was graded radiographically to assess for disease progression and the prevalence of risk factors related to reduced progression-free survival.In all, 686 patients met the inclusion criteria, with PCA disease identified in 282 (41.1%) patients. Of those 282 patients with PCMMD, disease severity ranged from 99 (35.1%) with mild, 72 (25.5%) with moderate, and 111 (39.4%) with severe. The total number of postoperative complications was significantly associated with PCMMD severity (P=0.0067). Additionally, PCMMD severity correlated with worse postoperative modified Rankin Scale scores (P<0.0001). At a mean follow-up of 6.0±3.9 (range, 0.1-25.0) years, a total of 60 (12.6%) patients showed new/worsening PCMMD. The overall postoperative, progression-free survival in patients with PCMMD was 95.4% at 1 year, 82.4% at 3 years, 68.8% at 5 years, and 28.3% at 10 years, with prognostic factors for progression including preoperative PCMMD status, history of tobacco use, and hypertension (P<0.0001, P<0.001, and P<0.0001, respectively).PCA disease involvement in MMD is associated with higher rates of ischemic perioperative complications and worsened functional outcomes, likely due to reduced collateral flow. Ten-year progression of PCA disease is highly likely and should be monitored throughout follow-up; future studies will assess the impact of PCA disease progression on long-term outcomes.

  View details for DOI 10.1161/STROKEAHA.123.044693

  View details for PubMedID 38567531

• Stanford University School of Medicine: Our Neurosurgical Heritage. Neurosurgery Veeravagu, A., Kim, L. H., Rao, V. L., Lim, M., Shuer, L. M., Harris, O. A., Steinberg, G. K. 2023

  Abstract

  The legacy of Stanford University's Department of Neurosurgery began in 1858, with the establishment of a new medical school on the West Coast. Stanford Neurosurgery instilled an atmosphere of dedication to neurosurgical care, scientific research, education, and innovation. We highlight key historical events leading to the formation of the medical school and neurosurgical department, the individuals who shaped the department's vision and expansion, as well as pioneering advances in research and clinical care. The residency program was started in 1961, establishing the basis of the current education model with a strong emphasis on training future leaders, and the Moyamoya Center, founded in 1991, became the largest Moyamoya referral center in the United States. The opening of Stanford Stroke Center (1992) and seminal clinical trials resulted in a significant impact on cerebrovascular disease by expanding the treatment window of IV thrombolysis and intra-arterial thrombectomy. The invention and implementation of CyberKnife® (1994) marks another important event that revolutionized the field of radiosurgery, and the development of Stanford's innovative Brain Computer Interface program is pushing the boundaries of this specialty. The more recent launch of the Neurosurgery Virtual Reality and Simulation Center (2017) exemplifies how Stanford is continuing to evolve in this ever-changing field. The department also became a model for diversity within the school as well as nationwide. The growth of Stanford Neurosurgery from one of the youngest neurosurgery departments in the country to a prominent comprehensive neurosurgery center mirrors the history of neurosurgery itself: young, innovative, and willing to overcome challenges.

  View details for DOI 10.1227/neu.0000000000002799

  View details for PubMedID 38095422

• Short- and long-term outcomes of moyamoya patients post-revascularization JOURNAL OF NEUROSURGERY Teo, M., Abhinav, K., Bell-Stephens, T. E., Madhugiri, V. S., Sussman, E. S., Azad, T., Ali, R., Esparza, R., Zhang, M., Steinberg, G. K. 2023; 138 (5): 1374-1384

  Abstract

  The post-bypass stroke risk factors and long-term outcomes of moyamoya patients are not well documented. Therefore, the authors studied 30-day stroke risks and patients' long-term physical, functional, and social well-being.This was a single-institution combined moyamoya disease (MMD) database interrogation and questionnaire study. From 1991 to 2014, 1250 revascularization procedures (1118 direct bypasses, 132 indirect bypasses) were performed in 769 patients. Completed questionnaires were received from and available for analysis on 391 patients, and 6-month follow-up data were available for 96.4% (741/769) of the patients.The patients consisted of 548 females and 221 males, with a mean age of 32 years (range 1-69 years). Three hundred fifty-eight bypasses were performed in 205 pediatric patients (73% direct bypasses), and 892 revascularizations were performed in 564 adults (96% direct bypasses). Fifty-two patients (6.8%) developed major strokes with a worsening modified Rankin Scale (mRS) score within 30 days postoperatively. The 30-day major stroke risk was 5.3% (41/769) and 2.6% (12/467) after the first and second bypasses, respectively. Logistic regression analysis revealed that older age, modified MRI (mMRI) score, and hemodynamic reserve (HDR) score are clearly associated with higher postoperative stroke risks. Over a mean follow-up of 7.3 years (range 0.5-26 years), the long-term stroke risk among 741 patients was 0.6% per patient-year; 75% of these patients had excellent outcomes (mRS score 0-1). The long-term outcome questionnaire study showed that 84% (234/277) of patients reported resolution or improvement in their preoperative headache, 83% (325/391) remained employed or in school, and 87% (303/348) were self-caring.In this large, single-center surgical series, most of the adult and pediatric patients had direct revascularization, with a 4.2% per-bypass-procedure (6.8% per patient) 30-day major stroke risk and a 0.6% per-patient-year long-term stroke risk. The authors identified various risk factors that are highly correlated with postoperative morbidity (age, mMRI score, and HDR score) and are involved in ongoing work to develop the predictive modeling for future patient selection and treatment.

  View details for DOI 10.3171/2022.8.JNS22336

  View details for Web of Science ID 000991272700004

  View details for PubMedID 36272120

• Decoding the molecular crosstalk between grafted stem cells and the stroke-injured brain. Cell reports Azevedo-Pereira, R. L., Manley, N. C., Dong, C., Zhang, Y., Lee, A. G., Zatulovskaia, Y., Gupta, V., Vu, J., Han, S., Berry, J. E., Bliss, T. M., Steinberg, G. K. 2023; 42 (4): 112353

  Abstract

  Stem cell therapy shows promise for multiple disorders; however, the molecular crosstalk between grafted cells and host tissue is largely unknown. Here, we take a step toward addressing this question. Using translating ribosome affinity purification (TRAP) with sequencing tools, we simultaneously decode the transcriptomes of graft and host for human neural stem cells (hNSCs) transplanted into the stroke-injured rat brain. Employing pathway analysis tools, we investigate the interactions between the two transcriptomes to predict molecular pathways linking host and graft genes; as proof of concept, we predict host-secreted factors that signal to the graft and the downstream molecular cascades they trigger in the graft. We identify a potential host-graft crosstalk pathway where BMP6 from the stroke-injured brain induces graft secretion of noggin, a known brain repair factor. Decoding the molecular interplay between graft and host is a critical step toward deciphering the molecular mechanisms of stem cell action.

  View details for DOI 10.1016/j.celrep.2023.112353

  View details for PubMedID 37043353

• Comprehensive Profiling of Secreted Factors in the Cerebrospinal Fluid of Moyamoya Disease Patients. Translational stroke research Abhinav, K., Lee, A. G., Pendharkar, A. V., Bigder, M., Bet, A., Rosenberg-Hasson, Y., Cheng, M. Y., Steinberg, G. K. 2023

  Abstract

  Moyamoya disease (MMD) is characterized by progressive occlusion of the intracranial internal carotid arteries, leading to ischemic and hemorrhagic events. Significant clinical differences exist between ischemic and hemorrhagic MMD. To understand the molecular profiles in the cerebrospinal fluid (CSF) of MMD patients, we investigated 62 secreted factors in both MMD subtypes (ischemic and hemorrhagic) and examined their relationship with preoperative perfusion status, the extent of postoperative angiographic revascularization, and functional outcomes. Intraoperative CSF was collected from 32 control and 71 MMD patients (37 ischemic and 34 hemorrhagic). Multiplex Luminex assay analysis showed that 41 molecules were significantly elevated in both MMD subtypes when compared to controls, including platelet-derived growth factor-BB (PDGF-BB), plasminogen activator inhibitor 1 (PAI-1), and intercellular adhesion molecule 1 (ICAM1) (p<0.001). Many of these secreted proteins have not been previously reported in MMD, including interleukins (IL-2, IL-4, IL-5, IL-7, IL-8, IL-9, IL-17, IL-18, IL-22, and IL-23) and C-X-C motif chemokines (CXCL1 and CXCL9). Pathway analysis indicated that both MMD subtypes exhibited similar cellular/molecular functions and pathways, including cellular activation, migration, and inflammatory response. While neuroinflammation and dendritic cell pathways were activated in MMD patients, lipid signaling pathways involving nuclear receptors, peroxisome proliferator-activated receptor (PPAR), and liver X receptors (LXR)/retinoid X receptors (RXR) signaling were inhibited. IL-13 and IL-2 were negatively correlated with preoperative cerebral perfusion status, while 7 factors were positively correlated with the extent of postoperative revascularization. These elevated cytokines, chemokines, and growth factors in CSF may contribute to the pathogenesis of MMD and represent potential future therapeutic targets.

  View details for DOI 10.1007/s12975-023-01135-7

  View details for PubMedID 36745304

• Radiosurgery as a microsurgical adjunct: outcomes after microsurgical resection of intracranial arteriovenous malformations previously treated with stereotactic radiosurgery. Journal of neurosurgery Bigder, M., Choudhri, O., Gupta, M., Gummidipundi, S., Han, S. S., Church, E. W., Chang, S. D., Levy, R. P., Do, H. M., Marks, M. P., Steinberg, G. K. 2021: 1-12

  Abstract

  OBJECTIVE: Microsurgical resection of arteriovenous malformations (AVMs) can be aided by staged treatment consisting of stereotactic radiosurgery followed by resection in a delayed fashion. This approach is particularly useful for high Spetzler-Martin (SM) grade lesions because radiosurgery can reduce flow through the AVM, downgrade the SM rating, and induce histopathological changes that additively render the AVM more manageable for resection. The authors present their 28-year experience in managing AVMs with adjunctive radiosurgery followed by resection.METHODS: The authors retrospectively reviewed records of patients treated for cerebral AVMs at their institution between January 1990 and August 2019. All patients who underwent stereotactic radiosurgery (with or without embolization), followed by resection, were included in the study. Of 1245 patients, 95 met the eligibility criteria. Univariate and multivariate regression analyses were performed to assess relationships between key variables and clinical outcomes.RESULTS: The majority of lesions treated (53.9%) were high grade (SM grade IV-V), 31.5% were intermediate (SM grade III), and 16.6% were low grade (SM grade I-II). Hemorrhage was the initial presenting sign in half of all patients (49.5%). Complete resection was achieved among 84% of patients, whereas 16% had partial resection, the majority of whom received additional radiosurgery. Modified Rankin Scale (mRS) scores of 0-2 were achieved in 79.8% of patients, and 20.2% had poor (mRS scores 3-6) outcomes. Improved (44.8%) or stable (19%) mRS scores were observed among 63.8% of patients, whereas 36.2% had a decline in mRS scores. This includes 22 patients (23.4%) with AVM hemorrhage and 6 deaths (6.7%) outside the perioperative period but prior to AVM obliteration.CONCLUSIONS: Stereotactic radiosurgery is a useful adjunct in the presurgical management of cerebral AVMs. Multimodal therapy allowed for high rates of AVM obliteration and acceptable morbidity rates, despite the predominance of high-grade lesions in this series of patients.

  View details for DOI 10.3171/2020.9.JNS201538

  View details for PubMedID 34116503

• 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

• Brain-wide neural dynamics of poststroke recovery induced by optogenetic stimulation. Science advances Vahdat, S., Pendharkar, A. V., Chiang, T., Harvey, S., Uchino, H., Cao, Z., Kim, A., Choy, M., Chen, H., Lee, H. J., Cheng, M. Y., Lee, J. H., Steinberg, G. K. 2021; 7 (33)

  Abstract

  Poststroke optogenetic stimulations can promote functional recovery. However, the circuit mechanisms underlying recovery remain unclear. Elucidating key neural circuits involved in recovery will be invaluable for translating neuromodulation strategies after stroke. Here, we used optogenetic functional magnetic resonance imaging to map brain-wide neural circuit dynamics after stroke in mice treated with and without optogenetic excitatory neuronal stimulations in the ipsilesional primary motor cortex (iM1). We identified key sensorimotor circuits affected by stroke. iM1 stimulation treatment restored activation of the ipsilesional corticothalamic and corticocortical circuits, and the extent of activation was correlated with functional recovery. Furthermore, stimulated mice exhibited higher expression of axonal growth-associated protein 43 in the ipsilesional thalamus and showed increased Synaptophysin+/channelrhodopsin+ presynaptic axonal terminals in the corticothalamic circuit. Selective stimulation of the corticothalamic circuit was sufficient to improve functional recovery. Together, these findings suggest early involvement of corticothalamic circuit as an important mediator of poststroke recovery.

  View details for DOI 10.1126/sciadv.abd9465

  View details for PubMedID 34380610

• 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

  View details for DOI 10.1093/neuros/nyz074

  View details for Web of Science ID 000515122000065

• 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

  View details for DOI 10.3171/2018.5.JNS173147

  View details for Web of Science ID 000493973300015

• 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

  View details for DOI 10.3171/2018.2.JNS172511

  View details for Web of Science ID 000478642100011

• Microsurgical laser resection of brainstem cavernous malformations. Neurosurgical focus: Video Church, E. W., Steinberg, G. K. 2019; 1 (1): V7

  Abstract

  This operative technique video demonstrates laser microsurgery for brainstem cavernous malformations (CMs). In case 1 we demonstrate CO2 laser microsurgery for a symptomatic pontine CM using far lateral craniotomy and olivary zone entry. Case 2 demonstrates the subtemporal approach and removal of a paratrigeminal CM, and case 3 is a dorsal midbrain CM. We illustrate several advantages of laser microsurgery including improved visualization in narrow corridors, precise cutting with reduced thermal damage, and effective sealing of small vessels. Over the past decade at Stanford University School of Medicine, over 120 brainstem CMs have been removed using laser microsurgery with good results. The video can be found here: https://youtu.be/DwwqWGv_vzo.

  View details for DOI 10.3171/2019.7.FocusVid.19163

  View details for PubMedID 36285069

  View details for PubMedCentralID PMC9541818

• 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

  View details for DOI 10.1016/j.wneu.2018.12.171

  View details for Web of Science ID 000463087800083

• 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 α1 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

• A Novel Phase 1/2A Study of Intraparenchymal Transplantation of Human Modified Bone Marrow-Derived Cells in Patients With Stable Ischemic Stroke Steinberg, G. K., Kondziolka, D., Schwartz, N. E., Wechsler, L., Lunsford, D., Coburn, M. L., Billigen, J. B., Keren-Gill, H., McGrogan, M., Case, C., Mori, K., Yankee, E. W. COGNIZANT COMMUNICATION CORP. 2014: 784

  View details for Web of Science ID 000338484000076

• 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

• Optogenetic Stimulation Of Motor Cortex Neurons Promotes Recovery After Stroke Cheng, M. Y., Woodson, W. J., Wang, E. H., Wang, S., Sun, G., Lee, A. G., Arac, A., Fenno, L., Deisseroth, K., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000330540200260

• 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

• Transplanted Stem Cell-Secreted VEGF Effects Post-Stroke Recovery, Inflammation, and Vascular Repair. Stem cells (Dayton, Ohio) 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

  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

• 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

• Predictors of Clinical and Angiographic Outcome Following Surgical or Endovascular Therapy of Very Large and Giant Intracranial Aneurysms 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. LIPPINCOTT WILLIAMS & WILKINS. 2010: E266

  View details for Web of Science ID 000276106100300

• Transplantation of human neural progenitor cells induces axonal plasticity in the host brain after stroke Andres, R. H., Horie, N., Sun, G., Shichinohe, H., Mcmillan, E., Svendsen, C. N., Schaar, B. T., Bliss, T. M., Steinberg, G. K. NATURE PUBLISHING GROUP. 2009: S38

  View details for Web of Science ID 000270329900042

• Transplanted Human Neural Progenitor Cells Enhance Endogenous Dendritic Plasticity And Axonal Sprouting After Stroke In Rat Horie, N., Andres, R. H., Keren-Gill, H., Slikker, W., Sun, G., McMillan, E., Svendsen, C., Bliss, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: E150

  View details for Web of Science ID 000264709500273

• 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

• Early Neurosurgical Education in the Era of Distant Learning: Incorporating Virtual Reality and Cadaveric Specimen Demonstrations. World neurosurgery Savchuk, S., Vigo, V., Chidambaram, S., NuÑez, M., Anthony, D., Jansen, T., Steinberg, G. K., Fernandez-Miranda, J. C. 2024

  Abstract

  Virtual reality (VR) has emerged as a powerful tool for neuroanatomy education of post-graduated medical trainees. However, its use in early training, such as of undergraduate, medical and physician assistant students, in neurosurgery has not been evaluated. We also have limited insight into how VR may be integrated with traditional teaching methods.We created the first of its kind elective course on neuroanatomy for medical students incorporating lecture-style didactics, case-based VR activities and cadaveric dissections. The course ran entirely remotely with each student tuning into class with their own VR headset. We asked the students to self-report their level of confidence with the material and complete knowledge quizzes, which were compared in aggregate between pre- vs post-course, and pre- vs post- each session.66.6% of students rated teaching quality of the course as excellent, and 33.3% as satisfactory. Most students (77.7-88.8%) also described the course as having a positive impact on their training. On aggregate analysis, the cohort reported increased levels of confidence in their understanding of neuroanatomy (mean 2.75 vs 5.4, p=0.02), neurosurgical approaches (mean 1.25 vs 5.7, p<0.0001) and the use of VR in neurosurgery (mean 1.5 vs 6.1, p<0.0001). Objectively, the cohort also performed better on post-session assessments, a difference which was statistically significant at p<0.05, in all but the first assessment.Integration of VR with traditional pedagogical tactics is well received by the learners and contributes to measurable learning outcomes. Our experience informs the future use of VR tools in medical education.

  View details for DOI 10.1016/j.wneu.2024.09.132

  View details for PubMedID 39414136

• Mesenchymal Stromal Cell Implants for Chronic Motor Deficits After Traumatic Brain Injury: Post Hoc Analysis of a Randomized Trial. Neurology Okonkwo, D. O., McAllister, P., Achrol, A. S., Karasawa, Y., Kawabori, M., Cramer, S. C., Lai, A., Kesari, S., Frishberg, B. M., Groysman, L. I., Kim, A. S., Schwartz, N. E., Chen, J. W., Imai, H., Yasuhara, T., Chida, D., Nejadnik, B., Bates, D., Stonehouse, A. H., Richardson, R. M., Steinberg, G. K., Poggio, E. C., Weintraub, A. H. 2024; 103 (7): e209797

  Abstract

  Traumatic brain injury (TBI) is frequently characterized by chronic motor deficits. Therefore, this clinical trial assessed whether intracranial implantation of allogeneic modified mesenchymal stromal (SB623) cells can improve chronic motor deficits after TBI.Post hoc analysis of the double-blind, randomized, prospective, surgical sham-controlled, phase 2, STEMTRA clinical trial (June 2016 and March 2019) with 48 weeks of follow-up was conducted. In this international, multicenter clinical trial, eligible participants had moderate-to-severe TBI, were ≥12 months postinjury, and had chronic motor deficits. Participants were randomized in a 1:1:1:1 ratio to stereotactic surgical intracranial implantation of SB623 cells (2.5 × 106, 5.0 × 106, 10 × 106) or surgical sham-controlled procedure. The prespecified primary efficacy end point was significantly greater change from baseline of the Fugl-Meyer Motor Scale (FMMS) score, a measure of motor status, for the SB623 pooled vs control arm at 24 weeks.A total of 211 participants were screened, 148 were excluded, and 63 underwent randomization, of which 61 (97%; mean age, 34 [SD, 12] years; 43 men [70.5%]) completed the trial. Single participants in the SB623 2.5 × 106 and 5.0 × 106 cell dose groups discontinued before surgery. Safety and efficacy (modified intent-to-treat) were assessed in participants who underwent surgery (N = 61; SB623 = 46, controls = 15). The primary efficacy end point (FMMS) was achieved (least squares mean [SE] SB623: +8.3 [1.4]; 95% CI 5.5-11.2 vs control: +2.3 [2.5]; 95% CI -2.7 to 7.3; p = 0.04), with faster improvement of the FMMS score in SB623-treated groups than in controls at 24 weeks and sustained improvement at 48 weeks. At 48 weeks, improvement of function and activities of daily living (ADL) was greater, but not significantly different in SB623-treated groups vs controls. The incidence of adverse events was equivalent in SB623-treated groups and controls. There were no deaths or withdrawals due to adverse events.Intraparenchymal implantation of SB623 cells was safe and significantly improved motor status at 24 weeks in participants with chronic motor deficits after TBI, with continued improvement of function and ADL at 48 weeks. Cell therapy can modify chronic neurologic deficits after TBI.ClinicalTrials.gov Identifier: NCT02416492. Submitted to registry: April 15, 2015. First participant enrolled: July 6, 2016. Available at: classic.clinicaltrials.gov/ct2/show/NCT02416492.This study provides Class I evidence that intracranial implantation of allogeneic stem (SB623) cells in adults with motor deficits from chronic TBI improves motor function at 24 weeks.

  View details for DOI 10.1212/WNL.0000000000209797

  View details for PubMedID 39231380

  View details for PubMedCentralID PMC11373674

• Perfusion imaging for delayed cerebral ischemia detection in patients following ruptured aneurysmal subarachnoid hemorrhage: Interrater reliability assessment. Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences Bombardieri, A. M., Wouters, A., Seners, P., Zamarud, A., Mlynash, M., Yuen, N., Albers, G. W., Sussman, E. S., Pulli, B., Lansberg, M. G., Steinberg, G. K., Heit, J. J. 2024: 15910199241277953

  Abstract

  Delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH) is associated with adverse neurological outcomes. Early and accurate diagnosis of DCI is crucial to prevent cerebral infarction. This study aimed to assess the diagnostic accuracy and interrater agreement of the visual assessment of neuroimaging perfusion maps to detect DCI in patients suspected of vasospasm after aSAH.In this case-control study, cases were adult aSAH patients with DCI who underwent magnetic resonance perfusion or computed tomography perfusion (CTP) imaging in the 24 h prior to digital subtraction angiography for vasospasm diagnosis. Controls were patients with dizziness and no aSAH on CTP imaging. Three independent raters, blinded to patients' clinical information, other neuroimaging studies, and angiographic results, visually assessed anonymized perfusion color maps to classify patients as either having DCI or not. Tmax delay was classified by symmetry into no delay, unilateral, or bilateral.Perfusion imaging of 54 patients with aSAH and 119 control patients without aSAH was assessed. Sensitivities for DCI diagnosis ranged from 0.65 to 0.78, and specificities ranged from 0.70 to 0.87, with interrater agreement ranging from 0.60 (moderate) to 0.68 (substantial).Visual assessment of perfusion color maps demonstrated moderate to substantial accuracy in diagnosing DCI in aSAH patients.

  View details for DOI 10.1177/15910199241277953

  View details for PubMedID 39219541

• Advancing diagnostic precision of delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage: The potential for a vasospasm index score on perfusion imaging to detect vasospasm. European journal of radiology Maria Bombardieri, A., Seners, P., Wouters, A., Zamarud, A., Mlynash, M., Yuen, N., Albers, G. W., Sussman, E. S., Pulli, B., Lansberg, M. G., Steinberg, G. K., Heit, J. J. 2024; 178: 111578

  Abstract

  The occurrence of delayed cerebral ischemia and vasospasm following aneurysmal subarachnoid hemorrhage (aSAH) results in high morbidity and mortality, but the diagnosis remains challenging. This study aimed to identify neuroimaging perfusion parameters indicative of delayed cerebral ischemia in patients with suspected vasospasm.This is a case-control study. Cases were adult aSAH patients who underwent magnetic resonance perfusion or computed tomography perfusion (CTP) imaging ≤ 24 h before digital subtraction angiography performed for vasospasm diagnosis and treatment. Controls were patients without aSAH who underwent CTP. Quantitative perfusion parameters at different thresholds, including Tmax 4-6-8-10 s delay, cerebral blood flow and cerebral blood volume were measured and compared between cases and controls. The Vasospasm Index Score was calculated as the ratio of brain volume with time-to-max (Tmax) delay > 6 s over volume with Tmax > 4 s.54 patients with aSAH and 119 controls without aSAH were included. Perfusion parameters with the strongest prediction of vasospasm on cerebral angiography were the combination of the Vasospasm Index Score (Tmax6/Tmax4) + CBV ≤ 48 % (area under the curve value of 0.85 [95 % CI 0.78-0.91]) with a sensitivity of 63 % and specificity of 95 %.The Vasospasm Index Score in combination with CBV ≤ 48 % on cerebral perfusion imaging reliably identified vasospasm as the cause of DCI on perfusion imaging.

  View details for DOI 10.1016/j.ejrad.2024.111578

  View details for PubMedID 38981177

• Turning brain MRI into diagnostic PET: 15O-water PET CBF synthesis from multi-contrast MRI via attention-based encoder-decoder networks. Medical image analysis Hussein, R., Shin, D., Zhao, M. Y., Guo, J., Davidzon, G., Steinberg, G., Moseley, M., Zaharchuk, G. 2023; 93: 103072

  Abstract

  Accurate quantification of cerebral blood flow (CBF) is essential for the diagnosis and assessment of a wide range of neurological diseases. Positron emission tomography (PET) with radiolabeled water (15O-water) is the gold-standard for the measurement of CBF in humans, however, it is not widely available due to its prohibitive costs and the use of short-lived radiopharmaceutical tracers that require onsite cyclotron production. Magnetic resonance imaging (MRI), in contrast, is more accessible and does not involve ionizing radiation. This study presents a convolutional encoder-decoder network with attention mechanisms to predict the gold-standard 15O-water PET CBF from multi-contrast MRI scans, thus eliminating the need for radioactive tracers. The model was trained and validated using 5-fold cross-validation in a group of 126 subjects consisting of healthy controls and cerebrovascular disease patients, all of whom underwent simultaneous 15O-water PET/MRI. The results demonstrate that the model can successfully synthesize high-quality PET CBF measurements (with an average SSIM of 0.924 and PSNR of 38.8 dB) and is more accurate compared to concurrent and previous PET synthesis methods. We also demonstrate the clinical significance of the proposed algorithm by evaluating the agreement for identifying the vascular territories with impaired CBF. Such methods may enable more widespread and accurate CBF evaluation in larger cohorts who cannot undergo PET imaging due to radiation concerns, lack of access, or logistic challenges.

  View details for DOI 10.1016/j.media.2023.103072

  View details for PubMedID 38176356

• Direct and indirect microvascular revascularization in the setting of moyamoya disease. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Gauden, A. J., Steinberg, G. K. 2023; 119: 112

  View details for DOI 10.1016/j.jocn.2023.10.022

  View details for PubMedID 37995408

• High flow bypass for revascularization in occlusive atherosclerotic cerebrovascular disease. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Gauden, A. J., Steinberg, G. K. 2023; 118: 176

  View details for DOI 10.1016/j.jocn.2023.10.021

  View details for PubMedID 37967501

• Combined high-flow bypass and endovascular sacrifice for dysplastic cavernous internal carotid artery aneurysm for recurrent epistaxis. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia Gauden, A. J., Dodd, R., Steinberg, G. K. 2023; 118: 175

  View details for DOI 10.1016/j.jocn.2023.10.023

  View details for PubMedID 37956500

• Segmenting Cervical Arteries in Phase Contrast Magnetic Resonance Imaging Using Convolutional Encoder-Decoder Networks APPLIED SCIENCES-BASEL Campbell, B., Yadav, D., Hussein, R., Jovin, M., Hoover, S., Halbert, K., Holley, D., Khalighi, M., Davidzon, G. A., Tong, E., Steinberg, G. K., Moseley, M., Zhao, M. Y., Zaharchuk, G. 2023; 13 (21)

  View details for DOI 10.3390/app132111820

  View details for Web of Science ID 001100429200001

• Final Analysis of the Double-Blind, Randomized, Surgical Sham-Controlled, Phase 2 Stemtra Trial: 1-Year Safety and Efficacy Outcomes in Patients With Chronic Motor Deficits Secondary to Traumatic Brain Injury Weintraub, A. H., Cramer, S. C., Steinberg, G. K., Kawabori, M., Kesari, S., Imai, H., Groysman, L. I., Yasuhara, T., Kim, A. S., Frishberg, B. M., Schwartz, N. E., Nejadnik, B., Bates, D., McAllister, P. TAYLOR & FRANCIS LTD. 2023: 44-45

  View details for Web of Science ID 001092280000086

• Combined near infrared photoacoustic imaging and ultrasound detects vulnerable atherosclerotic plaque. Biomaterials Schneider, M. K., Wang, J., Kare, A., Adkar, S. S., Salmi, D., Bell, C. F., Alsaigh, T., Wagh, D., Coller, J., Mayer, A., Snyder, S. J., Borowsky, A. D., Long, S. R., Lansberg, M. G., Steinberg, G. K., Heit, J. J., Leeper, N. J., Ferrara, K. W. 2023; 302: 122314

  Abstract

  Atherosclerosis is an inflammatory process resulting in the deposition of cholesterol and cellular debris, narrowing of the vessel lumen and clot formation. Characterization of the morphology and vulnerability of the lesion is essential for effective clinical management. Here, near-infrared auto-photoacoustic (NIRAPA) imaging is shown to detect plaque components and, when combined with ultrasound imaging, to differentiate stable and vulnerable plaque. In an ex vivo study of photoacoustic imaging of excised plaque from 25 patients, 88.2% sensitivity and 71.4% specificity were achieved using a clinically-relevant protocol. In order to determine the origin of the NIRAPA signal, immunohistochemistry, spatial transcriptomics and spatial proteomics were co-registered with imaging and applied to adjacent plaque sections. The highest NIRAPA signal was spatially correlated with bilirubin and associated blood-based residue and with the cytoplasmic contents of inflammatory macrophages bearing CD74, HLA-DR, CD14 and CD163 markers. In summary, we establish the potential to apply the NIRAPA-ultrasound imaging combination to detect vulnerable carotid plaque and a methodology for fusing molecular imaging with spatial transcriptomic and proteomic methods.

  View details for DOI 10.1016/j.biomaterials.2023.122314

  View details for PubMedID 37776766

• Short- and Long-Term MRI Assessed Hemodynamic Changes in Pediatric Moyamoya Patients After Revascularization. Journal of magnetic resonance imaging : JMRI Zhao, M. Y., Tong, E., Duarte Armindo, R., Fettahoglu, A., Choi, J., Bagley, J., Yeom, K. W., Moseley, M., Steinberg, G. K., Zaharchuk, G. 2023

  Abstract

  Cerebrovascular reserve (CVR) reflects the capacity of cerebral blood flow (CBF) to change following a vasodilation challenge. Decreased CVR is associated with a higher stroke risk in patients with cerebrovascular diseases. While revascularization can improve CVR and reduce this risk in adult patients with vasculopathy such as those with Moyamoya disease, its impact on hemodynamics in pediatric patients remains to be elucidated. Arterial spin labeling (ASL) is a quantitative MRI technique that can measure CBF, CVR, and arterial transit time (ATT) non-invasively.To investigate the short- and long-term changes in hemodynamics after bypass surgeries in patients with Moyamoya disease.Longitudinal.Forty-six patients (11 months-18 years, 28 females) with Moyamoya disease.3-T, single- and multi-delay ASL, T1-weighted, T2-FLAIR, 3D MRA.Imaging was performed 2 weeks before and 1 week and 6 months after surgical intervention. Acetazolamide was employed to induce vasodilation during the imaging procedure. CBF and ATT were measured by fitting the ASL data to the general kinetic model. CVR was computed as the percentage change in CBF. The mean CBF, ATT, and CVR values were measured in the regions affected by vasculopathy.Pre- and post-revascularization CVR, CBF, and ATT were compared for different regions of the brain. P-values <0.05 were considered statistically significant.ASL-derived CBF in flow territories affected by vasculopathy significantly increased after bypass by 41 ± 31% within a week. At 6 months, CBF significantly increased by 51 ± 34%, CVR increased by 68 ± 33%, and ATT was significantly reduced by 6.6 ± 2.9%.There may be short- and long-term improvement in the hemodynamic parameters of pediatric Moyamoya patients after bypass surgery.4 TECHNICAL EFFICACY: Stage 2.

  View details for DOI 10.1002/jmri.28902

  View details for PubMedID 37515518

• Corrigendum to: "Ten-Year Experience With Laparoscopic Pedicled Omental Flap for Cerebral Revascularization in Patients With Moyamoya Disease" J Pediatr Surg 57 (2022) 710-715. Journal of pediatric surgery Salimi-Jazia, F., Wood, L. S., Jones, R. E., Chandler, J., Rafeeqi, T., Dutta, S., Steinberg, G., Bruzoni, M. 2023

  View details for DOI 10.1016/j.jpedsurg.2023.07.002

  View details for PubMedID 37500373

• Pediatric Moyamoya Revascularization Perioperative Care: A Modified Delphi Study. Neurocritical care Sun, L. R., Jordan, L. C., Smith, E. R., Aldana, P. R., Kirschen, M. P., Guilliams, K., Gupta, N., Steinberg, G. K., Fox, C., Harrar, D. B., Lee, S., Chung, M. G., Dirks, P., Dlamini, N., Maher, C. O., Lehman, L. L., Hong, S. J., Strahle, J. M., Pineda, J. A., Beslow, L. A., Rasmussen, L., Mailo, J., Piatt, J., Lang, S. S., Adelson, P. D., Dewan, M. C., Mineyko, A., McClugage, S., Vadivelu, S., Dowling, M. M., Hersh, D. S. 2023

  Abstract

  Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities.Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement.Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery.In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

  View details for DOI 10.1007/s12028-023-01788-0

  View details for PubMedID 37470933

  View details for PubMedCentralID 5443666

• Vascular anomaly, lipoma, and polymicrogyria associated with schizencephaly: developmental and diagnostic insights. Illustrative case. Journal of neurosurgery. Case lessons Kumar, K. K., Toland, A., Fischbein, N., Morrell, M., Heit, J. J., Born, D. E., Steinberg, G. K. 2023; 5 (21)

  Abstract

  BACKGROUND: Schizencephaly is an uncommon central nervous system malformation. Intracranial lipomas are also rare, accounting for approximately 0.1% of brain "tumors." They are believed to be derived from a persistent meninx primitiva, a neural crest-derived mesenchyme that develops into the dura and leptomeninges.OBSERVATIONS: The authors present a case of heterotopic adipose tissue and a nonshunting arterial vascular malformation arising within a schizencephalic cleft in a 22-year-old male. Imaging showed right frontal gray matter abnormality and an associated suspected arteriovenous malformation with evidence of hemorrhage. Brain magnetic resonance imaging revealed right frontal polymicrogyria lining an open-lip schizencephaly, periventricular heterotopic gray matter, fat within the schizencephalic cleft, and gradient echo hypointensity concerning for prior hemorrhage. Histological assessment demonstrated mature adipose tissue with large-bore, thick-walled, irregular arteries. Mural calcifications and subendothelial cushions suggesting nonlaminar blood flow were observed. There were no arterialized veins or direct transitions from the arteries to veins. Hemosiderin deposition was scant, and hemorrhage was not present. The final diagnosis was consistent with ectopic mature adipose tissue and arteries with meningocerebral cicatrix.LESSONS: This example of a complex maldevelopment of derivatives of the meninx primitiva in association with cortical maldevelopment highlights the unique challenges from both a radiological and histological perspective during diagnostic workup.

  View details for DOI 10.3171/CASE2388

  View details for PubMedID 37218736

• Prediction of delayed cerebral ischemia after cerebral aneurysm rupture using explainable machine learning approach. Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences Taghavi, R. M., Zhu, G., Wintermark, M., Kuraitis, G. M., Sussman, E. S., Pulli, B., Biniam, B., Ostmeier, S., Steinberg, G. K., Heit, J. J. 2023: 15910199231170411

  Abstract

  Aneurysmal subarachnoid hemorrhage results in significant mortality and disability, which is worsened by the development of delayed cerebral ischemia. Tests to identify patients with delayed cerebral ischemia prospectively are of high interest.We created a machine learning system based on clinical variables to predict delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients. We also determined which variables have the most impact on delayed cerebral ischemia prediction using SHapley Additive exPlanations method.500 aneurysmal subarachnoid hemorrhage patients were identified and 369 met inclusion criteria: 70 patients developed delayed cerebral ischemia (delayed cerebral ischemia+) and 299 did not (delayed cerebral ischemia-). The algorithm was trained based upon age, sex, hypertension (HTN), diabetes, hyperlipidemia, congestive heart failure, coronary artery disease, smoking history, family history of aneurysm, Fisher Grade, Hunt and Hess score, and external ventricular drain placement. Random Forest was selected for this project, and prediction outcome of the algorithm was delayed cerebral ischemia+. SHapley Additive exPlanations was used to visualize each feature's contribution to the model prediction.The Random Forest machine learning algorithm predicted delayed cerebral ischemia: accuracy 80.65% (95% CI: 72.62-88.68), area under the curve 0.780 (95% CI: 0.696-0.864), sensitivity 12.5% (95% CI: -3.7 to 28.7), specificity 94.81% (95% CI: 89.85-99.77), PPV 33.3% (95% CI: -4.39 to 71.05), and NPV 84.1% (95% CI: 76.38-91.82). SHapley Additive exPlanations value demonstrated Age, external ventricular drain placement, Fisher Grade, and Hunt and Hess score, and HTN had the highest predictive values for delayed cerebral ischemia. Lower age, absence of hypertension, higher Hunt and Hess score, higher Fisher Grade, and external ventricular drain placement increased risk of delayed cerebral ischemia.Machine learning models based upon clinical variables predict delayed cerebral ischemia with high specificity and good accuracy.

  View details for DOI 10.1177/15910199231170411

  View details for PubMedID 37070145

• Correction to: Comprehensive Profiling of Secreted Factors in the Cerebrospinal Fluid of Moyamoya Disease Patients. Translational stroke research Abhinav, K., Lee, A. G., Pendharkar, A. V., Bigder, M., Bet, A., Rosenberg-Hasson, Y., Cheng, M. Y., Steinberg, G. K. 2023

  View details for DOI 10.1007/s12975-023-01149-1

  View details for PubMedID 36991240

• Percutaneous cervical sympathetic block to treat cerebral vasospasm and delayed cerebral ischemia: a review of the evidence. Journal of neurointerventional surgery Bombardieri, A. M., Albers, G. W., Rodriguez, S., Pileggi, M., Steinberg, G. K., Heit, J. J. 2022

  Abstract

  Delayed cerebral ischemia (DCI) affects 30% of patients following aneurysmal subarachnoid hemorrhage (aSAH) and is a major driver of morbidity, mortality, and intensive care unit length of stay for these patients. DCI is strongly associated with cerebral arterial vasospasm, reduced cerebral blood flow and cerebral infarction. The current standard treatment with intravenous or intra-arterial calcium channel antagonist and balloon angioplasty or stent has limited efficacy. A simple treatment such as a cervical sympathetic block (CSB) may be an effective therapy but is not routinely performed to treat vasospasm/DCI. CSB consists of injecting local anesthetic at the level of the cervical sympathetic trunk, which temporarily blocks the innervation of the cerebral arteries to cause arterial vasodilatation. CSB is a local, minimally invasive, low cost and safe technique that can be performed at the bedside and may offer significant advantages as complementary treatment in combination with more conventional neurointerventional surgery interventions. We reviewed the literature that describes CSB for vasospasm/DCI prevention or treatment in humans after aSAH. The studies outlined in this review show promising results for a CSB as a treatment for vasospasm/DCI. Further research is required to standardize the technique, to explore how to integrate a CSB with conventional neurointerventional surgery treatments of vasospasm and DCI, and to study its long-term effect on neurological outcomes.

  View details for DOI 10.1136/jnis-2022-019838

  View details for PubMedID 36597947

• Percutaneous cervical sympathetic block to treat cerebral vasospasm and delayed cerebral ischemia: a review of the evidence JOURNAL OF NEUROINTERVENTIONAL SURGERY Bombardieri, A., Albers, G. W., Rodriguez, S., Pileggi, M., Steinberg, G. K., Heit, J. J. 2022

  View details for DOI 10.1136/jnis-2022-019838

  View details for Web of Science ID 000894932400001

• Cervical sympathectomy to treat cerebral vasospasm: a scoping review. Regional anesthesia and pain medicine Bombardieri, A. M., Heifets, B. D., Treggiari, M., Albers, G. W., Steinberg, G. K., Heit, J. J. 2022

  Abstract

  Delayed cerebral ischemia (DCI) is the second-leading cause of death and disability in patients with aneurysmal subarachnoid hemorrhage (aSAH), and is associated with cerebral arterial vasospasm (CAV). Current treatments for CAV are expensive, invasive, and have limited efficacy. Cervical sympathetic block (CSB) is an underappreciated, but potentially highly effective therapy for CAV.To provide a comprehensive review of the preclinical and human literature pertinent to CSB in the context of CAV.This study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. We conducted a literature search using Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science until February 2022, to identify abstracts, conference proceedings, and full-text papers pertinent to cervical sympathectomy and CAV in animal/adult patients.We included six human and six experimental studies. Human studies were mostly prospective observational, except one retrospective and one randomized clinical trial, and used various imaging modalities to measure changes in arterial diameter after the block. Studies that used digital subtraction angiography showed an improvement in cerebral perfusion without change in vessel diameter. Transcranial Doppler studies found an approximately 15% statistically significant decrease in velocities consistent with arterial vasodilatation. Overall, the results suggest an increase in cerebral arterial diameter and neurological improvement in patients receiving a CSB. Animal studies demonstrate that sympathetic system ablation vasodilates cerebral vasculature and decreases the incidence of symptomatic vasospasm.This scoping review suggests that CSB may be a viable option for treatment and prevention of CAV/DCI in patients with aSAH, although the included studies were heterogeneous, mostly observational, and with a small sample size. Further research is needed to standardize the technique and prove its effectiveness to treat patients suffering of CAV/DCI after aSAH.

  View details for DOI 10.1136/rapm-2022-103999

  View details for PubMedID 36424089

• Revascularization improves vascular hemodynamics - a study assessing cerebrovascular reserve and transit time in Moyamoya patients using MRI. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Zhao, M. Y., Armindo, R. D., Gauden, A. J., Yim, B., Tong, E., Moseley, M., Steinberg, G. K., Zaharchuk, G. 2022: 271678X221140343

  Abstract

  Cerebrovascular reserve (CVR) reflects the capacity of cerebral blood flow (CBF) to change. Decreased CVR implies poor hemodynamics and is linked to a higher risk for stroke. Revascularization has been shown to improve CBF in patients with vasculopathy such as Moyamoya disease. Dynamic susceptibility contrast (DSC) can measure transit time to evaluate patients suspected of stroke. Arterial spin labeling (ASL) is a non-invasive technique for CBF, CVR, and arterial transit time (ATT) measurements. Here, we investigate the change in hemodynamics 4-12 months after extracranial-to-intracranial direct bypass in 52 Moyamoya patients using ASL with single and multiple post-labeling delays (PLD). Images were collected using ASL and DSC with acetazolamide. CVR, CBF, ATT, and time-to-maximum (Tmax) were measured in different flow territories. Results showed that hemodynamics improved significantly in regions affected by arterial occlusions after revascularization. CVR increased by 16 ± 11% (p < 0.01) and 25 ± 13% (p < 0.01) for single- and multi-PLD ASL, respectively. Transit time measured by multi-PLD ASL and post-vasodilation DSC reduced by 13 ± 7% (p < 0.01) and 9 ± 5% (p < 0.01), respectively. For all regions, ATT correlated significantly with Tmax (R2  =  0.59, p < 0.01). Thus, revascularization improved CVR and decreased transit times. Multi-PLD ASL can serve as an effective and non-invasive modality to examine vascular hemodynamics in Moyamoya patients.

  View details for DOI 10.1177/0271678X221140343

  View details for PubMedID 36408536

• Coronary Artery Disease in a Young Adult With Unilateral Moyamoya Disease. Journal of the Society for Cardiovascular Angiography & Interventions Stathogiannis, K. E., Pogatchnik, B. P., Steinberg, G. K., Sharma, R. P. 2022; 1 (6): 100459

  View details for DOI 10.1016/j.jscai.2022.100459

  View details for PubMedID 39132340

  View details for PubMedCentralID PMC11307966

• Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury JOURNAL OF NEUROSURGERY-SPINE McKenna, S. L., Ehsanian, R., Liu, C. Y., Steinberg, G. K., Jones, L., Lebkowski, J. S., Wirth III, E., Fessler, R. G. 2022; 37 (3): 321-330

  View details for Web of Science ID 000862865300002

• Intracranial Artery Morphology in Pediatric Moya Moya Disease and Moya Moya Syndrome. Neurosurgery Yedavalli, V. S., Quon, J. L., Tong, E., van Staalduinen, E. K., Mouches, P., Kim, L. H., Steinberg, G. K., Grant, G. A., Yeom, K. W., Forkert, N. D. 2022

  Abstract

  BACKGROUND: Moya Moya disease (MMD) and Moya Moya syndrome (MMS) are cerebrovascular disorders, which affect the internal carotid arteries (ICAs). Diagnosis and surveillance of MMD/MMS in children mostly rely on qualitative evaluation of vascular imaging, especially MR angiography (MRA).OBJECTIVE: To quantitatively characterize arterial differences in pediatric patients with MMD/MMS compared with normal controls.METHODS: MRA data sets from 17 presurgery MMD/MMS (10M/7F, mean age = 10.0 years) patients were retrospectively collected and compared with MRA data sets of 98 children with normal vessel morphology (49 male patients; mean age = 10.6 years). Using a level set segmentation method with anisotropic energy weights, the cerebral arteries were automatically extracted and used to compute the radius of the ICA, middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and basilar artery (BA). Moreover, the density and the average radius of all arteries in the MCA, ACA, and PCA flow territories were quantified.RESULTS: Statistical analysis revealed significant differences comparing children with MMD/MMS and those with normal vasculature (P < .001), whereas post hoc analyses identified significantly smaller radii of the ICA, MCA-M1, MCA-M2, and ACA (P < .001) in the MMD/MMS group. No significant differences were found for the radii of the PCA and BA or any artery density and average artery radius measurement in the flow territories (P > .05).CONCLUSION: His study describes the results of an automatic approach for quantitative characterization of the cerebrovascular system in patients with MMD/MMS with promising preliminary results for quantitative surveillance in pediatric MMD/MMS management.

  View details for DOI 10.1227/neu.0000000000002099

  View details for PubMedID 36084178

• A phase 1/2a dose-escalation study of oligodendrocyte progenitor cells in individuals with subacute cervical spinal cord injury. Journal of neurosurgery. Spine Fessler, R. G., Ehsanian, R., Liu, C. Y., Steinberg, G. K., Jones, L., Lebkowski, J. S., Wirth, E. D., McKenna, S. L. 2022: 1-9

  Abstract

  The primary objective of this study was to evaluate the safety of 3 escalating doses of oligodendrocyte progenitor cells (LCTOPC1; previously known as GRNOPC1 and AST-OPC1) administered at a single time point between 21 and 42 days postinjury to participants with subacute cervical spinal cord injuries (SCIs). The secondary objective was to evaluate changes in neurological function following administration of LCTOPC1.This study was designed as an open-label, dose-escalation, multicenter clinical trial. Twenty-five participants with C4-7 American Spinal Injury Association Impairment Scale grade A or B injuries received a single dose of either 2 × 106, 1 × 107, or 2 × 107 LCTOPC1 delivered via intraparenchymal injection into the spinal cord at the site of injury using a custom-designed syringe positioning device. Low-dose tacrolimus was administered until day 60. Outcome measures included adverse event (AE) monitoring and neurological function as measured by the International Standards for Neurological Classification of Spinal Cord Injury.All 25 participants experienced at least one AE, with a total of 534 AEs (32 study-related vs 502 study-unrelated anticipated complications of SCI) reported at the completion of 1-year follow-up. There were 29 serious AEs reported. Two grade 3 serious AEs (CSF leak in one participant and a bacterial infection in another) were considered related to the injection procedure and to immunosuppression with tacrolimus, respectively. The CSF leakage resolved with sequelae, including self-limited altered mental status, and the infection resolved with antibiotic therapy. For all participants, MRI scans demonstrated no evidence of an enlarging mass, spinal cord damage related to the injection procedure, inflammatory lesions in the spinal cord, or masses in the ventricular system. At 1-year follow-up, 21/22 (96%) of the intention-to-treat group recovered one or more levels of neurological function on at least one side of their body, and 7/22 (32%) recovered two or more levels of neurological function on at least one side of their body.LCTOPC1 can be safely administered to participants in the subacute period after cervical SCI. The injection procedure, low-dose temporary immunosuppression regimen, and LCTOPC1 were well tolerated. The safety and neurological function data support further investigation to determine the efficacy of LCTOPC1 in the treatment of SCI. Clinical trial registration no.: NCT02302157 (ClinicalTrials.gov).

  View details for DOI 10.3171/2022.5.SPINE22167

  View details for PubMedID 35901693

• ONE-YEAR EFFICACY AND SAFETY OUTCOMES IN PATIENTS WITH CHRONIC TRAUMATIC BRAIN INJURY: FINAL ANALYSIS OF THE PHASE 2 STEMTRA TRIAL Weintraub, A., Okonkwo, D., Steinberg, G., Kawabori, M., Imai, H., Yasuhara, T., Kim, A., Kondziolka, D., Achrol, A., Nejadnik, B., Bates, D., McAllister, P. MARY ANN LIEBERT, INC. 2022: A80

  View details for Web of Science ID 000840122300253

• Using PET/MRI to measure cerebrovascular reactivity in Moyamoya disease Zhao, M., Fan, A., Steinberg, G., Zaharchuk, G. SAGE PUBLICATIONS INC. 2022: 84

  View details for Web of Science ID 000802263300142

• Moyamoya disease: diagnosis and interventions. The Lancet. Neurology Ihara, M., Yamamoto, Y., Hattori, Y., Liu, W., Kobayashi, H., Ishiyama, H., Yoshimoto, T., Miyawaki, S., Clausen, T., Bang, O. Y., Steinberg, G. K., Tournier-Lasserve, E., Koizumi, A. 2022

  Abstract

  Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.

  View details for DOI 10.1016/S1474-4422(22)00165-X

  View details for PubMedID 35605621

• Laparoscopic Omental-cerebral Transposition for Repeat Revascularization of Refractory Moyamoya Disease Yim, B., Bruzoni, M., Dutta, S., Gauden, A., Steinberg, G. AMER ASSOC NEUROLOGICAL SURGEONS. 2022

  View details for Web of Science ID 001132701400143

• Ten-year safety of pluripotent stem cell transplantation in acute thoracic spinal cord injury. Journal of neurosurgery. Spine McKenna, S. L., Ehsanian, R., Liu, C. Y., Steinberg, G. K., Jones, L., Lebkowski, J. S., Wirth, E., Fessler, R. G. 2022: 1-10

  Abstract

  OBJECTIVE: The purpose of this study was to evaluate the safety of oligodendrocyte progenitor cells (LCTOPC1) derived from human pluripotent stem cells administered between 7 and 14 days postinjury to patients with T3 to T11 neurologically complete spinal cord injury (SCI). The rationale for this first-in-human trial was based on evidence that administration of LCTOPC1 supports survival and potential repair of key cellular components and architecture at the SCI site.METHODS: This study was a multisite, open-label, single-arm interventional clinical trial. Participants (n = 5) received a single intraparenchymal injection of 2 * 106 LCTOPC1 caudal to the epicenter of injury using a syringe positioning device. Immunosuppression with tacrolimus was administered for a total of 60 days. Participants were followed with annual in-person examinations and MRI for 5 years at the time of this report and will be followed with annual telephone questionnaires for 6 to 15 years postinjection. The primary endpoint was safety, as measured by the frequency and severity of adverse events related to the LCTOPC1 injection, the injection procedure, and/or the concomitant immunosuppression administered. The secondary endpoint was neurological function as measured by sensory scores and lower-extremity motor scores as measured by the International Standards for Neurological Classification of Spinal Cord Injury examinations.RESULTS: No unanticipated serious adverse events related to LCTOPC1 have been reported with 98% follow-up of participants (49 of 50 annual visits) through the first 10 years of the clinical trial. There was no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation. MRI results during the long-term follow-up period in patients administered LCTOPC1 cells showed that 80% of patients demonstrated T2 signal changes consistent with the formation of a tissue matrix at the injury site.CONCLUSIONS: This study provides crucial first-in-human safety data supporting the pursuit of future human embryonic stem cell-derived therapies. While we cannot exclude the possibility of future adverse events, the experience in this trial provides evidence that this cell type can be well tolerated by patients, with an event-free period of up to 10 years. Based on the safety profile of LCTOPC1 obtained in this study, a cervical dose escalation trial was initiated (NCT02302157).

  View details for DOI 10.3171/2021.12.SPINE21622

  View details for PubMedID 35364569

• Using arterial spin labeling to measure cerebrovascular reactivity in Moyamoya disease: Insights from simultaneous PET/MRI. Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism Zhao, M. Y., Fan, A. P., Chen, D. Y., Ishii, Y., Khalighi, M. M., Moseley, M., Steinberg, G. K., Zaharchuk, G. 2022: 271678X221083471

  Abstract

  Cerebrovascular reactivity (CVR) reflects the CBF change to meet different physiological demands. The reference CVR technique is PET imaging with vasodilators but is inaccessible to most patients. DSC can measure transit time to evaluate patients suspected of stroke, but the use of gadolinium may cause side-effects. Arterial spin labeling (ASL) is a non-invasive MRI technique for CBF measurements. Here, we investigate the effectiveness of ASL with single and multiple post labeling delays (PLD) to replace PET and DSC for CVR and transit time mapping in 26 Moyamoya patients. Images were collected using simultaneous PET/MRI with acetazolamide. CVR, CBF, arterial transit time (ATT), and time-to-maximum (Tmax) were measured in different flow territories. Results showed that CVR was lower in occluded regions than normal regions (by 68±12%, 52±5%, and 56±9%, for PET, single- and multi-PLD PCASL, respectively, all p<0.05). Multi-PLD PCASL correlated slightly higher with PET (CCC=0.36 and 0.32 in affected and unaffected territories respectively). Vasodilation caused ATT to reduce by 4.5±3.1% (p<0.01) in occluded regions. ATT correlated significantly with Tmax (R2>0.35, p<0.01). Therefore, multi-PLD ASL is recommended for CVR studies due to its high agreement with the reference PET technique and the capability of measuring transit time.

  View details for DOI 10.1177/0271678X221083471

  View details for PubMedID 35236136

• Intraoperative Blood Flow Changes Predict Angiographic Outcomes After Direct Cerebral Revascularization For Moyamoya Disease Ahmed, S., Lee, H., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1161/str.53.suppl_1.TMP80

  View details for Web of Science ID 000788100600249

• Optogenetic Stimulation Of Cortico-thalamic Circuits Promotes Oligodendrogenesis In The Degenerative Thalamus After Stroke Cao, Z., Chiang, T., Kim, A., Cheng, M. Y., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1161/str.53.suppl_1.TP238

  View details for Web of Science ID 000788100600521

• Optogenetic Stimulation Effects On Cortico-thalamic Circuit Plasticity After Stroke Chiang, T., Vahdat, S., Pendharkar, A., Harvey, S., Uchino, H., Cao, Z., Kim, A., Choy, M., Chen, H., Lee, H., Cheng, M. Y., Lee, J., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2022

  View details for DOI 10.1161/str.53.suppl_1.TMP117

  View details for Web of Science ID 000788100600285

• Ten-year experience with laparoscopic pedicled omental flap for cerebral revascularization in patients with Moyamoya disease. Journal of pediatric surgery Salimi-Jazi, F., Wood, L. S., Jones, R. E., Chandler, J., Rafeeqi, T., Dutta, S., Steinberg, G., Bruzoni, M. 2022

  Abstract

  BACKGROUND: The omental flap has numerous extraperitoneal applications in reconstruction and revascularization given its favorable immunologic and angiogenic properties. In patients with Moyamoya disease, cerebral revascularization using a pedicled omental flap has proven to be a viable option following direct revascularization procedures. Historically, harvesting omentum involved laparotomy with the associated risk of complications; herein we describe outcomes from a 10-year experience of laparoscopic harvesting of pedicled omental flap for cerebral revascularization in Moyamoya patients.METHODS: A retrospective chart review was performed of all patients with Moyamoya disease who underwent laparoscopic omental cerebral transposition between 2011 and 2021. Intraoperative and postoperative complications, length of stay (LOS), and outcomes at follow-up were analyzed.RESULTS: Twenty-one patients underwent the procedure during the study period. Three intraoperative complications occurred (one segmental transverse colectomy for mesenteric injury, one converted to omental free flap, and one requiring micro anastomosis). Average overall LOS was 6±6 days, with 3±3.5 days in the ICU (mean±SD). Following discharge, complications included epigastric incisional hernia at the graft fascial exit site, recurrent neck pain at subcutaneous tunneling site, and partial scalp necrosis. One patient required subsequent direct bypass seven months after the initial procedure owing to the progression of the disease. All other patients had partial or complete resolution of symptoms.CONCLUSION: Our retrospective observational study indicates that laparoscopic pedicled omental flap mobilization and transposition is a safe and effective method of indirect cerebral revascularization in patients with Moyamoya disease.LEVEL OF EVIDENCE: N/A.

  View details for DOI 10.1016/j.jpedsurg.2022.01.023

  View details for PubMedID 35197196

• The Safety and Efficacy of Induced Hypertension and Hypervolemia in Preventing Neurological Complications After Combined Direct and Indirect Bypass in Hemorrhagic Onset Moyamoya Disease. World neurosurgery Li, Y., Wang, A. R., Steinberg, G. 1800

  Abstract

  BACKGROUND: Perioperative management of blood pressure in patients undergoing surgical revascularization for moyamoya disease (MMD) remains a controversial topic. We evaluated the safety and efficacy of induced hypertension and hypervolemia (IHH) in preventing neurological complications during the perioperative period after direct surgical revascularization in a large hemorrhagic onset moyamoya disease (HOMMD) cohort.METHODS: We retrospectively reviewed a prospectively managed departmental database of all HOMMD patients treated between 1987 and 2019. One hundred and twenty-two direct surgical revascularization patients were included in the study. Patients were separated into groups, based on presence or absence of IHH therapy, and evaluated for occurrence of 30-day risk of transient neurologic events (TNEs), ischemic, and hemorrhagic complications.RESULTS: 203 revascularization procedures were performed on 122 patients for HOMMD treatment. Nineteen TNEs (9.4% of procedures) were observed in 18 (14.8%) patients. Two patients (1.6% and 1.0% of procedures) suffered from ischemic complications and one (0.8% and 0.5% of procedures) from hemorrhagic complications. No differences between groups in the severity, duration of TNEs, nor length of hospital stay were noted. No patient in the IHH therapy group experienced a recurring TNE or readmission after discharge; however, this was not statistically significant owing to the small sample size. There were no differences in the rates of ischemic or hemorrhagic complications between groups with or without IHH therapy (p=0.46 and 0.54 respectively).CONCLUSIONS: Induced hypertension and hypervolemia appears safe in HOMMD. There were no significant differences in complication or TNE rates between the groups with or without IHH therapy. While we believe it is important to employ IHH therapy in MMD patients who present with ischemic symptoms, these findings suggest that prophylactic IHH therapy may not be necessary in MMD patients presenting with hemorrhage.

  View details for DOI 10.1016/j.wneu.2022.01.017

  View details for PubMedID 35026459

• Corrigendum: Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke. Frontiers in aging neuroscience He, J. Q., Sussman, E. S., Steinberg, G. K. 2022; 14: 875925

  Abstract

  [This corrects the article DOI: 10.3389/fnagi.2020.575990.].

  View details for DOI 10.3389/fnagi.2022.875925

  View details for PubMedID 35360207

• Application of FLOW 800 in extracranial-to-intracranial bypass surgery for moyamoya disease. Neurosurgical focus: Video Yim, B., Gauden, A. J., Steinberg, G. K. 2022; 6 (1): V16

  Abstract

  The surgical treatment of moyamoya disease is heavily reliant upon a real-time understanding of cerebral hemodynamics. The application of FLOW 800 allows the surgeon to semiquantify the degree of perfusion to the cerebral cortex following extracranial-to-intracranial (EC-IC) bypass surgery. The authors present three illustrative cases demonstrating common intraoperative findings prior to and following anastomosis using FLOW 800. All patients were diagnosed by catheter angiogram with moyamoya disease and noninvasive imaging demonstrating hemispheric hypoperfusion. Superficial temporal artery (STA)-to-middle cerebral artery (MCA or M4) bypasses were performed to augment intracranial perfusion. The patients tolerated the procedures well and were discharged without event in stable neurological condition. The video can be found here: https://stream.cadmore.media/r10.3171/2021.10.FOCVID21191.

  View details for DOI 10.3171/2021.10.FOCVID21191

  View details for PubMedID 36284597

  View details for PubMedCentralID PMC9555355

• Cavernous malformations of the hypothalamus: a single-institution series of 12 cases and review of the literature JOURNAL OF NEUROSURGERY Khahera, A. S., Li, Y., Steinberg, G. K. 2021; 135 (6): 1617-1626

  Abstract

  There remains a paucity of literature on hypothalamic cavernous malformations (HCMs). Here, the authors present the largest series of HCMs to date and review the literature to gain additional insight into this rare disease subset.A prospectively managed database was retrospectively reviewed for patients diagnosed with symptomatic HCM and treated surgically between 1987 and 2019. Data gathered included demographics, presenting signs, radiological measurements, surgical approach, and postoperative events. Functional outcome was measured using the modified Rankin Scale (mRS) and Glasgow Outcome Scale-Extended (GOSE) pre- and postoperatively. A PRISMA guideline systematic review of HCM in the literature was performed.Our cohort study consisted of 12 patients with symptomatic, and radiographically confirmed, HCM treated with microsurgery by the senior author (G.K.S.). An additional 16 surgically or conservatively managed patients were also identified from the literature, and the authors analyzed the data of all 28 patients (with 54% of patients being male; mean age 39 ± 16 years, range 10-68 years). Patients harboring HCMs most commonly presented with headache (16/28, 57%), short-term memory impairment (11/28, 39%), and gait disturbance (8/28, 32%). Radiographically, lesions most commonly involved the mammillary region (18/23, 78%), the tuberal/infundibulum region (13/23, 57%), and the preoptic/lamina terminalis region (12/23, 52%), with a mean diameter of 2.5 ± 1.4 cm (range 0.8-7 cm) at presentation. Acute hemorrhage was identified in 96% (23/24) of patients on presentation, with 96% (23/24) intraparenchymal and 29% (7/24) intraventricular. Of 24 patients who were managed surgically, gross-total resection (GTR) was achieved in 88% (21/24) of cases. There were no reports of perioperative infarction or mortality. With a mean follow-up period of 41 months (range 0.5-309 months), 77% (20/26) of patients experienced functional improvement, while 12% (3/26) had no change, and 12% (3/26) experienced increased disability. In our cohort of 12 patients, 83% (10/12) continued to report symptoms at the last follow-up (mean 4.8 years, range 0.1-25.7 years). However, there was a significant improvement in mRS score noted after surgery (mean 1.4 vs 3.1, p = 0.0026) and a trend toward improvement in GOSE score (mean 6.3 vs 5.1, p = 0.09).Hemorrhage from HCMs can cause a symptomatic mass effect on adjacent eloquent structures. While patients are unlikely to be deficit free following surgery, GTR allows for functional improvement and reduces recurrent hemorrhage rates. Microsurgery remains a viable option for symptomatic HCMs in experienced hands.

  View details for DOI 10.3171/2020.10.JNS201419

  View details for Web of Science ID 000726723700004

  View details for PubMedID 34020425

• Direct brainstem somatosensory evoked potentials for cavernous malformations. Journal of neurosurgery Le, S., Nguyen, V., Lee, L., Cho, S. C., Malvestio, C., Jones, E., Dodd, R., Steinberg, G., Lopez, J. 2021: 1-7

  Abstract

  OBJECTIVE: Brainstem cavernous malformations (CMs) often require resection due to their aggressive natural history causing hemorrhage and progressive neurological deficits. The authors report a novel intraoperative neuromonitoring technique of direct brainstem somatosensory evoked potentials (SSEPs) for functional mapping intended to help guide surgery and subsequently prevent and minimize postoperative sensory deficits.METHODS: Between 2013 and 2019 at the Stanford University Hospital, intraoperative direct brainstem stimulation of primary somatosensory pathways was attempted in 11 patients with CMs. Stimulation identified nucleus fasciculus, nucleus cuneatus, medial lemniscus, or safe corridors for incisions. SSEPs were recorded from standard scalp subdermal electrodes. Stimulation intensities required to evoke potentials ranged from 0.3 to 3.0 mA or V.RESULTS: There were a total of 1 midbrain, 6 pontine, and 4 medullary CMs-all with surrounding hemorrhage. In 7/11 cases, brainstem SSEPs were recorded and reproducible. In cases 1 and 11, peripheral median nerve and posterior tibial nerve stimulations did not produce reliable SSEPs but direct brainstem stimulation did. In 4/11 cases, stimulation around the areas of hemosiderin did not evoke reliable SSEPs. The direct brainstem SSEP technique allowed the surgeon to find safe corridors to incise the brainstem and resect the lesions.CONCLUSIONS: Direct stimulation of brainstem sensory structures with successful recording of scalp SSEPs is feasible at low stimulation intensities. This innovative technique can help the neurosurgeon clarify distorted anatomy, identify safer incision sites from which to evacuate clots and CMs, and may help reduce postoperative neurological deficits. The technique needs further refinement, but could potentially be useful to map other brainstem lesions.

  View details for DOI 10.3171/2021.7.JNS21317

  View details for PubMedID 34740189

• MRI quantification of brain oxygenation and relationship with cerebrovascular reactivity in Moyamoya disease using simultaneous [O-15]-water PET/MRI Fan, A. P., Chen, D., Shin, D. D., Zhao, M. Y., Park, J., Shen, B., Khalighi, M. M., Holley, D., Halbert, K., Steinberg, G. K., Zaharchuk, G. SAGE PUBLICATIONS INC. 2021: 64-65

  View details for Web of Science ID 000815523000045

• Surgical treatment of brainstem cavernous malformations: an international Delphi consensus. Journal of neurosurgery Dammann, P., Abla, A. A., Al-Shahi Salman, R., Andrade-Barazarte, H., Benes, V., Cenzato, M., Connolly, E. S., Cornelius, J. F., Couldwell, W. T., Sola, R. G., Gomez-Paz, S., Hauck, E., Hernesniemi, J., Kivelev, J., Lanzino, G., Macdonald, R. L., Morcos, J. J., Ogilvy, C. S., Steiger, H., Steinberg, G. K., Santos, A. N., Rauschenbach, L., Darkwah Oppong, M., Schmidt, B., Spetzler, R. F., Schaller, K., Lawton, M. T., Sure, U. 2021: 1-11

  Abstract

  OBJECTIVE: Indication for surgery in brainstem cavernous malformations (BSCMs) is based on many case series, few comparative studies, and no randomized controlled trials. The objective of this study was to seek consensus about surgical management aspects of BSCM.METHODS: A total of 29 experts were invited to participate in a multistep Delphi consensus process on the surgical treatment of BSCM.RESULTS: Twenty-two (76%) of 29 experts participated in the consensus. Qualitative analysis (content analysis) of an initial open-ended question survey resulted in 99 statements regarding surgical treatment of BSCM. By using a multistep survey with 100% participation in each round, consensus was reached on 52 (53%) of 99 statements. These were grouped into 4 categories: 1) definitions and reporting standards (7/14, 50%); 2) general and patient-related aspects (11/16, 69%); 3) anatomical-, timing of surgery-, and BSCM-related aspects (22/37, 59%); and 4) clinical situation-based decision-making (12/32, 38%). Among other things, a consensus was reached for surgical timing, handling of associated developmental venous anomalies, handling of postoperative BSCM remnants, assessment of specific anatomical BSCM localizations, and treatment decisions in typical clinical BSCM scenarios.CONCLUSIONS: A summary of typical clinical scenarios and a catalog of various BSCM- and patient-related aspects that influence the surgical treatment decision have been defined, rated, and interpreted.

  View details for DOI 10.3171/2021.3.JNS2156

  View details for PubMedID 34598135

• Increased Autoimmunity in Individuals With Down Syndrome and Moyamoya Disease FRONTIERS IN NEUROLOGY Santoro, J. D., Lee, S., Wang, A. C., Ho, E., Nagesh, D., Khoshnood, M., Tanna, R., Durazo-Arvizu, R. A., Manning, M. A., Skotko, B. G., Steinberg, G. K., Rafii, M. S. 2021; 12: 724969

  Abstract

  Objective: To determine if elevated rates of autoimmune disease are present in children with both Down syndrome and moyamoya disease given the high rates of autoimmune disease reported in both conditions and unknown etiology of angiopathy in this population. Methods: A multi-center retrospective case-control study of children with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome without cerebrovascular disease was performed. Outcome measures included presence of autoimmune disease, presence of autoantibodies and angiopathy severity data. Comparisons across groups was performed using the Kruskal-Wallis, χ2 and multivariate Poisson regression. Results: The prevalence of autoimmune disease were 57.7, 20.3, and 35.3% in persons with Down syndrome and moyamoya syndrome, idiopathic moyamoya disease, and Down syndrome only groups, respectively (p < 0.001). The prevalence of autoimmune disease among children with Down syndrome and moyamoya syndrome is 3.2 times (p < 0.001, 95% CI: 1.82-5.58) higher than the idiopathic moyamoya group and 1.5 times (p = 0.002, 95% CI: 1.17-1.99) higher than the Down syndrome only group when adjusting for age and sex. The most common autoimmune diseases were thyroid disorders, type I diabetes and Celiac disease. No individuals with idiopathic moyamoya disease had more than one type of autoimmune disorder while 15.4% of individuals with Down syndrome and moyamoya syndrome and 4.8% of individuals with Down syndrome only had >1 disorder (p = 0.05, 95%CI: 1.08-6.08). Interpretation: This study reports elevated rates of autoimmune disease in persons with Down syndrome and moyamoya syndrome providing a nidus for study of the role of autoimmunity in angiopathy in this population.

  View details for DOI 10.3389/fneur.2021.724969

  View details for Web of Science ID 000697626100001

  View details for PubMedID 34566869

  View details for PubMedCentralID PMC8455812

• Age-dependent Intracranial Artery Morphology in Healthy Children. Clinical neuroradiology Quon, J. L., Mouches, P., Kim, L. H., Jabarkheel, R., Zhang, Y., Steinberg, G. K., Grant, G. A., Edwards, M. S., Yeom, K. W., Forkert, N. D. 2021

  Abstract

  PURPOSE: Evaluation of intracranial artery morphology plays an important role in diagnosing avariety of neurovascular diseases. In addition to clinical symptoms, diagnosis currently relies on qualitative rather than quantitative evaluation of vascular imaging sequences, such as magnetic resonance angiography (MRA). However, there is a paucity of literature on normal arterial morphology in the pediatric population across brain development. We aimed to quantitatively assess normal, age-related changes in artery morphology in children.METHODS: We performed retrospective analysis of pediatric MRA data obtained from atertiary referral center. An MRA dataset from 98children (49boys/49girls) aged 0.6-20years (median =11.5years) with normal intracranial vasculature was retrospectively collected between 2011 and 2018. All arteries were automatically segmented to determine the vessel radius. Using an atlas-based approach, the average radius and density of arteries were measured in the three main cerebral vascular territories and the radius of five major arteries was determined at corresponding locations.RESULTS: The radii of the major arteries as well as the average artery radius and density in the different vascular territories in the brain remained constant throughout childhood and adolescence (|r| <0.369 in all cases).CONCLUSION: This study presents the first automated evaluation of intracranial vessel morphology on MRA across childhood. Our results can serve as aframework for quantitative evaluation of cerebral vessel morphology in the setting of pediatric neurovascular diseases.

  View details for DOI 10.1007/s00062-021-01071-9

  View details for PubMedID 34427700

• Arteriovenous Malformations-Current Understanding of the Pathogenesis with Implications for Treatment. International journal of molecular sciences Schimmel, K., Ali, M. K., Tan, S. Y., Teng, J., Do, H. M., Steinberg, G. K., Stevenson, D. A., Spiekerkoetter, E. 2021; 22 (16)

  Abstract

  Arteriovenous malformations are a vascular anomaly typically present at birth, characterized by an abnormal connection between an artery and a vein (bypassing the capillaries). These high flow lesions can vary in size and location. Therapeutic approaches are limited, and AVMs can cause significant morbidity and mortality. Here, we describe our current understanding of the pathogenesis of arteriovenous malformations based on preclinical and clinical findings. We discuss past and present accomplishments and challenges in the field and identify research gaps that need to be filled for the successful development of therapeutic strategies in the future.

  View details for DOI 10.3390/ijms22169037

  View details for PubMedID 34445743

• A neurovascular-unit-on-a-chip for the evaluation of the restorative potential of stem cell therapies for ischaemic stroke. Nature biomedical engineering Lyu, Z., Park, J., Kim, K., Jin, H., Wu, H., Rajadas, J., Kim, D., Steinberg, G. K., Lee, W. 2021

  Abstract

  The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.

  View details for DOI 10.1038/s41551-021-00744-7

  View details for PubMedID 34385693

• Stem Cells for Aging-Related Disorders. Stem cell reviews and reports Borlongan, M. C., Farooq, J., Sadanandan, N., Wang, Z., Cozene, B., Lee, J., Steinberg, G. K. 2021

  Abstract

  This review captures recent advances in biological and translational research on stem cells. In particular, we discuss new discoveries and concepts regarding stem cell treatment of aging-related disorders. A myriad of stem cell sources exists, from hematopoietic to mesenchymal and neural cell lineages. We examine current applications of exogenous adult bone marrow-derived stem cells as an effective and safe transplantable cell source, as well as the use of electrical stimulation to promote endogenous neurogenesis for Parkinson's disease. We also explore the potential of transplanting exogenous umbilical cord blood cells and mobilizing host resident stem cells in vascular dementia and aging. In addition, we assess the ability of small molecules to recruit resident stem cells in Alzheimer's disease. Finally, we evaluate mechanisms of action recently implicated in stem cell therapy, such as the role of long non-coding RNAs, G-protein coupled receptor 5, and NeuroD1. Our goal is to provide a synopsis of recent milestones regarding the application of stem cells in aging.

  View details for DOI 10.1007/s12015-021-10222-x

  View details for PubMedID 34374944

• Early Experience With Virtual and Synchronized Augmented Reality Platform for Preoperative Planning and Intraoperative Navigation: A Case Series. Operative neurosurgery (Hagerstown, Md.) Louis, R. G., Steinberg, G. K., Duma, C., Britz, G., Mehta, V., Pace, J., Selman, W., Jean, W. C. 2021

  Abstract

  BACKGROUND: Virtual reality (VR) allows for presurgical planning. Intraoperatively, augmented reality (AR) enables integration of segmented anatomic information with neuronavigation into the microsurgical scene to provide guidance without workflow disruption. Combining VR and AR solutions may help guide microsurgical technique to improve safety, efficiency, and ergonomics.OBJECTIVE: To describe a VR/AR platform that provides VR planning and intraoperative guidance via microscope ocular injection of a comprehensive AR overlay of patient-specific 360°/3D anatomic model aligned and synchronized with neuronavigation.METHODS: Custom 360° models from preoperative imaging of 49 patients were utilized for preoperative planning using a VR-based surgical rehearsal platform. Each model was imported to SyncAR, the platform's intraoperative counterpart, which was coregistered with Medtronic StealthStation S8 and Zeiss or Leica microscope. The model was injected into the microscope oculars and referenced throughout by adjusting overlay opacity. For anatomic shifts or misalignment, the overlay was reregistered via manual realignment with known landmarks.RESULTS: No SyncAR-related complications occurred. SyncAR contributed positively to the 3D understanding of patient-specific anatomy and ability to operate. Preoperative planning and intraoperative AR with 360° models allowed for more precise craniotomy planning and execution. SyncAR was useful for guiding dissection, identifying critical structures including hidden anatomy, understanding regional anatomy, and facilitating resection. Manual realignment was performed in 48/49 surgeries. Gross total resection was achieved in 34/40 surgeries. All aneurysm clipping and microvascular decompression procedures were completed without complications.CONCLUSION: SyncAR combined with VR planning has potential to enhance surgical performance by providing critical information in a user-friendly, continuously available, heads-up display format.

  View details for DOI 10.1093/ons/opab188

  View details for PubMedID 34171909

• Patient-specific virtual reality technology for complex neurosurgical cases: illustrative cases. Journal of neurosurgery. Case lessons Anthony, D., Louis, R. G., Shekhtman, Y., Steineke, T., Frempong-Boadu, A., Steinberg, G. K. 2021; 1 (23): CASE21114

  Abstract

  Virtual reality (VR) offers an interactive environment for visualizing the intimate three-dimensional (3D) relationship between a patient's pathology and surrounding anatomy. The authors present a model for using personalized VR technology, applied across the neurosurgical treatment continuum from the initial consultation to preoperative surgical planning, then to intraoperative navigation, and finally to postoperative visits, for various tumor and vascular pathologies.Five adult patients undergoing procedures for spinal cord cavernoma, clinoidal meningioma, anaplastic oligodendroglioma, giant aneurysm, and arteriovenous malformation were included. For each case, 360-degree VR (360°VR) environments developed using Surgical Theater were used for patient consultation, preoperative planning, and/or intraoperative 3D navigation. The custom 360°VR model was rendered from the patient's preoperative imaging. For two cases, the plan changed after reviewing the patient's 360°VR model from one based on conventional Digital Imaging and Communications in Medicine imaging.Live 360° visualization with Surgical Theater in conjunction with surgical navigation helped validate the decisions made intraoperatively. The 360°VR models provided visualization to better understand the lesion's 3D anatomy, as well as to plan and execute the safest patient-specific approach, rather than a less detailed, more standardized one. In all cases, preoperative planning using the patient's 360°VR model had a significant impact on the surgical approach.

  View details for DOI 10.3171/CASE21114

  View details for PubMedID 36046517

  View details for PubMedCentralID PMC9394696

• Editorial: Stem Cells and Aging FRONTIERS IN AGING NEUROSCIENCE Borlongan, C. V., Steinberg, G. K. 2021; 13: 690613

  View details for DOI 10.3389/fnagi.2021.690613

  View details for Web of Science ID 000656053200001

  View details for PubMedID 34079451

  View details for PubMedCentralID PMC8165171

• Commentary: Direct vs Indirect Revascularization in a North American Cohort of Moyamoya Disease. Neurosurgery Ahmed, S. U., Lee, H., Steinberg, G. K. 2021

  View details for DOI 10.1093/neuros/nyab165

  View details for PubMedID 33957669

• Direct and Combined Revascularization Versus Indirect Revascularization in the Treatment of Moyamoya Disease: A Systematic Review and Meta-Analysis Lee, K. S., Teo, M., Zhang, J., Steinberg, G. K. OXFORD UNIV PRESS. 2021

  View details for DOI 10.1093/bjs/znab135.011

  View details for Web of Science ID 000654739500609

• 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

• Ischemic Postconditioning Protects Against Hemorrhagic Transformation Induced by Hyperglycemia in Ischemic Stroke Chen Hansen, Cheng, M. Y., Bliss, T., Zhao Heng, Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.P781

  View details for Web of Science ID 000670883500890

• Incidence and Outcomes of Posterior Circulation Involvement in Moyamoya Disease. Tigchelaar, S. S., Wang, A., Li Yiping, Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.MP9

  View details for Web of Science ID 000670883500074

• Racial Differences in Adult Moyamoya Disease: Clinical Presentation, Angiographic Characteristics, and Outcomes After Revascularization. Wang, A. R., Li Yiping, Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.MP45

  View details for Web of Science ID 000670883500109

• Incidence and Progression of Posterior Circulation Involvement in Moyamoya Disease. Li Yiping, Wang, A. R., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.P568

  View details for Web of Science ID 000670883500683

• Decoding the Cross-Talk Between Grafted Neural Stem Cells and Host Brain to Predict the Molecular Mechanisms of Stem Cell-Induced Functional Recovery After Stroke. Tigchelaar, S. S., Azevedo-Pereira, R. L., Dong Chen, Liang Xibin, Bliss, T., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.P815

  View details for Web of Science ID 000670883500923

• Influence of Thyroid Disease on Presentation and Outcomes of Moyamoya Disease. Wang, A. R., Li Yiping, Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.P565

  View details for Web of Science ID 000670883500680

• Functional and Molecular Characterization of Endothelial and Vascular Smooth Muscle Cells Derived From Moyamoya Disease-Induced Pluripotent Stem Cells. Rao, S., Uchino, H., Pendharkar, A., Zhang Qian, Cheng, M. Y., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.P749

  View details for Web of Science ID 000670883500858

• Clinicoradiological Outcomes of Surgical Revascularization for Moyamoya Disease With Minimum 10-Year Follow-Up. Yiping, L., Wang, A. R., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2021

  View details for DOI 10.1161/str.52.suppl_1.MP47

  View details for Web of Science ID 000670883500111

• 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

• Introduction. Translational research advances in the evaluation and management of moyamoya disease. Neurosurgical focus Smith, E. R., Lanzino, G., Steinberg, G. K., Xu, B. 2021; 51 (3): E1

  View details for DOI 10.3171/2021.6.FOCUS21373

  View details for PubMedID 34469864

• Brain Arteriovenous Malformation Presurgical Planning with Open-source Horos™ Software. World neurosurgery Mandel, M., Li, Y., Figueiredo, E. G., Teixeira, M. J., Steinberg, G. K. 2021

  Abstract

  Surgical planning for treating brain arteriovenous malformations (bAVMs) is challenging because it entails visualizing 3-dimensional (3D) relationships between the nidus, its feeding and en passage arteries, and draining veins. Surgical experience in developing the capacity to mentally visualize pathological bAVM angio-architecture could be complemented by this software, and thus potentially lower the steep learning curve for understanding complex bAVM angio-architecture. We evaluated the clinical application of freely available online 3D reconstruction software in facilitating visualization of AVM angio-architecture for pre-surgical planning.Preoperative DICOM MRI/MRA images of 56 superficial bAVMs from 2013-2018 were processed using open-source software Horos™. 3D rendered images were compared with the surgical view to evaluate software accuracy and determine its value as a pre-operative tool. 3-D reconstructed images were compared to intraoperative recordings.A useful image identifying both the main feeding artery and draining vein was achieved in 35/56 cases (62.5%). Reconstructions of small AVMs (nidus ≤ 2 cm) and those located within the temporal or cerebellar cortex were less useful due to soft tissue artifacts. Frontal and parietal lobe lesions had significantly higher rates of identifying feeding arteries and draining veins (p < 0.05).Pre-surgical planning for resection of superficial bAVMs using Horos™ software allows for a comprehensive 3D analysis of the bAVM angio-architecture. This technique is most useful for frontal and parietal lobe lesions, and aids the surgeon in formulating an optimal surgical strategy. The 3D reconstruction of the brain surface offers a surgical map not influenced by brain shift.

  View details for DOI 10.1016/j.wneu.2021.09.081

  View details for PubMedID 34582999

• Acetazolamide-Challenged Arterial Spin Labeling Detects Augmented Cerebrovascular Reserve After Surgery for Moyamoya Stroke Rao, V. L., et al 2021

  View details for DOI 10.1161/STROKEAHA.121.036616

• 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

  View details for Web of Science ID 000590040201088

• 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

  View details for DOI 10.1016/j.neurad.2018.12.004

  View details for Web of Science ID 000515216000004

• 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

  View details for DOI 10.1093/neuros/nyz025

  View details for Web of Science ID 000515122000054

• 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

  View details for Web of Science ID 000590040200229

• ime-Course Characterization of Blood-Brain Barrier Disruption in Secondary Thalamic Injury After Stroke Cao, Z., Harvey, S., Pendharkar, A., Chiang, T., Cheng, M., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2020

  View details for Web of Science ID 000590040201358

• 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

• 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

• 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

• 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

• 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

• 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

• 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

  View details for Web of Science ID 000492749600297

• 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

  View details for Web of Science ID 000473954100059

• 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

  View details for Web of Science ID 000502867400113

• 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

  View details for DOI 10.1089/neu.2018.6053

  View details for Web of Science ID 000469288400001

• 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: 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 DOI 10.3389/fncel.2019.00126

  View details for PubMedID 31001088

  View details for PubMedCentralID PMC6457367

• 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

  View details for DOI 10.3389/fncel.2019.00126

  View details for Web of Science ID 000463647300001

• 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

  View details for DOI 10.3171/2018.11.PEDS18498

  View details for Web of Science ID 000462877000011

• 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

  View details for DOI 10.1016/j.jocn.2018.10.109

  View details for Web of Science ID 000460844400022

• 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

  View details for DOI 10.1016/j.jocn.2018.09.023

  View details for Web of Science ID 000460844400039

• 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

  View details for DOI 10.1161/STROKEAHA.118.023426

  View details for Web of Science ID 000469346800028

• 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

  View details for Web of Science ID 000478733402029

• 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

  View details for Web of Science ID 000478733400025

• 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

  View details for Web of Science ID 000478733400334

• 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

  View details for Web of Science ID 000478733400360

• 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

• 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

• 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

• 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

  View details for DOI 10.1016/j.jocn.2018.09.029

  View details for Web of Science ID 000457660200003

• 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 < 0.0001).ASL is highly sensitive and specific in the detection of residual cerebral AVM following SRS treatment.

  View details for PubMedID 30658138

• 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

• 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

• 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

  View details for DOI 10.1093/neuros/nyx610

  View details for Web of Science ID 000454360000027

• 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)

  View details for DOI 10.1542/peds.2018-0840

  View details for Web of Science ID 000449034300026

• 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): 2191-2199

  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 DOI 10.1161/STROKEAHA.118.021508

  View details for PubMedID 30354987

  View details for PubMedCentralID PMC6205731

• 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

  View details for DOI 10.1016/j.biomaterials.2018.06.010

  View details for Web of Science ID 000440959000006

• 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

  View details for DOI 10.1161/STROKEAHA.118.021508

  View details for Web of Science ID 000442858100035

• 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

  View details for DOI 10.23736/S0390-5616.18.04425-9

  View details for Web of Science ID 000445306900018

• 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

  View details for DOI 10.1097/SLA.0000000000002548

  View details for Web of Science ID 000435846900003

• 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

  View details for Web of Science ID 000568996400001

• 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

  View details for Web of Science ID 000568996400019

• 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

  View details for Web of Science ID 000495363500017

• 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

  View details for DOI 10.1093/neuros/nyx329

  View details for Web of Science ID 000440467800015

• 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

  View details for Web of Science ID 000401083600496

• 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

• 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-SIRPα 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

• 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

• 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

• 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 (κ = .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

• 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

• 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

  View details for Web of Science ID 000394956300329

• 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

• 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

  View details for Web of Science ID 000399956101215

• 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

  View details for Web of Science ID 000399956102235

• 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., 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 PubMedID 26564435

  View details for PubMedCentralID PMC4752884

• 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

  View details for Web of Science ID 000399956102128

• 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

  View details for Web of Science ID 000399956100067

• 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

• 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

  View details for Web of Science ID 000362668600511

• 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

• Safety of stereotactic intracranial injection of modified bone marrow-derived mesenchymal stem cells (SB623) in chronic stroke patients: A Phase 1/2A study Steinberg, G. K., Kondziolka, D., Wechsler, L., Lunsford, L. D., Kim, A. S., Johnson, J. N., Bates, D., McGrogan, M., Yankee, E. W., Schwartz, N. E. WILEY-BLACKWELL. 2015: 88

  View details for Web of Science ID 000359304000204

• Clinical improvement and cortical flair hyperintensity associated with stereotactic intracranial injection of modified bone marrow-derived mesenchymal stem cells (SB623) in chronic stroke patients Steinberg, G. K., Kondziolka, D., Wechsler, L., Lunsford, L. D., Kim, A. S., Johnson, J. N., Bates, D., McGrogan, M., Yankee, E. W., Schwartz, N. E. WILEY-BLACKWELL. 2015: 11

  View details for Web of Science ID 000359304000025

• 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

  View details for Web of Science ID 000337854400190

• 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

  View details for DOI 10.1227/NEU.0000000000000119

  View details for Web of Science ID 000489097000011

• 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

  View details for DOI 10.1227/NEU.0000000000000212

  View details for Web of Science ID 000489097000017

• 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-γ, TNF-α, IL-2, IL-1β 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

  View details for Web of Science ID 000533168000020

• 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

  View details for Web of Science ID 000329228000147

• 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

  View details for Web of Science ID 000338484000050

• 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

• 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

  View details for Web of Science ID 000327456200565

• 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

  View details for Web of Science ID 000327456200563

• 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

  View details for Web of Science ID 000327456200564

• 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 < 0.05) elevated autoantibodies in Moyamoya Disease, including those against CAMK2A, CD79A and EFNA3. Pathway analysis associated these autoantibodies with post-translational modification, neurological disease, inflammatory response, and DNA damage repair and maintenance. Using the novel functional interpolating single-nucleotide polymorphisms bioinformatics approach, we identified 6 Moyamoya Disease-associated autoantibodies against APP, GPS1, STRA13, CTNNB1, ROR1 and EDIL3. The expression of these 6 autoantibodies was validated by custom-designed reverse ELISAs for an independent group of Moyamoya Disease patients compared to patients with other cerebrovascular diseases.We report the first high-throughput analysis of autoantibodies in Moyamoya Disease, the results of which may provide valuable insight into the immune-related pathology of Moyamoya Disease and may potentially advance diagnostic clinical tools.

  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

  View details for Web of Science ID 000332068606183

• 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

  View details for Web of Science ID 000330540200265

• Monocyte-derived Macrophages Can Reduce Damage After Experimental Ischemic Stroke Nishiyama, Y., Arac, A., Bliss, T. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2013

  View details for Web of Science ID 000330540201187

• 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

  View details for Web of Science ID 000330540200433

• 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

  View details for Web of Science ID 000330540201322

• 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

  View details for Web of Science ID 000330540201336

• 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

  View details for Web of Science ID 000330540200438

• 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

  View details for Web of Science ID 000319780500016

• 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

  View details for Web of Science ID 000312658800114

• 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 GSK3β activity. After stroke, Akt activity contributes to neuronal survival while GSK3β 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 GSK3β protein levels, or the degradation of β-catenin, a substrate of GSK3β, which is consistent with previous findings that long-term treatment is required for lithium to alter GSK3β 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

• 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): 226-33

  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 GSK3β activity. After stroke, Akt activity contributes to neuronal survival while GSK3β 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 GSK3β protein levels, or the degradation of β-catenin, a substrate of GSK3β, which is consistent with previous findings that long-term treatment is required for lithium to alter GSK3β 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

  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 SIRPα, 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

  View details for Web of Science ID 000303204801225

• 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

  View details for Web of Science ID 000303204802226

• 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

• 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)-α, 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 αB-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

  View details for DOI 10.1016/j.wneu.2010.12.048

  View details for Web of Science ID 000292779600008

• 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

  View details for Web of Science ID 000287479400172

• 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

  View details for Web of Science ID 000287479400328

• 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

  View details for Web of Science ID 000287479400092

• 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

  View details for Web of Science ID 000287479401261

• 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

  View details for Web of Science ID 000287479400539

• 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

  View details for Web of Science ID 000290196600032

• 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 εPKC activity, while inhibiting ROS production, and δPKC 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-GSK3β 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)

  View details for DOI 10.1227/01.NEU.0000372319.54415.1F

  View details for Web of Science ID 000278006200072

  View details for PubMedID 20495398

• 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

  View details for DOI 10.1016/j.nbd.2010.03.001

  View details for Web of Science ID 000277648200021

• 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

  View details for Web of Science ID 000276106100136

• 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

  View details for Web of Science ID 000276106100095

• 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

  View details for Web of Science ID 000276106100131

• 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

  View details for Web of Science ID 000276106100293

• 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

  View details for Web of Science ID 000275274002422

• 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

  View details for DOI 10.1007/978-4-431-99703-0_49

  View details for Web of Science ID 000276108800049

• 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

  View details for Web of Science ID 000277419400029

• 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

  View details for Web of Science ID 000270329900188

• 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

  View details for Web of Science ID 000270329900103

• 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

  View details for Web of Science ID 000270329900675

• 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

• Monitoring The Fate of Grafted Human Embryonic Stem Cell-Derived Neural Stem Cells In Stroke Experimental Model. Daadi, M., Li, Z., Arac, A., Grueter, B. A., Wu, J. C., Malenka, R. C., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: E170

  View details for Web of Science ID 000264709500351

• 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

  View details for Web of Science ID 000264709500527

• 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

  View details for Web of Science ID 000264709500346

• 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

  View details for Web of Science ID 000264709500355

• 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

  View details for Web of Science ID 000266340800026

• 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

  View details for Web of Science ID 000266753100400

• 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–

  View details for Web of Science ID 000266340800014

• 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

  View details for Web of Science ID 000256245300023

• 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

• 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

• 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

• 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

• 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

  View details for Web of Science ID 000252726100828

• 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

  View details for Web of Science ID 000252726100088

• 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

  View details for Web of Science ID 000252726100095

• 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

  View details for Web of Science ID 000252726100112

• Ischemia-induced angiogenesis is enhanced by hCNS-SCn transplantation Horie, N., Bliss, T., Shichinohe, H., Palmer, T., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2008: 658

  View details for Web of Science ID 000252726100577

• 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

  View details for Web of Science ID 000252726100589

• 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

  View details for Web of Science ID 000252726100626

• Moyamoya disease in children - Response NEUROSURGICAL FOCUS Guzman, R., Veeravagu, A., Steinberg, G. K. 2008; 24 (2)

  View details for Web of Science ID 000256268400020

• 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

  View details for Web of Science ID 000252726100863

• 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

  View details for Web of Science ID 000252726100614

• 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

  View details for Web of Science ID 000252726100834

• 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

  View details for Web of Science ID 000252726100601

• 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

  View details for Web of Science ID 000255930500016

• 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

  View details for Web of Science ID 000244122600122

• 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

  View details for Web of Science ID 000244122600115

• 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

  View details for Web of Science ID 000244122600536

• 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

  View details for Web of Science ID 000244122600481

• 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

  View details for DOI 10.1016/j.expneurol.2006.02.034

  View details for Web of Science ID 000236866400047

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

  View details for Web of Science ID 000237128900001

• 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–

  View details for Web of Science ID 000234829800489

• 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

  View details for Web of Science ID 000234829800371

• Neural stem cells do not require CXCR4 for targeted migration toward an ischemic lesion 31st International Stroke Conference Bliss, T., Guzman, R., Sun, G. H., Rausch, H., Zou, Y. R., Palmer, T., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: 731–32

  View details for Web of Science ID 000234829800646

• Cerebral perfusion imaging in vasospasm. Neurosurgical focus Lad, S. P., Guzman, R., Kelly, M. E., Li, G., Lim, M., Lovbald, K., Steinberg, G. K. 2006; 21 (3): E7-?

  Abstract

  Vasospasm following cerebral aneurysm rupture is one of the most devastating sequelae and the most common cause of delayed ischemic neurological deficit (DIND). Because vasospasm also is the most common cause of morbidity and mortality in patients who survive the initial bleeding episode, it is imperative not only to diagnose the condition but also to predict which patients are likely to become symptomatic. The exact pathophysiology of vasospasm is complex and incompletely elucidated. Early recognition of vasospasm is essential because the timely use of several therapeutic interventions can counteract this disease and prevent the occurrence of DIND. However, the prompt implementation of these therapies depends on the ability to predict impending vasospasm or to diagnose it at its early stages. A number of techniques have been developed during the past several decades to evaluate cerebral perfusion, including positron emission tomography, xenon-enhanced computed tomography, single-photon emission computed tomography, perfusion- and diffusion-weighted magnetic resonance imaging, and perfusion computed tomography. In this article, the authors provide a general overview of the currently available perfusion imaging techniques and their applications in treating vasospasm after a patient has suffered a subarachnoid hemorrhage. The use of cerebral perfusion imaging techniques for the early detection of vasospasm is becoming more common and may provide opportunities for early therapeutic intervention to counteract vasospasm in its earliest stages and prevent the occurrence of DINDs.

  View details for PubMedID 17029346

• Hypothermia protects against cerebral ischemia by suppressing delta PKC activation Shimohata, T., Zhao, H., Steinberg, G. ELSEVIER IRELAND LTD. 2006: S64–S64

  View details for Web of Science ID 000238609700348

• The transition from hunterian ligation to intracranial aneurysm clips: a historical perspective. Neurosurgical focus Polevaya, N. V., Kalani, M. Y., Steinberg, G. K., Tse, V. C. 2006; 20 (6): E3-?

  Abstract

  The description of cerebral aneurysms dates back to antiquity. Little was known, however, about the pathological mechanisms of aneurysm formation and treatment options for this disease until 200 years ago. The modern era of aneurysm treatment began with the hunterian ligation of the proximal artery, followed by clip and coil occlusion. In this article, the authors describe the transition from conservative therapy to internal carotid artery (ICA) ligation and gradual occlusion of the ICA to the direct placement of clips on aneurysms. The driving forces and rationale behind each major advancement are summarized, and the authors attempt to predict what these innovations mean for the future of intracranial aneurysm management.

  View details for PubMedID 16819811

• Progression of unilateral Moyamoya disease: A clinical series CEREBROVASCULAR DISEASES Kelly, M. E., Bell-Stephens, T. E., Marks, M. P., Do, H. M., Steinberg, G. K. 2006; 22 (2-3): 109-115

  Abstract

  The natural history of unilateral moyamoya disease (MMD) in adult patients is not clearly described in the literature. We present a series of 18 patients with unilateral MMD and analyze the risk factors for progression to bilateral disease.A retrospective review of 157 MMD patients treated at Stanford University Medical Center from 1991 to 2005 identified 28 patients with unilateral MMD (defined as none, equivocal or mild involvement on the contralateral side).Eighteen patients (5 males and 13 females) were identified with unilateral MMD and angiographic follow-up of > or =5 months. Mean radiologic follow-up (+/- standard error of the mean) was 19.3 +/- 3.4 months and mean clinical follow-up was 24.5 +/- 3.7 months. Five patients had childhood onset MMD and 13 patients had adult onset disease. Angiographic progression from unilateral to bilateral disease was seen in 7 patients (38.9%) at a mean follow-up of 12.7 +/- 2.4 months. Four of the 7 patients had significant clinical and radiologic progression requiring surgical intervention. Five of 7 patients that progressed had adult onset MMD. The presence of equivocal or mild stenotic changes of the contralateral anterior cerebral artery (ACA), middle cerebral artery (MCA) or internal carotid artery (ICA) was an important predictor of progression (p < 0.01); 6 of 8 patients (75%) with equivocal or mild contralateral disease progressed, whereas only 1 of 10 patients (10.0%) with no initial contralateral disease progressed to bilateral MMD. One patient had mild or equivocal MCA, ICA and ACA stenosis at the time of initial diagnosis and this patient progressed.Contralateral progression in the adult form occurs more commonly than previously reported. The presence of minor changes in the contralateral ACA, intracranial ICA and MCA is an important predictor of increased risk of progression. Patients with a completely normal angiogram on the contralateral side have a very low risk of progression.

  View details for DOI 10.1159/000093238

  View details for PubMedID 16685122

• Neurogenesis in rats after focal cerebral ischemia is enhanced by indomethacin STROKE Hoehn, B. D., Palmer, T. D., Steinberg, G. K. 2005; 36 (12): 2718-2724

  Abstract

  Newborn cells may participate in repair following ischemic brain injury, but their survival and function may be influenced by inflammation.We investigated the effects of indomethacin, a nonsteroidal antiinflammatory drug, on the fate of newborn cells following transient focal ischemia.Bromodeoxyuridine (BrdU)-labeled cells, including migrating neuroblasts, were observed in the neighboring striatum and overlying cortex 1 day poststroke. The density of BrdU+ cells labeled with doublecortin, nestin, glial fibrillary acidic protein, or NG2 was increased at 14 and 28 days. Indomethacin increased BrdU+ cells of all lineages and reduced microglial/monocyte activation.Indomethacin enhanced the accumulation of newborn cells following stroke.

  View details for DOI 10.1161/01.STR.0000190020.30282.cc

  View details for Web of Science ID 000233452400047

  View details for PubMedID 16282546

• Akt contributes to neuroprotection by hypothermia against cerebral ischemia in rats JOURNAL OF NEUROSCIENCE Zhao, H., Shimohata, T., Wang, J. Q., Sun, G. H., Schaal, D. W., Sapolsky, R. M., Steinberg, G. K. 2005; 25 (42): 9794-9806

  Abstract

  Activation of the Akt/protein kinase B (PKB) kinase pathway can be neuroprotective after stroke. Akt is activated by growth factors via a phosphorylation-dependent pathway involving the kinases phosphoinositide 3 (PI3) kinase and phosphoinositide-dependent protein kinase-1 (PDK1) and is negatively regulated by phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Akt kinase blocks apoptosis by phosphorylating the substrates forkhead transcription factor (FKHR) and glycogen synthase kinase 3beta (GSK3beta). We found that intra-ischemic hypothermia (30 degrees C) reduced infarct size and improved functional outcomes up to 2 months. Changes in phosphorylation levels of Akt, as measured by Western blots and immunostaining, differed from levels of Akt activity measured in an in vitro assay in normothermic animals. Hypothermia blocked most of these changes and maintained Akt activity. Inhibition of PI3/Akt enlarged infarct size in hypothermic animals. Hypothermia improved phosphorylation of PDK1, PTEN, and FKHR. Hypothermia did not improve GSK3beta (Ser9) phosphorylation but blocked the nuclear translocation of phosphorylated beta-catenin (Ser33/37/Thr41) downstream of GSK3beta. Phosphorylation levels of PTEN, Akt, and Akt substrate decreased before apoptotic cytochrome c release and degradation of microtubule-associated protein-2, a marker of neuronal survival. Hypothermia may protect from ischemic damage in part by preserving Akt activity and attenuating the apoptotic effects of PTEN, PDK1, and FKHR.

  View details for DOI 10.1523/JNEUROSCI.3163-05.2005

  View details for Web of Science ID 000232669300024

  View details for PubMedID 16237183

• Visual field preservation after curative multi-modality treatment of occipital lobe artemovenous malformations NEUROSURGERY Sinclair, J., Marks, M. P., Levy, R. P., Adler, J. R., Chang, S. D., Lopez, J. R., Do, H. M., Bell-Stephens, T. E., Lim, M., Steinberg, G. K. 2005; 57 (4): 655-666

  Abstract

  Occipital lobe arteriovenous malformations (AVMs) provide challenging management decisions because of their proximity to the visual cortex and optic radiations. Preservation of visual function throughout treatment is the mainstay of therapeutic planning. We reviewed visual field (VF) outcomes of all patients who received curative treatment for occipital AVMs at Stanford University to evaluate the efficacy of different treatment strategies.We conducted a retrospective review of 55 patients with occipital AVMs treated at Stanford University between 1984 and 2003. Clinical presentation, AVM morphology, and treatment modality were correlated with VF function before and after therapeutic intervention.Of 55 patients, 48 (87.3%) underwent multimodality AVM treatment (7 patients < 3 yr from radiosurgery were excluded from final analysis). One patient died from intracerebral hemorrhage 11 months post-radiosurgery, and five patients deferred further treatment. Forty-two patients (87.5%) were cured, with no residual AVM on final angiography. Curative therapeutic modalities used included embolization alone (2 patients), microsurgery alone (6 patients), microsurgery with radiosurgery (1 patient), microsurgery with embolization (23 patients), radiosurgery with embolization (4 patients), and embolization with radiosurgery and microsurgery (6 patients). Mean follow-up was 5.8 years including treatment. VF follow-up was available in all 42 patients. Twenty-eight (66.7%) patients experienced no change in VFs, six (14.3%) patients with previously abnormal VFs improved, and eight (19.0%) patients showed worsening of VFs (although none developed a new homonymous VF deficit). Duration of treatment was related to VF outcome in patients who presented without a history of AVM-related hemorrhage.Occipital AVMs can be safely cured using multimodality strategies with minimal risk to visual function despite the proximity of these lesions to the visual cortex and associated pathways.

  View details for DOI 10.1227/01.NEU.0000175547.05291.85

  View details for PubMedID 16239877

• Paradoxical cerebral herniation secondary to lumbar puncture after decompressive craniectomy for large space-occupying hemispheric stroke: Case report NEUROSURGERY Oyelese, A. A., Steinberg, G. K., Huhn, S. L., Wijman, C. A. 2005; 57 (3): 594-594

  View details for DOI 10.1227/01.NEU.0000170437.79760DF

  View details for Web of Science ID 000231782400039

• Paradoxical cerebral herniation secondary to lumbar puncture after decompressive craniectomy for a large space-occupying hemispheric stroke: case report. Neurosurgery Oyelese, A. A., Steinberg, G. K., Huhn, S. L., Wijman, C. A. 2005; 57 (3): E594-?

  Abstract

  The risk of transtentorial herniation after removal of cerebrospinal fluid from the lumbar cistern in the setting of a supratentorial lesion with significant mass effect, increased cerebrospinal fluid pressure, or midline shift is well known. We report a case of cerebral herniation from intracranial hypotension (so-called paradoxical herniation) secondary to a lumbar puncture 1 month after decompressive hemicraniectomy for a large right hemispheric stroke.A 50-year-old woman was transferred to our neurosurgical service for obtundation 4 days after a lumbar puncture to rule out meningitis and 1 month after decompressive craniectomy for a large right hemispheric stroke.Eighty grams of mannitol was administered before transfer. On arrival at our hospital, the patient was intubated and a computed tomographic scan was performed. The patient was diagnosed with low-pressure herniation after review of the computed tomographic scan. Rehydration was initiated, and the patient was placed in the Trendelenburg position. She became easier to arouse, but her pupils remained dilated. She experienced a sudden severe cardiac arrhythmia leading to a cardiac arrest. Attempted resuscitation was unsuccessful, and the patient was pronounced dead.Lumbar punctures may result in lethal intracranial hypotension in patients after hemicraniectomy and are thus contraindicated unless care is taken to remove the pressure gradient of atmospheric air across the lumbar cistern.

  View details for PubMedID 16145506

• Biphasic cytochrome c release after transient global ischemia and its inhibition by hypothermia JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Zhao, H., Yenari, M. A., Cheng, D., Sapolsky, R. M., Steinberg, G. K. 2005; 25 (9): 1119-1129

  Abstract

  Hypothermia is effective in preventing ischemic damage. A caspase-dependent apoptotic pathway is involved in ischemic damage, but how hypothermia inhibits this pathway after global cerebral ischemia has not been well explored. It was determined whether hypothermia protects the brain by altering cytochrome c release and caspase activity. Cerebral ischemia was produced by two-vessel occlusion plus hypotension for 10 mins. Body temperature in hypothermic animals was reduced to 33 degrees C before ischemia onset and maintained for 3 h after reperfusion. Western blots of subcellular fractions revealed biphasic cytosolic cytochrome c release, with an initial peak at about 5 h after ischemia, which decreased at 12 to 24 h, and a second, larger peak at 48 h. Caspase-3 and -9 activity increased at 12 and 24 h. A caspase inhibitor, Z-DEVD-FMK, administered 5 and 24 h after ischemia onset, protected hippocampal CA1 neurons from injury and blocked the second cytochrome c peak, suggesting that caspases mediate this second phase. Hypothermia (33 degrees C), which prevented CA1 injury, did not inhibit cytochrome c release at 5 h, but reduced cytochrome c release at 48 h. Caspase-3 and -9 activity was markedly attenuated by hypothermia at 12 and 24 h. Thus, biphasic cytochrome c release occurs after transient global ischemia and mild hypothermia protects against ischemic damage by blocking the second phase of cytochrome c release, possibly by blocking caspase activity.

  View details for DOI 10.1038/sj.jcbfm.9600111

  View details for Web of Science ID 000231576100003

  View details for PubMedID 15789032

• Neurotransplantation for patients with subcortical motor stroke: a Phase 2 randomized trial JOURNAL OF NEUROSURGERY Kondziolka, D., Steinberg, G. K., Wechsler, L., Meltzer, C. C., Elder, E., Gebel, J., DeCesare, S., Jovin, T., Zafonte, R., Lebowitz, J., Flickinger, J. C., Tong, D., Marks, M. P., Jamieson, C., Luu, D., Bell-Stephens, T., Teraoka, J. 2005; 103 (1): 38-45

  Abstract

  No definitive treatment exists to restore lost brain function following a stroke. Transplantation of cultured neuronal cells has been shown to be safe and effective in animal models of stroke and safe in a Phase 1 human trial. In the present study the authors tested the usefulness of human neuron transplantation followed by participation in a 2-month stroke rehabilitation program compared with rehabilitation alone in patients with substantial fixed motor deficits associated with a basal ganglia stroke.Human neuronal cells (LBS-Neurons; Layton BioScience, Inc.) were delivered frozen and then thawed and formulated on the morning of surgery. The entry criteria in this randomized, observer-blinded trial of 18 patients included age between 18 and 75 years, completed stroke duration of 1 to 6 years, presence of a fixed motor deficit that was stable for at least 2 months, and no contraindications to stereotactic surgery. Patients were randomized at two centers to receive either 5 or 10 million implanted cells in 25 sites (seven patients per group) followed by participation in a stroke rehabilitation program, or to serve as a nonsurgical control group (rehabilitation only; four patients). The surgical techniques used were the same at both centers. All patients underwent extensive pre- and postoperative motor testing and imaging. Patients received cyclosporine A for 1 week before and 6 months after surgery. The primary efficacy measure was a change in the European Stroke Scale (ESS) motor score at 6 months. Secondary outcomes included Fugl-Meyer, Action Research Arm Test, and Stroke Impact Scale scores, as well as the results of other motor tests. Nine strokes were ischemic in origin and nine were hemorrhagic. All 14 patients who underwent surgery (ages 40-70 years) underwent uncomplicated surgeries. Serial evaluations (maximum duration 24 months) demonstrated no cell-related adverse serological or imaging-defined effects. One patient suffered a single seizure, another had a syncopal event, and in another there was burr-hole drainage of an asymptomatic chronic subdural hematoma. Four of seven patients who received 5 million cells (mean improvement 6.9 points) and two of seven who received 10 million cells had improved ESS scores at 6 months; however, there was no significant change in the ESS motor score in patients who received cell implants (p = 0.756) compared with control or baseline values (p = 0.06). Compared with baseline, wrist movement and hand movement scores recorded on the Fugl-Meyer Stroke Assessment instrument were not improved (p = 0.06). The Action Research Arm Test gross hand-movement scores improved compared with control (p = 0.017) and baseline (p = 0.001) values. On the Stroke Impact Scale, the 6-month daily activities score changed compared with baseline (p = 0.045) but not control (p = 0.056) scores, and the Everyday Memory test score improved in comparison with baseline (p = 0.004) values.Human neuronal cells can be produced in culture and implanted stereotactically into the brains of patients with motor deficits due to stroke. Although a measurable improvement was noted in some patients and this translated into improved activities of daily living in some patients as well, this study did not find evidence of a significant benefit in motor function as determined by the primary outcome measure. This experimental trial indicates the safety and feasibility of neuron transplantation for patients with motor stroke.

  View details for Web of Science ID 000231000200011

  View details for PubMedID 16121971

• Neural transplantation - Response JOURNAL OF NEUROSURGERY Kondziolka, D., Wechsler, L., Steinberg, G. K. 2005; 103 (1): 8

  View details for Web of Science ID 000231000200006

• Intracranial Angioplasty without stenting for symptomatic atherosclerotic stenosis: Long-term follow-up AMERICAN JOURNAL OF NEURORADIOLOGY Marks, M. P., Marcellus, M. L., Do, H. M., Schraedley-Desmond, P. K., Steinberg, G. K., Tong, D. C., Albers, G. W. 2005; 26 (3): 525-530

  Abstract

  Angioplasty and stent placement have been reported for the treatment of intracranial stenosis. This study was undertaken to assess the efficacy and long-term clinical outcome of angioplasty without stent placement for patients with symptomatic intracranial stenosis.A retrospective study was done to evaluate 36 patients with 37 symptomatic atherosclerotic intracranial stenosis who underwent primary balloon angioplasty. All patients had symptoms despite medical therapy. Thirty-four patients were available for follow-up ranging from 6 to 128 months. Mean follow-up was 52.9 months.Mean pretreatment stenosis was 84.2% before angioplasty and 43.3% after angioplasty. The periprocedural death and stroke rate was 8.3% (two deaths and one minor stroke). Two patients had strokes in the territory of angioplasty at 2 and 37 months after angioplasty. The annual stroke rate in the territory appropriate to the site of angioplasty was 3.36%, and for those patients with a residual stenosis of > or =50% it was 4.5%. Patients with iatrogenic dissection (n=11) did not have transient ischemic attacks or strokes after treatment.Results of long-term follow-up suggest that intracranial angioplasty without stent placement reduces the risk of further stroke in symptomatic patients.

  View details for PubMedID 15760860

• Revascularization of the posterior circulation SKULL BASE-AN INTERDISCIPLINARY APPROACH Coert, B. A., Chang, S. D., Marks, M. P., Steinberg, G. K. 2005; 15 (1): 43-62

  Abstract

  The primary objective of revascularization procedures in the posterior circulation is the prevention of vertebrobasilar ischemic stroke. Specific anatomical and neurophysiologic characteristics such as posterior communicating artery size affect the susceptibility to ischemia. Current indications for revascularization include symptomatic vertebrobasilar ischemia refractory to medical therapy and ischemia caused by parent vessel occlusion as treatment for complex aneurysms. Treatment options include endovascular angioplasty and stenting, surgical endarterectomy, arterial reimplantation, extracranial-to-intracranial anastomosis, and indirect bypasses. Pretreatment studies including cerebral blood flow measurements with assessment of hemodynamic reserve can affect treatment decisions. Careful blood pressure regulation, neurophysiologic monitoring, and neuroprotective measures such as mild brain hypothermia can help minimize the risks of intervention. Microscope, microinstruments and intraoperative Doppler are routinely used. The superficial temporal artery, occipital artery, and external carotid artery can be used to augment blood flow to the superior cerebellar artery, posterior cerebral artery, posterior inferior cerebellar artery, or anterior inferior cerebellar artery. Interposition venous or arterial grafts can be used to increase length. Several published series report improvement or relief of symptoms in 60 to 100% of patients with a reduction of risk of future stroke and low complication rates.

  View details for PubMedID 16148983

• Stroke initiates targeted migration of transplanted iron-labeled neural progenitor cells as revealed by magnetic resonance imaging Guzman, R., Bliss, T., Greve, J., Palmer, T., Sun, G. H., Moseley, M., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2005: 469

  View details for Web of Science ID 000227523800257

• Conditions of protection by hypothermia on apoptotic pathways in a model of permanent middle cerebral artery occlusion Zhao, H., Wang, J. Q., Sun, G. H., Yenari, M. A., Sapolsky, R. M., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2005: 512

  View details for Web of Science ID 000227523800480

• Hypothermia attenuates the decrease in phosphorylation of proteins in AKT cell signal pathway after permanent middle cerebral artery occlusion in rats 30th International Stroke Conference Zhao, H., Shimohata, T., Wang, J. Q., Sun, G. H., Yenari, M. A., Sapolsky, R. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2005: 514–14

  View details for Web of Science ID 000227523800492

• Characterization of avb3 integrin in vascular malformations 30th International Stroke Conference Lim, M., Harsh, G., Haddix, T., Vogel, H., Chu, P. L., Steinberg, G., Guccione, S. LIPPINCOTT WILLIAMS & WILKINS. 2005: 517–17

  View details for Web of Science ID 000227523800504

• Mild intraoperative hypothermia during surgery for intracranial aneurysm NEW ENGLAND JOURNAL OF MEDICINE Todd, M. M., Hindman, B. J., Clarke, W. R., Torner, J. C., Todd, M., Hindman, B., Clarke, W., Chaloner, K., Torner, J., Davis, P., Howard, M., Tranel, D., Anderson, S., Todd, M., Hindman, B., Weeks, J., Moss, L., Winn, J., Clarke, W., Chaloner, K., Wichman, M., Peters, R., Hansen, M., Anderson, D., Lang, J., Yoo, B., Adams, H., Clifton, G., Gelb, A., Loftus, C., Schubert, A., Warner, D., Young, W., Frankowski, R., Kieburtz, K., Prough, D., Sternau, L., Marler, J., Moy, C., Matta, B., Kirkpatrick, P., Chatfield, D., Skilbeck, C., Kirollos, R., Rasulo, F., English, K., Duffy, C., Pedersen, K., Scurrah, N., Burnstein, R., Prabhu, A., Salmond, C., Blackwell, A., Birrell, J., Jackson, S., Kassell, N., Pajewski, T., Fraley, H., Morris, A., Alden, T., Shaffrey, M., Bogdonoff, D., Durieux, M., Zuo, Z., Littlewood, K., Nemergut, E., Bedford, R., Stone, D., Balestrieri, P., Mason, J., Henry, G., Ting, P., Shafer, J., Blount, T., Kim, L., James, A., Farace, E., Clark, L., Irons, M., Sasaki, T., Webb, K., Short, T., Mee, E., Ormrod, J., Jane, J., Alden, T., Heppner, P., Olson, S., Ellegala, D., Lind, C., Sheehan, J., Woodfield, M., Law, A., Harrison, M., DAVIES, P., Campbell, D., Robertson, N., Fry, R., Sage, D., Laurent, S., Bradfield, C., Pedersen, K., Smith, K., Young, Y., Chambers, C., Hodkinson, B., Biddulph, J., Jensen, L., Ogden, J., Thayer, Z., Lee, F., Crump, S., Quaedackers, J., Wray, A., Roelfsema, V., Greif, R., Kleinpeter, G., Lothaller, C., Knosp, E., Pfisterer, W., Schatzer, R., Salem, C., Kutalek, W., Tuerkkan, E., Koller, L., Weber, T., Buchmann, A., Merhaut, C., Graf, M., Rapf, B., Lam, A., NEWELL, D., Tanzi, P., Lee, L., Domino, K., Vavilala, M., Bramhall, J., Souter, M., Britz, G., Winn, H., Bybee, H., Costello, T., Murphy, M., Harris, K., Thien, C., Nye, D., Han, T., McNeill, P., O'Brien, B., Cormack, J., Wyss, A., Grauer, R., Popovic, R., Jones, S., Deam, R., Heard, G., Watson, R., Evered, L., Bardenhagen, F., Meade, C., Haartsen, J., Kruger, J., Wilson, M., Maktabi, M., Traynelis, V., McAllister, A., Leonard, P., Hindman, B., Brian, J., Mensink, F., From, R., Papworth, D., Schmid, P., Dehring, D., Howard, M., Hitchon, P., VanGilder, J., Weeks, J., Moss, L., Manzel, K., Anderson, S., Tack, R., Taggard, D., Lennarson, P., Menhusen, M., Gelb, A., Lownie, S., Craen, R., Novick, T., Ferguson, G., Duggal, N., Findlay, J., Ng, W., Cowie, D., Badner, N., Herrick, I., Smith, H., Heard, G., Peterson, R., Howell, J., Lindsey, L., Carriere, L., von Lewinski, M., Schaefer, B., Bisnaire, D., Doyle-Pettypiece, P., McTaggart, M., Giannotta, S., Zelman, V., Thomson, E., Babayan, E., McCleary, C., Fishback, D., Samra, S., Thompson, B., Chandler, W., McGillicuddy, J., Tremper, K., Turner, C., Smythe, P., Dy, E., Pai, S., Portman, V., Palmisano, J., Auer, D., Quigley, M., Giordani, B., Freymuth, A., Scott, P., Silbergleit, R., Hickenbottom, S., Litt, L., Lawton, M., Hannegan, L., Gupta, D., Bickler, P., Dodson, B., Talke, P., Rampil, I., Chen, B., Wright, P., Mitchell, J., Ryan, S., Walker, J., Quinnine, N., Applebury, C., Myles, P., Rosenfeld, J., Hunt, J., Wallace, S., D'Urso, P., Thien, C., McMahon, J., Wadanamby, S., Siu, K., Malham, G., Laidlaw, J., Salerno, S., Alatakis, S., Madder, H., Cairo, S., Konstantatos, A., Smart, J., Lindholm, D., Bain, D., Machlin, H., Moloney, J., Buckland, M., Silvers, A., Downey, G., Molnar, A., Langley, M., McIlroy, D., Daly, D., Bennett, P., Forlano, L., Testa, R., Burnett, W., Johnson, F., Angliss, M., Fletcher, H., Manninen, P., Wallace, M., Lukitto, K., Tymianski, M., Porter, P., Gentili, F., El-Beheiry, H., Mosa, M., Mak, P., Balki, M., Shaikh, S., Sawyer, R., Quader, K., Chelliah, R., Berklayd, P., Merah, N., Ghazali, G., McAndrews, M., Ridgley, J., Odukoya, O., Yantha, S., Wilson, J., Petrozza, P., Miller, C., O'Brien, K., Tong, C., Olympio, M., Reynolds, J., Colonna, D., Glazier, S., Nobles, S., Hill, D., Hulbert, H., Jenkins, W., Lanier, W., Piepgras, D., Wilson, R., Meyer, F., Atkinson, J., Link, M., Weglinski, M., Berge, K., McGregor, D., Trenerry, M., Smith, G., Walkes, J., Felmlee-Devine, M., Van Aken, H., Greiner, C., Freise, H., Brors, H., Hahnenkamp, K., de Oliveira, N. M., Schul, C., Moskopp, D., Greiner, C., Woelfer, J., Hoenemann, C., Gramke, H., Bone, H., Gibmeier, I., Wirtz, S., Lohmann, H., Freyhoff, J., Bauer, B., Hogan, K., Dempsey, R., Rusy, D., Badie, B., Iskandar, B., Resnick, D., Deshmukh, P., Fitzpatrick, J., Sasse, F., Broderick, T., Willmann, K., Connery, L., Kish, J., Weasler, C., Page, N., Hermann, B., Jones, J., Dulli, D., Stanko, H., Geraghty, M., Elbe, R., Salevsky, F., Leblanc, R., Lapointe, N., MacGregor, H., Sinclair, D., Sirhan, D., Maleki, M., Abou-Madi, M., Chartrand, D., Angle, M., Milovan, D., Painchaud, Y., Mirski, M., Tamargo, R., Rice, S., Olivi, A., Kim, D., Rigamonti, D., Naff, N., Hemstreet, M., Berkow, L., Chery, P., Ulatowski, J., Moore, L., CUNNINGHAM, T., McBee, N., Hartman, T., Heidler, J., HILLIS, A., Tuffiash, E., Chase, C., Kane, A., Greene-Chandos, D., Torbey, M., Ziai, W., Lane, K., Bhardwaj, A., Subhas, N., Schubert, A., Mayberg, M., Beven, M., Rasmussen, P., Bhatia, S., Ebrahim, Z., Lotto, M., Vasarhelyi, F., Munis, J., GRAVES, K., Woletz, J., Chelune, G., Samples, S., Evans, J., Blair, D., Abou-Chebl, A., Shutway, F., Manke, D., Beven, C., Fogarty-Mack, P., Stieg, P., Eliazo, R., Li, P., Riina, H., Lien, C., Ravdin, L., Wang, J., Kuo, Y., Jaffe, R., Steinberg, G., Luu, D., Chang, S., Giffard, R., Lemmens, H., Morgan, R., Mathur, A., Angst, M., Meyer, A., Yi, H., Karzmark, P., Bell-Stephens, T., Marcellus, M., Sneyd, J., Pobereskin, L., Salsbury, S., Whitfield, P., Sawyer, R., Dashfield, A., Struthers, R., DAVIES, P., Rushton, A., Petty, V., Harding, S., Richardson, E., Yonas, H., Gyulai, F., Kirby, L., Kassam, A., Bircher, N., Meng, L., Krugh, J., Seever, G., Hendrickson, R., Gebel, J., Cowie, D., Fabinyi, G., Poustie, S., Davis, G., Drnda, A., Chandrasekara, D., Sturm, J., Phan, T., Shelton, A., Clausen, M., Micallef, S., Sills, A., Steinman, F., Sutton, P., Sanders, J., Van Alstine, D., Leggett, D., Cunningham, E., Hamm, W., Frankel, B., Sorenson, J., Atkins, L., Redmond, A., Dalrymple, S., Black, S., Fisher, W., Hall, C., Wilhite, D., Moore, T., Blanton, I. P., Sha, Z., Szmuk, P., Kim, D., Ashtari, A., Hagberg, C., Matuszczak, M., Shahen, A., Moise, O., Novy, D., Govindaraj, R., Jameson, L., Breeze, R., Awad, I., Mattison, R., ANDERSON, T., Salvia, L., Mosier, M., Loftus, C., Smith, J., Lilley, W., White, B., Lenaerts, M. 2005; 352 (2): 135-145

  Abstract

  Surgery for intracranial aneurysm often results in postoperative neurologic deficits. We conducted a randomized trial at 30 centers to determine whether intraoperative cooling during open craniotomy would improve the outcome among patients with acute aneurysmal subarachnoid hemorrhage.A total of 1001 patients with a preoperative World Federation of Neurological Surgeons score of I, II, or III ("good-grade patients"), who had had a subarachnoid hemorrhage no more than 14 days before planned surgical aneurysm clipping, were randomly assigned to intraoperative hypothermia (target temperature, 33 degrees C, with the use of surface cooling techniques) or normothermia (target temperature, 36.5 degrees C). Patients were followed closely postoperatively and examined approximately 90 days after surgery, at which time a Glasgow Outcome Score was assigned.There were no significant differences between the group assigned to intraoperative hypothermia and the group assigned to normothermia in the duration of stay in the intensive care unit, the total length of hospitalization, the rates of death at follow-up (6 percent in both groups), or the destination at discharge (home or another hospital, among surviving patients). At the final follow-up, 329 of 499 patients in the hypothermia group had a Glasgow Outcome Score of 1 (good outcome), as compared with 314 of 501 patients in the normothermia group (66 percent vs. 63 percent; odds ratio, 1.14; 95 percent confidence interval, 0.88 to 1.48; P=0.32). Postoperative bacteremia was more common in the hypothermia group than in the normothermia group (5 percent vs. 3 percent, P=0.05).Intraoperative hypothermia did not improve the neurologic outcome after craniotomy among good-grade patients with aneurysmal subarachnoid hemorrhage.

  View details for Web of Science ID 000226251700006

  View details for PubMedID 15647576

• Mild hypothermia decreases GSK3 beta expression following global cerebral ischemia NEUROCRITICAL CARE Kelly, S., Cheng, D. Y., Steinberg, G. K., Yenari, M. A. 2005; 2 (2): 212-217

  Abstract

  The serine/threonine kinase glycogen synthase kinase 3beta (GSK3beta) is abundant in the central nervous system and is neuron-specific. GSK3beta plays a pivotal role in the regulation of numerous cellular functions (including phosphorylation) and, thereby, regulation of many metabolic, signaling, and structural proteins as well as transcription factors that can influence cell survival. This article reports that GSK3beta expression following global cerebral ischemia (GCI) is altered by the neuroprotectant, mild hypothermia (33 degrees C).Male Sprague-Dawley rats were anesthetized and subjected to GCI; arterial blood pressure was reduced to 30 mmHg by blood withdrawal via the jugular vein, and both common carotid arteries were occluded with aneurysm clips for 8 minutes. Hypothermia (33 degrees C) was induced in half the rats 10 minutes prior to GCI and was maintained for 3 hours. Rats were killed 24 or 72 hours later to assess cell death and GSK3beta expression.At 72 hours post-GCI, levels of GSK3beta expression were significantly lower in hypothermic rats than in normothermic rats. This reduction in GSK3beta correlated with marked neuroprotection and reduced terminal deoxynucleotidyl transferase-mediated uridine 5'-triphosphate-biotin nick end labeling staining in hippocampal CA1 neurons. No significant changes in phosphorylated GSK3beta expression were observed.These data suggest that GSK3beta plays a role in GCI pathology that can be altered by mild hypothermia.

  View details for DOI 10.1385/Neurocrit.Care2005;2:212-217

  View details for Web of Science ID 000230639100018

  View details for PubMedID 16159068

• Characterization of the integrin alpha v beta 3 in arteriovenous malformations and cavernous malformations CEREBROVASCULAR DISEASES Lim, M., Haddix, T., Harsh, G. R., Vogel, H., Steinberg, G. K., Guccione, S. 2005; 20 (1): 23-27

  Abstract

  Alpha V beta 3 (alphavbeta3) is an integrin specifically expressed on the endothelial cells of central nervous system (CNS) neoplasms. However, no data exist on the expression of alphavbeta3 in vascular malformations of the CNS. In this study, we investigate the expression of alphavbeta3 in arteriovenous malformations (AVMs) and cavernous malformations (CMs).Frozen samples of AVMs from 12 patients and CMs from 5 patients were obtained intraoperatively. Once the final pathology had been confirmed, immunohistochemistry was performed using an antibody to the integrin alphavbeta3. The alphavbeta3 expression pattern was graded according to the percentage of positively staining vessels.Ten of 12 AVMs demonstrated alphavbeta3 immunopositivity. Six of these 10 AVMs had moderate or strong staining. Most notably, 5 of the 6 moderate or strongly staining AVMs came from patients 22 years of age or younger. Four of these 6 AVMs had previously been embolized. None of the cavernous malformations demonstrated alphavbeta3 immunopositivity.alphavbeta3 may contribute to the formation of AVMs in younger patients. alphavbeta3 may also provide a potential therapeutic target. The lack of alphavbeta3 expression in cavernous malformations, despite their high vascular densities, suggests that the pathophysiology of their formation differs from that of AVMs.

  View details for DOI 10.1159/000086123

  View details for PubMedID 15925879

• Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Kelly, S., Bliss, T. M., Shah, A. K., Sun, G. H., Ma, M., Foo, W. C., Masel, J., Yenari, M. A., Weissman, I. L., Uchida, N., Palmer, T., Steinberg, G. K. 2004; 101 (32): 11839-11844

  Abstract

  We characterize the survival, migration, and differentiation of human neurospheres derived from CNS stem cells transplanted into the ischemic cortex of rats 7 days after distal middle cerebral artery occlusion. Transplanted neurospheres survived robustly in naive and ischemic brains 4 wk posttransplant. Survival was influenced by proximity of the graft to the stroke lesion and was negatively correlated with the number of IB4-positive inflammatory cells. Targeted migration of the human cells was seen in ischemic animals, with many human cells migrating long distances ( approximately 1.2 mm) predominantly toward the lesion; in naive rats, cells migrated radially from the injection site in smaller number and over shorter distances (0.2 mm). The majority of migrating cells in ischemic rats had a neuronal phenotype. Migrating cells between the graft and the lesion expressed the neuroblast marker doublecortin, whereas human cells at the lesion border expressed the immature neuronal marker beta-tubulin, although a small percentage of cells at the lesion border also expressed glial fibrillary acid protein (GFAP). Thus, transplanted human CNS (hCNS)-derived neurospheres survived robustly in naive and ischemic brains, and the microenvironment influenced their migration and fate.

  View details for DOI 10.1073/pnas.0404474101

  View details for Web of Science ID 000223276700056

  View details for PubMedID 15280535

  View details for PubMedCentralID PMC511061

• Protein kinase C delta mediates cerebral reperfusion injury in vivo JOURNAL OF NEUROSCIENCE Bright, R., Raval, A. P., Dembner, J. M., Perez-Pinzon, M. A., Steinberg, G. K., Yenari, M. A., Mochly-Rosen, D. 2004; 24 (31): 6880-6888

  Abstract

  Protein kinase C (PKC) has been implicated in mediating ischemic and reperfusion damage in multiple organs. However, conflicting reports exist on the role of individual PKC isozymes in cerebral ischemic injury. Using a peptide inhibitor selective for deltaPKC, deltaV1-1, we found that deltaPKC inhibition reduced cellular injury in a rat hippocampal slice model of cerebral ischemia [oxygen-glucose deprivation (OGD)] when present both during OGD and for the first 3 hr of reperfusion. We next demonstrated peptide delivery to the brain parenchyma after in vivo delivery by detecting biotin-conjugateddeltaV1-1 and by measuring inhibition of intracellular deltaPKC translocation, an indicator of deltaPKC activity. Delivery of deltaV1-1 decreased infarct size in an in vivo rat stroke model of transient middle cerebral artery occlusion. Importantly, deltaV1-1 had no effect when delivered immediately before ischemia. However, delivery at the onset, at 1 hr, or at 6 hr of reperfusion reduced injury by 68, 47, and 58%, respectively. Previous work has implicated deltaPKC in mediating apoptotic processes. We therefore determined whether deltaPKC inhibition altered apoptotic cell death or cell survival pathways in our models. We found that deltaV1-1 reduced numbers of terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling-positive cells, indicating decreased apoptosis, increased levels of phospho-Akt, a kinase involved in cell survival pathways, and inhibited BAD (Bcl-2-associated death protein) protein translocation from the cell cytosol to the membrane, indicating inhibition of proapoptotic signaling. These data support a deleterious role for deltaPKC during reperfusion and suggest that deltaV1-1 delivery, even hours after commencement of reperfusion, may provide a therapeutic advantage after cerebral ischemia.

  View details for DOI 10.1523/JNEUROSCI.4474-03.2004

  View details for PubMedID 15295022

• Comparison of endovascular and surface cooling during unruptured cerebral aneurysm repair NEUROSURGERY Steinberg, G. K., Ogilvy, C. S., Shuer, L. M., Connolly, E. S., Solomon, R. A., Lam, A., Kassell, N. F., Baker, C. J., Giannotta, S. L., Cockroft, K. M., Bell-Stephens, T. E., Allgren, R. L. 2004; 55 (2): 307-314

  Abstract

  To compare endovascular versus surface methods for the induction and reversal of hypothermia during neurosurgery in a multicenter, prospective, randomized study.Patients undergoing elective open craniotomy for repair of an unruptured cerebral aneurysm (n = 153) were randomly assigned (2:1) to undergo whole-body hypothermia to 33 degrees C, either with an endovascular cooling device placed in the inferior vena cava via the femoral vein (n = 92) or with a surface convective air blanket (n = 61). Active rewarming was accomplished using the same devices.Cooling rates in endovascular and surface blanket groups averaged 4.77 and 0.87 degrees C/h, respectively (P < 0.001). When the first temporary arterial or aneurysm clip was placed, 99% of endovascular patients and 20% of surface blanket patients had reached the target of 33 degrees C (P < 0.001). Obese patients were cooled efficiently with the endovascular approach (3.56 degrees C/h). Rewarming rates averaged 1.88 degrees C/h for endovascular patients and 0.69 degrees C/h for surface blanket patients (P < 0.001). By the end of surgery, 89 and 53% of these patients, respectively, had rewarmed to at least 35 degrees C (P < 0.001). On leaving the operating room, 14% of endovascular patients and 28% of surface blanket patients were still intubated (P = 0.035). The overall safety of the two procedures was comparable. No clinically significant catheter-related thrombotic, bleeding, or infectious complications were reported in the endovascular group.Endovascular cooling provided superior induction, maintenance, and reversal of hypothermia compared with the surface blanket, without an increase in complications. Endovascular cooling may have clinical benefit for patients undergoing cerebrovascular surgery, as well as patients with acute stroke, head injury, or acute myocardial infarction.

  View details for DOI 10.1227/01.NEU.0000129683.99430.8C

  View details for PubMedID 15271236

• Glycogen synthase kinase 3 beta inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral ischemia EXPERIMENTAL NEUROLOGY Kelly, S., Zhao, H., Sun, G. H., Cheng, D. Y., Qiao, Y. L., Luo, J., Martin, K., Steinberg, G. K., Harrison, S. D., Yenari, M. A. 2004; 188 (2): 378-386

  Abstract

  The serine/threonine kinase, glycogen synthase kinase 3beta (GSK3beta), is abundant in CNS and is neuron specific. GSK3beta plays a pivotal role in the regulation of numerous cellular functions. GSK3beta phosphorylates and thereby regulates many metabolic, signaling, and structural proteins which can influence cell survival. Increased GSK3beta correlates with increased cell death, whereas reduced GSK3beta expression correlates with increased cell survival. We report that the GSK3beta inhibitor Chir025 is neuroprotective in vitro and in vivo. First, Chir025 reduced cultured hippocampal neuron death following glutamate exposure by 15-20% versus vehicle-treated controls. Second, Chir025 significantly reduced cultured cortical neuron death following oxygen-glucose deprivation (OGD) by approximately 50%. Third, Chir025 reduced infarct size following focal cerebral ischemia by nearly 20%. There were no significant differences in the number of TUNEL-positive neurons or in caspase-3 and -9 activities between Chir025- and vehicle-treated rats, although Chir025 elevated cytosolic Bcl-2 expression. These data show that Chir025-mediated inhibition of GSK3beta is neuroprotective and that the mechanism is probably not anti-apoptotic.

  View details for DOI 10.1016/j.expneurol.2004.04.004

  View details for PubMedID 15246837

• Chaperones, protein aggregation, and brain protection from hypoxic/ischemic injury JOURNAL OF EXPERIMENTAL BIOLOGY Giffard, R. G., Xu, L. J., Heng, Z., Carrico, W., Ouyang, Y. B., Qiao, Y. L., Sapolsky, R., Steinberg, G., Hu, B. R., Yenari, M. A. 2004; 207 (18): 3213-3220

  Abstract

  Chaperones, especially the stress inducible Hsp70, have been studied for their potential to protect the brain from ischemic injury. While they protect from both global and focal ischemia in vivo and cell culture models of ischemia/reperfusion injury in vitro, the mechanism of protection is not well understood. Protein aggregation is part of the etiology of chronic neurodegenerative diseases such as Huntington's and Alzheimer's, and recent data demonstrate protein aggregates in animal models of stroke. We now demonstrate that overexpression of Hsp70 in hippocampal CA1 neurons reduces evidence of protein aggregation under conditions where neuronal survival is increased. We have also demonstrated protection by the cochaperone Hdj-2 in vitro and demonstrated that this is associated with reduced protein aggregation identified by ubiquitin immunostaining. Hdj-2 can prevent protein aggregate formation by itself, but can only facilitate protein folding in conjunction with Hsp70. Pharmacological induction of Hsp70 was found to reduce both apoptotic and necrotic astrocyte death induced by glucose deprivation or oxygen glucose deprivation. Protection from ischemia and ischemia-like injury by chaperones thus involves at least anti-apoptotic, anti-necrotic and anti-protein aggregation mechanisms.

  View details for DOI 10.1242/jeb.01034

  View details for Web of Science ID 000224132000014

  View details for PubMedID 15299042

• Bcl-2 transfection via herpes simplex virus blocks apoptosis-inducing factor translocation after focal ischemia in the rat JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Zhao, H., Yenari, M. A., Cheng, D., Barreto-Chang, O. L., Sapolsky, R. M., Steinberg, G. K. 2004; 24 (6): 681-692

  Abstract

  Apoptosis plays a critical role in many neurologic diseases, including stroke. Cytochrome c release and activation of various caspases are known to occur after focal and global ischemia. However, recent reports indicate that caspase-independent pathways may also be involved in ischemic damage. Apoptosis-inducing factor (AIF) is a novel flavoprotein that helps mediate caspase-independent apoptotic cell death. AIF translocates from mitochondria to nuclei where it induces caspase-independent DNA fragmentation. Bcl-2, a mitochondrial membrane protein, protects against apoptotic and necrotic death induced by different insults, including cerebral ischemia. In the present study, Western blots confirmed that AIF was normally confined to mitochondria but translocated to nuclei or cytosol 8, 24, and 48 hours after onset of ischemia. Overall, AIF protein levels also increased after stroke. Confocal microscopy further demonstrated that nuclear AIF translocation occurred in the peri-infarct region but not in the ischemic core where only some cytosolic AIF release was observed. Our data also suggest that AIF translocated into nuclei after cytochrome c was released into the cytosol. Bcl-2 transfection in the peri-infarct region blocked nuclear AIF translocation and improved cortical neuron survival.

  View details for Web of Science ID 000221824000011

  View details for PubMedID 15181376

• Catalase over-expression protects striatal neurons from transient focal cerebral ischemia NEUROREPORT Gu, W. P., Zhao, H., Yenari, M. A., Sapolsky, R. M., Steinberg, G. K. 2004; 15 (3): 413-416

  Abstract

  Reactive oxygen species (ROS) play key roles in the cascade of brain injury after stroke, and strategies to increase the antioxidant defenses of neurons after stroke hold great promise. In this study we evaluate the neuroprotective potential of using a herpes simplex viral vector to over-express catalase in rats. Vector was microinfused into the striatum either prior to or after middle cerebral artery occlusion (MCAO). Catalase over-expression was protective (relative to control vector) when the vector was delivered 14-16 h prior to ischemia, but not when delivered after ischemia. Thus, the timing of catalase over-expression relative to ischemia is a critical variable determining its potential therapeutic value.

  View details for DOI 10.1097/01.wnr.000011132738420.12

  View details for Web of Science ID 000225140000006

  View details for PubMedID 15094494

• Mild postischemic hypothermia prolongs the time window for gene therapy by inhibiting cytochrome C release STROKE Zhao, H., Yenari, M. A., Sapolsky, R. M., Steinberg, G. K. 2004; 35 (2): 572-577

  Abstract

  We showed previously that Bcl-2 overexpression with the use of herpes simplex viral (HSV) vectors improved striatal neuron survival when delivered 1.5 hours after stroke but not when delivered 5 hours after stroke onset. Here we determine whether hypothermia prolongs the therapeutic window for gene therapy.Rats were subjected to focal ischemia for 1 hour. Hypothermia (33 degrees C) was induced 2 hours after insult and maintained for 3 hours. Five hours after ischemia onset, HSV vectors expressing Bcl-2 plus beta-gal or beta-gal alone were injected into each striatum. Rats were killed 2 days later.Striatal neuron survival of Bcl-2-treated, hypothermic animals was improved 2- to 3-fold over control-treated, hypothermic animals and Bcl-2-treated, normothermic animals. Neuron survival among normothermic, Bcl-2-treated animals was not different from control normothermics or control hypothermics. Double immunostaining of cytochrome c and beta-gal demonstrated that Bcl-2 plus hypothermia significantly reduced cytochrome c release.Postischemic mild hypothermia extended the time window for gene therapy neuroprotection using Bcl-2 and reduced cytochrome c release.

  View details for DOI 10.1161/01.STR.0000110787.42083.58

  View details for Web of Science ID 000188669500057

  View details for PubMedID 14726551

• Evaluation of surgical techniques for neuronal cell transplantation used in patients with stroke CELL TRANSPLANTATION Kondziolka, D., Steinberg, G. K., Cullen, S. B., McGrogan, M. 2004; 13 (7-8): 749-754

  Abstract

  Transplantation of cultured neuronal cells was performed in two human clinical trials after safety and efficacy was demonstrated in animal models of stroke. The studies tested the utility of human neuronal cellular transplantation into and around the small stroke volume. We developed a stereotactic surgical technique for cell delivery and evaluated that method in 26 patients with basal ganglia region motor stroke. Human neuronal cells (hNT cells; LBS neurons) were delivered frozen then thawed and formulated on the morning of surgery. Patients in a first trial received 2 or 6 million cells in three or nine implants, and in a second trial, 5 or 10 million in 25 implants. A novel cell delivery cannula was designed, manufactured, tested, and used in surgery. Immediate postoperative CT scans and later serial MR scans were used to evaluate the surgical site. Tests on the cell implantation cannula showed that the cells were not damaged and remained viable after injection. All patients underwent uncomplicated surgeries. Cells could be implanted within a 2-h period, maintaining viability of the preparation. Serial evaluations (maximum 5 years) showed no cell-related adverse serologic or imaging-defined effects. One patient had burr hole drainage of an asymptomatic chronic subdural hematoma. Human neuronal cells can be produced in culture and implanted stereotactically into the brains of patients with stroke. Surgical cell delivery did not lead to new neurological deficits, and imaging studies showed no adverse effects. The cannula used allowed precise injection of the clinical cell dose within a time period that maintained cell viability.

  View details for Web of Science ID 000226394100004

  View details for PubMedID 15690976

• Mild hypothermia inhibits cytochrome c/caspase-mediated apoptosis after global cerebral ischemia in rats 29th International Stroke Conference Zhao, H., Yenari, M. A., Cheng, D., Sapolsky, R. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2004: 249–49

  View details for Web of Science ID 000187630500123

• Cellular and molecular events underlying ischemia-induced neuronal apoptosis DRUG NEWS & PERSPECTIVES Zheng, Z., Zhao, H., Steinberg, G. K., Yenari, A. A. 2003; 16 (8): 497-503

  Abstract

  Neurons subjected to ischemia undergo necrosis or apoptosis depending on their anatomic distribution and the severity and duration of ischemia. Recent work has shown that apoptosis can occur in some settings, primarily within the ischemic penumbra. It is recognized that both mitochondrial and death-receptor pathways are involved in the transduction of apoptotic signals in the context of cerebral ischemia. Recent data also highlight the pivotal role of caspase 3 in the execution of ischemia-induced apoptosis, although a caspase-independent pathway is gaining increasing attention. In this review, we examine some of these findings and their potential therapeutic implications for ischemic stroke.

  View details for Web of Science ID 000187028700005

  View details for PubMedID 14668947

• Glutathione peroxidase overexpression inhibits cytochrome c release and proapoptotic mediators to protect neurons from experimental stroke STROKE Hoehn, B., Yenari, M. A., Sapolsky, R. M., Steinberg, G. K. 2003; 34 (10): 2489-2494

  Abstract

  Ischemic injury and reperfusion increases superoxide (O2-) production and reduces the ability of neurons to scavenge free radicals, leading to the release of cytochrome c and apoptosis. Here we test whether overexpression with the use of gene therapy of the antioxidant glutathione peroxidase (Gpx), delivered before or after experimental stroke, is protective against ischemic injury.Sixty-two rats underwent middle cerebral artery occlusion for 1 hour. Defective herpes simplex viral vectors expressing Gpx/lacZ or lacZ alone (control) were delivered into each striatum 12 hours before or 2 or 5 hours after ischemia onset.Striatal neuron survival at 2 days was improved by 36% when Gpx was delivered 12 hours before ischemia onset, 26% with a 2-hour delay, and 25% when delayed 5 hours. After ischemia, Gpx overexpression significantly reduced cytosolic translocation of cytochrome c and increased the proportion of Bcl-2-positive cells compared with cells transfected with control vector. Bax and activated caspase-3, while present in control-transfected neurons after ischemia, were rarely noted in Gpx-transfected cells.Expression from these herpes simplex viral vectors begins 4 to 6 hours after injection, which suggests a 9- to 11-hour temporal therapeutic window for Gpx. This is the first study to show that overexpression of Gpx with the use of gene therapy protects against experimental stroke, even with postischemic transfection, and the neuroprotective mechanism involves attenuation of apoptosis-related events.

  View details for DOI 10.1161/01.STR.0000091268.25816.19

  View details for Web of Science ID 000185679100056

  View details for PubMedID 14500933

• Neurophysiological monitoring in the endovascular therapy of aneurysms AMERICAN JOURNAL OF NEURORADIOLOGY Liu, A. Y., Lopez, J. R., Do, H. M., Steinberg, G. K., Cockroft, K., Marks, M. P. 2003; 24 (8): 1520-1527

  Abstract

  Endovascular aneurysm therapy has associated risks of ischemic complications. We undertook this study to evaluate the efficacy of neurophysiological monitoring (NPM) techniques in the detection of ischemic changes that may be seen during endovascular treatment of cerebral aneurysms.Thirty-five patients underwent NPM during endovascular treatment of cerebral aneurysms. The patients underwent a total of 50 endovascular procedures, including balloon test occlusion (19 patients), GDC embolization (22 patients), and permanent vessel occlusion (nine patients). NPM included electroencephalography, somatosensory evoked potentials, and/or brain stem auditory evoked potentials, depending on the location of the aneurysm.NPM changes were seen in nine (26%) of 35 patients and altered the management in five (14%) of 35 patients. In three of the five cases, NPM changes were observed without corresponding neurologic physical examination changes after balloon test occlusion (performed while the patients were under general anesthesia in two cases). In the two other cases in which NPM changes altered management, ischemia was detected at the time of intra-aneurysmal therapy while the patients were under general anesthesia. Overall, 18 of 35 patients underwent a total of 19 balloon test occlusion procedures. Of the 17 remaining patients, 13 underwent aneurysm coiling, two were not treated because of inability to safely place coils, and two were treated for distal aneurysms. Two patients developed transient neurologic deficits without concurrent NPM changes, representing false-negative NPM test results.NPM is a valuable adjunct to endovascular treatment of cerebral aneurysms. Our study suggests that these monitoring techniques may reduce ischemic complications and can be used to help guide therapeutic decisions.

  View details for PubMedID 13679263

• Mutational analysis of 206 families with cavernous malformations JOURNAL OF NEUROSURGERY Laurans, M. S., DiLuna, M. L., Shin, D., Niazi, F., Voorhees, J. R., Nelson-Williams, C., Johnson, E. W., Siegel, A. M., Steinberg, G. K., Berg, M. J., Scott, R. M., Tedeschi, G., Enevoldson, T. P., Anson, J., Rouleau, G. A., Ogilvy, C., Awad, I. A., Lifton, R. P., Gunel, M. 2003; 99 (1): 38-43

  Abstract

  A gene contributing to the autosomal-dominant cerebral cavernous malformation (CCM) phenotype, KRIT1 (an acronym for Krev Interaction Trapped 1), has been identified through linkage analysis and mutation screening. The authors collected blood samples from 68 patients with familial CCM and 138 patients with apparently sporadic CCM as well as from their families, in an effort to characterize the prevalence and spectrum of disease-causing sequence variants in the KRIT1 gene.The authors used single-strand conformational polymorphism analysis to identify genomic variants in KRIT1, which were sequenced to determine the specific mutation. Among 43 Hispanic-American kindreds who immigrated to the southwestern US from northern Mexico, 31 share an identical founder mutation. This Q455X mutation is found in 18 (86%) of 21 persons with a positive family history and in 13 (59%) of 22 persons with apparently sporadic CCM. This mutation was not found among 13 persons with CCM who were recruited from Mexico. These findings establish the key role of a recent founder mutation in Hispanic persons with CCM who live in the US. Although nearly all Hispanic families in the US in which there are multiple CCM cases linked to the CCM1 locus, only 13 of 25 non-Hispanic CCM-carrying families have displayed evidence of linkage to the CCM1 locus. Among these 13 families, the authors identified eight independent mutations in nine kindreds. They identified four additional mutations among 22 familial CCM kindreds with no linkage information, bringing the total number of independent mutations to 12. Inherited KRIT1 mutations were not detected among 103 non-Hispanic persons in whom a family history of CCM was rigorously excluded.All mutations were nonsense mutations, frame-shift mutations predicting premature termination, or splice-site mutations located throughout the KRIT1 gene, suggesting that these are genetic loss-of-function mutations. These genetic findings, in conjunction with the clinical phenotype, are consistent with a two-hit model for the occurrence of CCM.

  View details for Web of Science ID 000183865500007

  View details for PubMedID 12854741

• Multimodality treatment of giant intracranial arteriovenous malformations NEUROSURGERY Chang, S. D., Marcellus, M. L., Marks, M. P., Levy, R. P., Do, H. M., Steinberg, G. K. 2003; 53 (1): 1-11

  Abstract

  Giant arteriovenous malformations (AVMs) (i.e., those greater than 6 cm at maximum diameter) are difficult to treat and often carry higher treatment morbidity and mortality rates than do smaller AVMs. In this study, we reviewed the treatment, angiographic results, and clinical outcomes in 53 patients with giant AVMs who were treated at Stanford between 1987 and 2001.The patients selected included 20 males (38%) and 33 females (62%). Their presenting symptoms were hemorrhage (n = 20; 38%), seizures (n = 18; 34%), headaches (n = 8; 15%), and progressive neurological deficits (n = 7; 13%). One patient was in Spetzler-Martin Grade III, 9 were in Spetzler-Martin Grade IV, and 43 were in Spetzler-Martin Grade V. The mean AVM size was 6.8 cm (range, 6-15 cm). AVM venous drainage was superficial (n = 7), deep (n = 20), or both (n = 26). At presentation, 31 patients (58%) were graded in excellent neurological condition, 17 were graded good (32%), and 5 were graded poor (9%).The patients were treated with surgery (n = 27; 51%), embolization (n = 52; 98%), and/or radiosurgery (n = 47; 89%). Most patients received multimodality treatment with embolization followed by surgery (n = 5), embolization followed by radiosurgery (n = 23), or embolization, radiosurgery, and surgery (n = 23). Nineteen patients (36%) were completely cured of their giant AVMs, 90% obliteration was achieved in 4 patients (8%), less than 90% obliteration was achieved in 29 patients (55%) who had residual AVMs even after multimodality therapy, and 1 patient was lost to follow-up. Of the 33 patients who either completed treatment or were alive more than 3 years after undergoing their most recent radiosurgery, 19 patients (58%) were cured of their AVMs. The long-term treatment-related morbidity rate was 15%. The clinical results after mean follow-up of 37 months were 27 excellent (51%), 15 good (28%), 3 poor (6%), and 8 dead (15%).The results in this series of patients with giant AVMs, which represents the largest series reported to date, suggest that selected symptomatic patients with giant AVMs can be treated successfully with good outcomes and acceptable risk. Multimodality treatment is usually necessary to achieve AVM obliteration.

  View details for PubMedID 12823868

• Attenuation of nitric oxide synthase isoform expression by mild hypothermia after focal cerebral ischemia: variations depending on timing of cooling JOURNAL OF NEUROSURGERY Karabiyikoglu, M., Han, H. S., Yenari, M. A., Steinberg, G. K. 2003; 98 (6): 1271-1276

  Abstract

  In this study the authors examined the influence of mild hypothermia on early expression of nitric oxide synthase (NOS) isoforms and peroxynitrite generation after experimental stroke.In 82 male Sprague-Dawley rats, middle cerebral artery occlusion was performed for 2 hours by using the intraluminal suture model. The rats were maintained at their normal body temperature or exposed to 2 hours of intraischemic or postischemic (2-hour delay) mild hypothermia. Brains were collected 2, 6, and 24 hours after onset of ischemia for immunohistochemical and Western blot analysis of neuronal (n)NOS and inducible (i)NOS expression and peroxynitrite generation.Western blots showed significantly increased nNOS and iNOS expression in the ischemic cortex at 2, 6, and 24 hours compared with sham-operated animals. The NOS expression was highest at 24 hours. Postischemic hypothermia attenuated nNOS expression at 6 and 24 hours to a greater extent than intraischemic hypothermia. Intraischemic hypothermia reduced iNOS expression at both 2 and 24 hours, whereas postischemic hypothermia decreased iNOS expression at 24 hours. Results of immunohistochemical studies showed that nNOS colocalized with the neuronal marker MAP-2 at all time points, whereas iNOS was initially localized to vessels, and then localized to activated microglia by 24 hours. Intraischemic but not postischemic hypothermia decreased the number of nitrotyrosine-positive cells in the ischemic cortex at 24 hours. Mild hypothermia significantly but differentially attenuates increases in NOS isoforms, with more robust nNOS suppression when cooling is delayed. This may have important implications for understanding the mechanism of hypothermic neuroprotection and for stroke therapy.

  View details for Web of Science ID 000183337600020

  View details for PubMedID 12816275

• Parent vessel occlusion for vertebrobasilar fusiform and dissecting aneurysms AMERICAN JOURNAL OF NEURORADIOLOGY Leibowitz, R., Do, H. M., Marcellus, M. L., Chang, S. D., Steinberg, G. K., Marks, M. P. 2003; 24 (5): 902-907

  Abstract

  Previous reports of outcome with permanent vessel occlusion (PVO) for large, giant, or fusiform aneurysms in the posterior circulation have been limited. We undertook this study to evaluate the perioperative (within 30 days) and follow-up outcomes for patients treated with permanent occlusion of the vertebral artery for vertebrobasilar fusiform and dissecting aneurysms.Thirteen consecutive patients were studied. Two groups were defined for the study. Group I patients underwent PVO to achieve complete thrombosis of the aneurysm. Group II patients underwent PVO to reduce flow to the aneurysm where complete thrombosis was not desirable. Modified Rankin scores were obtained at presentation and at follow-up (follow-up range, 1-76 months; mean, 22.0 months).All group I aneurysms were shown to be thrombosed on the angiograms obtained at the immediate follow-up examinations. Improvement in outcome scores was achieved by all group I patients. Improvement in Rankin scores after endovascular treatment was statistically significant (P =.026). All group II patients had complete occlusion of the vertebral artery; however, continued filling of the fusiform aneurysm was still observed. Four patients in group II died during the follow-up period. Two of these deaths were attributable to the aneurysms. Of the remaining three patients, two experienced clinical worsening and one remained stable.In this series, PVO for chronic fusiform and acute dissecting aneurysms of the vertebrobasilar system proved to be a useful therapeutic endovascular technique. Long-term outcomes suggest that patients with aneurysms involving only one vertebral artery, where complete thrombosis can be achieved, have better clinical outcomes than those who have aneurysms involving the basilar artery or both vertebral arteries, where complete thrombosis cannot achieved by using PVO.

  View details for Web of Science ID 000183021100024

  View details for PubMedID 12748092

• Prospects for the treatment of stroke using gene therapy. Expert review of neurotherapeutics Zhao, H., Yenari, M. A., Sapolsky, R. M., Steinberg, G. K. 2003; 3 (3): 357-372

  Abstract

  Recent advances have demonstrated the use of gene therapy in the treatment of stroke in experimental animal models of focal ischemia, global ischemia and subarachnoid hemorrhage. Several different vectors for gene transfer have been studied including herpes simplex virus, adenovirus, adeno-associated virus and liposomes. Genetically modified cell lines (e.g., bone marrow-derived cells) have been studied for ex vivo gene therapy. The effects of gene transfer to several brain regions including the striatum, cortex, hippocampus, subarachnoid space and blood vessels are reviewed. Targets of gene therapy, such as molecular cascades after ischemia onset (Ca2+ influx, ATP loss, increased nitric oxide) and events associated with apoptosis are also reviewed, in addition to how gene transfer may be used to understand pathomechanisms underlying ischemic injury and the temporal therapeutic windows following ischemia within which protective effects of gene therapy have been achieved. The prospects for gene therapy for stroke are discussed in light of these findings and it is concluded that solutions to key technological problems will allow gene therapy to be a viable treatment modality.

  View details for DOI 10.1586/14737175.3.3.357

  View details for PubMedID 19810903

• Bcl-2 overexpression protects against neuron loss within the ischemic margin following experimental stroke and inhibits cytochrome c translocation and caspase-3 activity JOURNAL OF NEUROCHEMISTRY Zhao, H., Yenari, M. A., Cheng, D. Y., Sapolsky, R. M., Steinberg, G. K. 2003; 85 (4): 1026-1036

  Abstract

  Bcl-2 protects against both apoptotic and necrotic death induced by several cerebral insults. We and others have previously demonstrated that defective herpes simplex virus vectors expressing Bcl-2 protect against various insults in vitro and in vivo, including cerebral ischemia. Because the infarct margin may be a region that is most amenable to treatment, we first determined whether gene transfer to the infarct margin is possible using a focal ischemia model. Since ischemic injury with and without reperfusion may occur by different mechanisms, we also determined whether Bcl-2 protects against focal cerebral ischemic injury either with or without reperfusion in rats. Bax expression, cytochrome c translocation and activated caspase-3 expression were also assessed. Viral vectors overexpressing Bcl-2 were delivered to the infarct margin. Reperfusion resulted in larger infarcts than permanent occlusion. Bcl-2 overexpression significantly improved neuron survival in both ischemia models. Bcl-2 overexpression did not alter overall Bax expression, but inhibited cytosolic accumulation of cytochrome c and caspase-3 activation. Thus, we provide the first evidence that gene transfer to the infarct margin is feasible, that overexpression of Bcl-2 protects against damage to the infarct margin induced by ischemia with and without reperfusion, and that Bcl-2 overexpression using gene therapy attenuates apoptosis-related proteins. This suggests a potential therapeutic strategy for stroke.

  View details for DOI 10.1046/j.1471-4159.2003.01756.x

  View details for Web of Science ID 000182476400020

  View details for PubMedID 12716434

• Deep arteriovenous malformations of the basal ganglia and thalamus: natural history JOURNAL OF NEUROSURGERY Fleetwood, I. G., Marcellus, M. L., Levy, R. P., Marks, M. P., Steinberg, G. K. 2003; 98 (4): 747-750

  Abstract

  Patients with arteriovenous malformations (AVMs) in a deep location and with deep venous drainage are thought to be at higher risk for hemorrhage than those with AVMs in other locations. Despite this, the natural history of AVMs of the basal ganglia and thalamus has not been well studied.The authors retrospectively evaluated a cohort of 96 patients with AVMs in the basal ganglia and thalamus with respect to the tendency of these lesions to hemorrhage between the time of detection and their eventual successful management. The 96 patients studied had a mean age of 22.7 years at diagnosis, and 51% were male. Intracranial hemorrhage (ICH) was the event leading to clinical detection in 69 patients (71.9%), and 85.5% of these patients were left with hemiparesis. After diagnosis, 25 patients bled a total of 49 times. The cumulative clinical follow up after detection but before surgical management was 500.2 patient-years. The risk of hemorrhage after detection of an AVM of the basal ganglia or thalamus was 9.8% per patient-year.The rate of ICH in patients with AVMs of the basal ganglia or thalamus (9.8%/year) is much higher than the rate in patients with AVMs in other locations (2-4%/year). The risk of incurring a neurological deficit with each hemorrhagic event is high. Treatment of these patients at specialized centers is recommended to prevent neurological injury from a spontaneous ICH.

  View details for PubMedID 12691399

• Aneurysmal subarachnoid hemorrhage in patient's with Hunt and Hess grade 4 or 5: Treatment using the Guglielmi detachable coil system AMERICAN JOURNAL OF NEURORADIOLOGY Weir, R. U., Marcellus, M. L., Do, H. M., Steinberg, G. K., Marks, M. P. 2003; 24 (4): 585-590

  Abstract

  Patients in poor clinical condition (Hunt and Hess grade 4 or 5) after subarachnoid hemorrhage (SAH) have historically fared poorly and many often were excluded from aggressive treatment. Early aggressive surgical treatment of SAH can produce good-quality survival for a higher percentage of patients than previously reported. We assessed the outcome of patients with Hunt and Hess grade 4 or 5 who were treated with Guglielmi detachable coil (GDC) embolization.We retrospectively evaluated the records of 27 consecutive grade 4 and 5 patients with 29 aneurysms treated within 72 hours of SAH by using GDCs. Percentage aneurysm occlusion after embolization, perioperative complications, and symptoms of vasospasm were evaluated. Outcome was assessed with the Glasgow Outcome Scale.Sixteen patients (59%) were grade 4, and 11 (41%) were grade 5. Eighteen (67%) had one aneurysm, six (22%) had two aneurysms, and three (11%) had three aneurysms. Twenty-nine aneurysms were treated. Fourteen (48%) were completely occluded, and four (14%) were nearly completely occluded (>/=95% occlusion) at embolization. Eleven aneurysms (38%) had partial coiling (<95% occlusion). In the 27 patients, one technical (4%) and one clinical (4%) complication occurred at embolization. No rehemorrhage occurred in any patients (follow-up, 6-44 months; mean, 23 months). Twenty-five (92%) had vasospasm, and seven required endovascular treatment because of worsening clinical status. Sixteen patients (59%) died within 30 days of SAH. Eight patients (30%) had a good clinical outcome at a mean follow-up of 23 months.Patients with Hunt and Hess grade 4 or 5 after SAH can undergo successful coil embolization of the aneurysms despite their poor medical condition and a high frequency of vasospasm at the time of treatment. Morbidity and mortality rates with this disease are still high. These findings compare favorably with those published in surgical series for aggressively treated patients with Hunt and Hess grade 4 or 5.

  View details for PubMedID 12695185

• Early carotid endarterectomy after ischemic stroke improves diffusion/perfusion mismatch on magnetic resonance imaging: Report of two cases NEUROSURGERY Krishnamurthy, S., Tong, D., McNamara, K. P., Steinberg, G. K., Cockroft, K. M. 2003; 52 (1): 238-241

  Abstract

  The functional magnetic resonance imaging techniques of diffusion-weighted imaging and perfusion-weighted imaging allow for ultra-early detection of brain infarction and concomitant identification of blood flow abnormalities in surrounding regions, which may represent brain "at risk."We report two patients with acute ischemic stroke associated with ipsilateral high-grade carotid stenosis. The first patient, a 64-year-old woman with a remote history of ischemic stroke and a vertebral artery aneurysm, presented with worsening of her preexisting right hemiparesis. The second patient, another 64-year-old woman with known multiple intracranial aneurysms and bilateral high-grade internal carotid artery stenosis, was admitted for the elective microsurgical clipping of an enlarging giant left carotid-ophthalmic artery aneurysm. Postoperatively, she developed right hemiparesis and mild aphasia. Both patients showed progressive worsening of their neurological deficits in the setting of small or undetected diffusion-weighted imaging abnormalities and large perfusion-weighted imaging defects.After prompt carotid endarterectomy, symptoms in both patients resolved or improved. Follow-up magnetic resonance imaging scans demonstrated resolution or significant improvement in the perfusion abnormalities in both patients.Carotid endarterectomy in the setting of diffusion-weighted/perfusion-weighted imaging mismatch can lead to improvement in cerebral perfusion as evidenced by resolution of the perfusion-weighted imaging lesion. Diffusion/perfusion magnetic resonance imaging may be useful in identifying patients with severe neurological deficits but without large territories of infarction who may safely undergo early surgical revascularization.

  View details for DOI 10.1227/01.NEU.0000039562.07785.A8

  View details for Web of Science ID 000180195800059

  View details for PubMedID 12493125

• HSV-mediated Bcl-2 transfection blocks apoptosis inducing factor (AIF) translocation after focal ischemia in rat 28th International Stroke Conference Zhao, H., Yenari, M. A., Cheng, D. Y., Sapolsky, R. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2003: 241–41

  View details for Web of Science ID 000180251100077

• Comparison of endovascular cooling to surface cooling during unruptured cerebral aneurysm repair 28th International Stroke Conference Steinberg, G. K., Bell-Stephens, T. E., Shuer, L. M., Ogilvy, C. S., Connolly, E. S., Solomon, R., Lam, A., Giannotta, S., Cockroft, K., Hershey, M. S., Dobak, J., Allgren, R. L. LIPPINCOTT WILLIAMS & WILKINS. 2003: 246–46

  View details for Web of Science ID 000180251100101

• Gene therapy and hypothermia for stroke treatment 6th International Conference on Neuroprotective Agents Yenari, M. A., Zhao, H., Giffard, R. G., Sobel, R. A., Sapolsky, R. M., Steinberg, G. K. NEW YORK ACAD SCIENCES. 2003: 54–68

  Abstract

  We have previously reported studies of gene therapy using a neurotropic herpes simplex viral (HSV) vector system containing bipromoter vectors to transfer various protective genes to neurons. Using this system in experimental models of stroke, cardiac arrest, and excitotoxicity, we found that it is possible to enhance neuron survival against such cerebral insults by overexpressing genes that target various facets of injury. Among the genes we studied, the anti-apoptotic protein BCL-2 improved neuron survival following various insults, and was protective even when administered after stroke onset. BCL-2 is thought to protect cells from apoptotic death by preventing cytochrome c release from the mitochondria and subsequent caspase activation. We and others have established that cooling the brain by a few degrees markedly reduces ischemic injury and improves neurologic deficits in models of cerebral ischemia and trauma. This hypothermic neuroprotection is also associated with BCL-2 upregulation in some instances. Furthermore, hypothermia suppresses many aspects of apoptotic death including cytochrome c release, caspase activation, and DNA fragmentation. Here we show that two different kinds of protective therapies, BCL-2 overexpression and hypothermia, both inhibit aspects of apoptotic cell death cascades, and that a combination treatment can prolong the temporal therapeutic window for gene therapy.

  View details for Web of Science ID 000184303000006

  View details for PubMedID 12853295

• Sensitivity of scalp EEG, cortical EEG, and somatosensory evoked responses during surgery for intracranial aneurysms SURGICAL NEUROLOGY Martin, C. J., Sinson, G., Patterson, T., Zager, E. L., Stecker, M. M., Solomon, R. A., Steinberg, G. K. 2002; 58 (5): 317-321

  Abstract

  We estimated the relative sensitivity and reliability of scalp EEG, cortical EEG and somatosensory evoked potentials (SSEPs) to detect significant changes during aneurysm surgery.Two observers independently reviewed data from 18 patients who were monitored with scalp EEG, cortical EEG, and SSEPs to determine which if any modality demonstrated significant changes during 25 different episodes of temporary intracranial vascular occlusion.Kappa scores indicating the degree of agreement between the two observers were highest for the cortical strip EEG (kappa = 0.92) and the SSEPs (kappa = 0.82) and much greater than for the scalp EEG data (kappa = -0.07). The cortical strip recordings showed changes more often than either the scalp EEG or SSEP during temporary vascular occlusion. In no case did the scalp EEG change when neither the strip nor SSEP changed. In only 4% of events did the observers feel that the SSEP changed when the strip did not, but in 16% of cases, the strip changed without changes in any of the other modalities.Recording of EEG from strip electrodes placed on the cortical surface detects changes more frequently than either scalp EEG or SSEPs during vascular occlusion. Different observers were more likely to agree on whether the cortical strip EEG changed during vascular occlusion than the other modalities. This argues for the possible advantages of recording from strip electrodes during aneurysm surgery.

  View details for Web of Science ID 000180103500006

• Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia NEUROBIOLOGY OF DISEASE Maier, C. M., Sun, G. H., Cheng, D. Y., Yenari, M. A., Chan, P. H., Steinberg, G. K. 2002; 11 (1): 28-42

  Abstract

  Following a transient ischemic insult there is a marked increase in free radical (FR) production within the first 10-15 min of reperfusion and again at the peak of the inflammatory process. Hypothermia decreases lipid peroxidation following global ischemia, raising the possibility that it may act by reducing FR production early on and by maintaining or increasing endogenous antioxidant systems. By means of FR fluorescence, Western blot, immunohistochemistry, and enzymatic assay, we studied the effects of mild hypothermia on superoxide (O(-*)(2)) anion production, superoxide dismutase SOD expression, and activity following focal cerebral ischemia in rats. Mild hypothermia significantly reduced O(-*)(2) generation in the ischemic penumbra and corresponding contralateral region, but did not alter the bilateral SOD expression. SOD enzymatic activity in the ischemic core was slightly reduced in hypothermia-treated animals compared with normothermic controls. Our results suggest that the neuroprotective effect of mild hypothermia may be due, in part, to a reduction in neuronal and endothelial O(-*)(2) production during early reperfusion.

  View details for DOI 10.1006/nbdi.2002.0513

  View details for Web of Science ID 000179314100003

  View details for PubMedID 12460544

• Quality of evidence for management of arteriovenous malformations of the brain - Reply LANCET Steinberg, G. K., Fleetwood, I. G. 2002; 360 (9338): 1023

  View details for DOI 10.1016/S0140-6736(02)11108-1

  View details for Web of Science ID 000178249000034

• Gene transfer of HSP72 protects cornu ammonis 1 region of the hippocampus neurons from global ischemia: Influence of Bcl-2 ANNALS OF NEUROLOGY Kelly, S., Zhang, Z. J., Zhao, H., Xu, L. J., Giffard, R. G., Sapolsky, R. M., Yenari, M. A., Steinberg, G. K. 2002; 52 (2): 160-167

  Abstract

  We investigated whether HSV gene transfer of HSP72 in vivo and in vitro: (1) protected cornu ammonis 1 region of the hippocampus neurons from global cerebral ischemia; and (2) affected Bcl-2 expression. HSV vectors expressing HSP72 and beta-galactosidase (reporter) or beta-galactosidase only (control vector) were injected into cornu ammonis 1 region of the hippocampus 15 hours before induction of global cerebral ischemia (n = 10) and sham-operated rats (n = 8). HSP72 vector-treated rats displayed significantly more surviving transfected neurons (X-gal-positive, 31 +/- 8) compared with control vector-treated rats (10 +/- 4) after global cerebral ischemia. Sham-operated rats displayed similar numbers of X-gal-positive neurons (HSP72 vector 18 +/- 8 vs control vector 20 +/- 7). The percentage of beta-galactosidase and Bcl-2 coexpressing neurons in HSP72-treated rats after global cerebral ischemia (84 +/- 4%) was greater than that in control vector-treated rats (58 +/- 9%). The percentage of beta-galactosidase and Bcl-2 coexpressing neurons in sham-operated rats was similar in HSP72 (93 +/- 7%) and in control vector-treated rats (88 +/- 12%). HSP72 vector transfection led to 12 times as much Bcl-2 expression as the control vector in uninjured hippocampal neuronal cultures. In injured (oxygen-glucose deprivation) hippocampal neuron cultures, HSP72 vector transfection led to 2.8 times as much Bcl-2 expression as control vector. We show that HSP72 overexpression protects cornu ammonis 1 region of the hippocampus neurons from global cerebral ischemia, and that this protection may be mediated in part by increased Bcl-2 expression.

  View details for DOI 10.1002/ana.10264

  View details for Web of Science ID 000177140000005

  View details for PubMedID 12210785

• N-butyl cyanoacrylate embolization of cerebral arteriovenous malformations: Results of a prospective, randomized, multi-center trial AMERICAN JOURNAL OF NEURORADIOLOGY Purdy, P., Horowitz, M., Kopitnik, T., Samson, D., Dion, J., Joseph, G., Dawson, R., Owens, D., Barrow, D., Barr, J., Powers, S., Cockroft, K., Holmes, B., Sumas, M., Wallace, R., Masaryk, T., Perl, J., Chyatte, D., Tomsick, T., Tew, J. M., van Loveren, H., Zuccarello, M., Marks, M., Norbash, A., Steinberg, G., Halbach, V., Higashida, R., Dowd, C., Lawton, M., Wilson, C., McDougall, C., Spetzler, R., Nesbit, G., Barnwell, S., Nichols, D., Thielen, K., Atkinson, J., Meyer, F., Piepgras, D., Choi, I. S., Day, J. D., Berenstein, A., Setton, A., Pryor, J., Niimi, Y., Flamm, E., DeNardo, A., Scott, J., Murtagh, F. R. 2002; 23 (5): 748-755

  Abstract

  Liquid N-butyl cyanoacrylate (n-BCA) use for the treatment of arteriovenous malformations (AVM) in the brain has become part of medical practice. However, no study has led to the Food and Drug Administration's approval of n-BCA for intravascular use. The purpose of this study was to verify the effectiveness and safety of an n-BCA/Tantalum Powder/Ethiodized Oil mixture, compared with conventional treatment (Trufill polyvinyl alcohol [PVA]) for preoperative embolization of cerebral AVM.Between October 15, 1996, and March 24, 1999, 104 patients at 13 centers were prospectively randomized to undergo embolization using an n-BCA/Tantalum Powder/Ethiodol mixture or Trufill PVA. The pre-embolization therapy goals were determined in terms of the number of pedicles to be embolized and the percent of nidus reduction expected. Embolization results were evaluated by a central laboratory. Subsequent surgical resection data were recorded. Safety evaluation data included recording device complications, procedure complications, and intracranial events/overall neurologic outcomes, which could be either device-related, procedure-related, or both.The reduction of AVM dimensions (79.4% in the n-BCA group and 86.9% in the PVA group) and the mean number of vessels embolized (2.2 in the n-BCA group and 2.1 in the PVA group) was similar in the two groups. Coils were used more commonly with PVA embolization (P<.0001). No differences were detected in surgical resection time, number of patients who required transfusion, volume and number of transfusion units, or type and volume of fluid replacement. Glasgow Outcome Scale scores were not significantly different between the two groups before treatment, after embolization, or after resection. Two of 42 patients who underwent resection and had been treated with n-BCA experienced post-resection hematoma, compared with eight of 45 patients who underwent resection and had been treated with PVA (P<.05).This prospective, randomized trial showed that n-BCA is equivalent to PVA as a preoperative embolic agent for treatment of cerebral AVM as determined by percent of nidus reduction and number of feeding pedicles embolized.

  View details for Web of Science ID 000175599300003

  View details for PubMedID 12006271

• Overexpression of HSP-72 protects against protein aggregation induced by transient cerebral ischemia Zhao, H., Hu, B. R., Sapolsky, R. M., Steinberg, G. K., Yenari, M. A. LIPPINCOTT WILLIAMS & WILKINS. 2002: A237

  View details for Web of Science ID 000174875900597

• Arteriovenous malformations LANCET Fleetwood, I. G., Steinberg, G. K. 2002; 359 (9309): 863-873

  Abstract

  Arteriovenous malformations of the brain are congenital vascular lesions that affect 0.01-0.50% of the population, and are generally present in patients aged 20-40 years. The usual clinical presentations are haemorrhage, seizures, progressive neurological deficit, or headache. Results of natural history studies have shown a yearly haemorrhage rate of 1-4%. Frequency of rebleeding has increased over the years, and several factors that increase risk of haemorrhage have been identified. Although substantial, the morbidity associated with haemorrhages could be less than previously thought. Over the past decade, great advances have been made in application of endovascular embolisation techniques, stereotactic radiosurgery, and microsurgery, allowing effective multidisciplinary treatment of arteriovenous malformations, including those previously deemed to be untreatable. Increasing attention has been paid to management of flow-related aneurysms associated with these malformations. Finally, many reports of recurrent arteriovenous malformations have coincided with new theories regarding the embryogenesis of these disorders and laboratory work suggesting their proliferative potential.

  View details for Web of Science ID 000174329600030

  View details for PubMedID 11897302

• Safety and performance of a novel intravascular catheter for induction and reversal of hypothermia in a porcine model NEUROSURGERY Inderbitzen, B., Yon, S., LASHERAS, J., Dobak, J., Perl, J., Steinberg, G. K. 2002; 50 (2): 364-370

  Abstract

  This study was undertaken to assess the acute safety and feasibility of rapidly inducing, maintaining, then reversing hypothermia using a novel heat transfer catheter and a closed-loop automatic feedback temperature control system to overcome limitations imposed by current clinical practices used for perioperative cooling and warming.Six swine (mean mass, 53.8 +/- 3.6 kg) were studied. The heat transfer catheter was placed in the inferior vena cava via the femoral vein. Hypothermia to 32 degrees C was induced, maintained for 6 hours, then reversed to 36 degrees C. The time needed to induce and reverse hypothermia was recorded via continuous temperature monitoring of the lower esophagus, cerebrum, and rectum. Electrocardiography provided continuous monitoring, and blood draws were made at baseline and at 2-hour intervals. Examination of the catheter in situ was performed after the animals were killed.Cooling from 36.2 to 32.0 degrees C was rapid and uniform (mean, 7.3 +/- 0.7 degrees C/h), with animals reaching the target temperature within 60 minutes. Rewarming was also easily controlled, with animals' temperatures reaching 36 degrees C within 130 minutes. No arrhythmia was observed, and all hematological variables were within the normal range for swine. There was no evidence of hemolysis or platelet changes. Little to no thrombosis was observed.The data presented here suggest that rapid induction and reversal of hypothermia are technically possible using a core intravenous cooling catheter; this method would provide a safe, rapid, and exquisitely reproducible way to induce hypothermia with subsequent restoration of normothermia.

  View details for Web of Science ID 000173427300030

  View details for PubMedID 11844272

• Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Xu, L. J., Yenari, M. A., Steinberg, G. K., Giffard, R. G. 2002; 22 (1): 21-28

  Abstract

  Recent experimental work has shown that hypothermia with even small decreases in temperature is broadly neuroprotective, but the mechanism of this protection remains unclear. Although reduction of metabolism could explain protection by deep hypothermia, it does not explain the robust protection found with mild hypothermia. Several reports have suggested that ischemic apoptosis is reduced by hypothermia. The authors examined the effects of hypothermia on neuronal apoptosis using serum deprivation, a well-accepted model that induces neuronal apoptosis. Mild hypothermia (33 degrees C) significantly reduced the number of morphologically apoptotic neurons to less than half the number seen in normothermic culture temperatures (37 degrees C) after 48 hours. They examined the effect of hypothermia on several steps in the cascade. Caspase-3, -8, and -9 activity was significantly increased after 24 hours at 37 degrees C, and was significantly lower in cultures deprived of serum at 33 degrees C. Cytochrome c translocation was reduced by hypothermia. Western blot analysis failed to detect significant changes in Bax, bcl -2, or hsp -70 at early time points, whereas hypothermia significantly reduced cJun N-terminal kinase activation. The authors conclude that small decreases in temperature inhibit apoptosis very early, possibly at the level of the initiation of apoptosis, as suggested by reduced cJun N-terminal kinase activation and before the translocation of cytochrome c, with subsequent prevention of caspase activation.

  View details for Web of Science ID 000172930900003

  View details for PubMedID 11807390

• Mild post-ischemic hypothermia prolongs the time window for gene therapy Zhao, H., Yenari, M. A., Sapolsky, R. M., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2002: 347–47

  View details for Web of Science ID 000173147700101

• The role of radiosurgery in the treatment of giant arteriovenous malformations 5th Meeting of the International-Stereotactic-Radiosurgery-Society Chang, S. D., Levy, R. P., Marks, M. P., Marcellus, M., Steinberg, G. K. KARGER. 2002: 42–53

  View details for Web of Science ID 000176153400006

• Upregulation of Bcl-2 in CA1 neurons protected from global cerebral ischemia by HSP72 gene transfer Kelly, S., Zhang, Z. J., Xu, L. J., Giffard, R. G., Sapolsky, R. M., Yenari, M. A., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2002: 355–56

  View details for Web of Science ID 000173147700150

• Mild hypothermia attenuates cytochrome C release but does not alter Bcl-2 expression or caspase activation after experimental stroke JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Yenari, M. A., Iwayama, S., Cheng, D. Y., Sun, G. H., Fujimura, M., Morita-Fujimura, Y., Chan, P. H., Steinberg, G. K. 2002; 22 (1): 29-38

  Abstract

  Mild hypothermia protects the brain from ischemia, but the underlying mechanisms of this effect are not well known. The authors previously found that hypothermia reduces the density of apoptotic cells, but it is not certain whether temperature alters associated biochemical events. Mitochondrial release of cytochrome c has recently been shown to be a key trigger in caspase activation and apoptosis via the intrinsic pathway. Using a model of transient focal cerebral ischemia, the authors determined whether mild hypothermia altered expression of Bcl-2 family proteins, mitochondrial release of cytochrome c, and caspase activation. Mild hypothermia significantly decreased the amount of cytochrome c release 5 hours after the onset of ischemia, but mitochondrial translocation of Bax was not observed until 24 hours. Mild hypothermia did not alter Bcl-2 and Bax expression, and caspase activation was not observed. The present study provides the first evidence that intraischemic mild hypothermia attenuates the release of cytochrome c in the brain, but does not appear to affect other biochemical aspects of the intrinsic apoptotic pathway. They conclude that necrotic processes may have been interrupted to prevent cytochrome c release, and that the ameliorative effect of mild hypothermia may be a result of maintaining mitochondrial integrity. Furthermore, the authors show it is unlikely that mild hypothermia alters the intrinsic apoptotic pathway.

  View details for Web of Science ID 000172930900004

  View details for PubMedID 11807391

• Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia MOLECULAR BRAIN RESEARCH Zhang, Z. J., Sobel, R. A., Cheng, D. Y., Steinberg, G. K., Yenari, M. A. 2001; 95 (1-2): 75-85

  Abstract

  Mild hypothermia protects the brain against experimental ischemia, but the reasons are not well known. We examined whether the protective effects of mild hypothermia could be correlated with alterations in expression of Bcl-2, an anti-apoptotic protein in a rat model of transient global ischemia. Following 10 min of forebrain ischemia, hippocampal neurons were examined 72 h later for survival, expression of Bcl-2 family proteins and apoptosis. Intraischemic mild hypothermia was applied for 3 h (33 degrees C, isch-33) or normal body temperature was maintained (37 degrees C, isch-37). Survival of CA1 neurons was significantly improved in the isch-33 group compared to the isch-37 group (90 vs. 53% survival; P<0.01). The proportion of Bcl-2-positive cells among surviving CA1 neurons in the isch-33 group was increased compared to that of sham and isch-37 groups (P<0.01). Bax expression in CA1 was no different between sham and isch-33 groups, but was significantly decreased in isch-37 (P<0.05). TUNEL staining was positive in many isch-37 CA1 neurons, but absent in isch-33. Utilizing electron microscopy, more cells meeting criteria for apoptosis were observed in the isch-37 than isch-33. These data suggest that mild hypothermia attenuates apoptotic death, and that this protection may be related to increases in Bcl-2.

  View details for Web of Science ID 000172299300008

  View details for PubMedID 11687278

• Overexpression of HSP72 after induction of experimental stroke protects neurons from ischemic damage JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Hoehn, B., Ringer, T. M., Xu, L. J., Giffard, R. G., Sapolsky, R. M., Steinberg, G. K., Yenari, M. A. 2001; 21 (11): 1303-1309

  Abstract

  The 72-kD inducible heat shock protein (HSP72) can attenuate cerebral ischemic injury when overexpressed before ischemia onset. Whether HSP72 overexpression is protective when applied after ischemia onset is not known, but would have important clinical implications. Fifty-seven rats underwent middle cerebral artery occlusion for 1 hour. Defective herpes simplex viral (HSV) vectors expressing hsp72 with lacZ as a reporter were delivered 0.5, 2, and 5 hours after ischemia onset into each striatum. Control animals received an identical vector containing only lacZ. Striatal neuron survival at 2 days was improved by 23% and 15% when HSP72 vectors were delayed 0.5 and 2 hours after ischemic onset, respectively ( P < 0.05). However, when delayed by 5 hours, HSP72 overexpression was no longer protective. This is the first demonstration that HSP72 gene transfer even after ischemia onset is neuroprotective. Because expression from these HSV vectors begins 4 to 6 hours after injection, this suggests that the temporal therapeutic window for HSP72 is at least 6 hours after ischemia onset. Future strategies aimed at enhancing HSP72 expression after clinical stroke may be worth pursuing. The authors suggest that in the future HSP72 may be an effective treatment for stroke.

  View details for Web of Science ID 000172087000006

  View details for PubMedID 11702045

• Hyperperfusion syndrome with hemorrhage after angioplasty for middle cerebral artery stenosis AMERICAN JOURNAL OF NEURORADIOLOGY Liu, A. Y., Do, H. M., Albers, G. W., Lopez, J. R., Steinberg, G. K., Marks, M. P. 2001; 22 (8): 1597-1601

  Abstract

  Hyperperfusion syndrome is a well-documented complication of carotid endarterectomy, as well as internal carotid artery angioplasty and stent placement. We report a similar complication after distal intracranial (middle cerebral artery [MCA] M2 segment) angioplasty. To our knowledge, this is the first report of hyperperfusion syndrome after intracranial angioplasty of a distal MCA branch.

  View details for PubMedID 11559514

• Familial trigeminal neuralgia - Case report and review of the literature JOURNAL OF NEUROSURGERY Fleetwood, I. G., Innes, A. M., Hansen, S. R., Steinberg, G. K. 2001; 95 (3): 513-517

  Abstract

  The authors report the case of a 45-year-old woman with medically intractable trigeminal neuralgia (TN) in whom a good clinical response to partial sectioning of the trigeminal nerve was attained. No evidence of vascular compression was found intraoperatively. Several other members of her family, involving three generations, also suffered from TN. The treatment of all affected patients is discussed in the context of a literature review in which the controversies surrounding the origins of the disease and treatment options for patients with the familial variant of TN are addressed.

  View details for Web of Science ID 000170894600023

  View details for PubMedID 11565877

• Imaging of cerebral and brain stem amyloidomas AMERICAN JOURNAL OF NEURORADIOLOGY Symko, S. C., Hattab, E. M., Steinberg, G. K., Lane, B. 2001; 22 (7): 1353-1356

  Abstract

  CNS amyloidomas are rare. We describe a 51-year-old man with isolated amyloidomas in the cerebral white matter and in the pons. CT and MR imaging showed a heterogeneous, enhancing mass in the deep cerebral white matter. A second, much smaller linear serpiginous lesion was present in the pons.

  View details for Web of Science ID 000170437200021

  View details for PubMedID 11498426

• Posterior cerebral circulation revascularization NEUROSURGERY CLINICS OF NORTH AMERICA Chang, S. D., Ryu, S. I., Steinberg, G. K. 2001; 12 (3): 519-?

  Abstract

  Posterior circulation revascularization has evolved as a method to treat selected patients with vertebrobasilar ischemia who have inaccessible atherosclerotic occlusive disease and who have failed maximal medical therapy. In addition, complex unclippable aneurysms of the posterior circulation are another indication for revascularization of the vertebrobasilar territory. Careful preoperative evaluation and meticulous attention to detail intraoperatively yield good patient outcomes with minimal morbidity and mortality. This article reviews the vascular anatomy of the posterior circulation and the indications, preoperative evaluation, operative techniques, clinical outcomes, and alternative treatments for patients requiring posterior circulation revascularization procedures.

  View details for Web of Science ID 000169857500006

  View details for PubMedID 11390312

• Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors NEUROLOGICAL RESEARCH Yenari, M. A., Dumas, T. C., Sapolsky, R. M., Steinberg, G. K. 2001; 23 (5): 543-552

  Abstract

  Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is becoming increasingly clear that some of the genes induced during cerebral ischemia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at levels high enough to be protective. One of the most exciting arenas of such interventions is the use of viral vectors to deliver potentially neuroprotective genes at high levels. Neurotrophic herpes simplex viral strains are an obvious choice for gene therapy to the brain, and we have utilized bipromoter vectors that are capable of transferring various genes to neurons. Using this system in experimental models of stroke, cardiac arrest and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insults by over-expressing genes that target various facets of injury. These include energy restoration by the glucose transporter (GLUT-1), buffering calcium excess by calbindin, preventing protein malfolding or aggregation by stress proteins and inhibiting apoptotic death by BCL-2. We show that in some cases, gene therapy is also effective after the onset of injury, and also address whether successful gene therapy necessarily spares function. Although gene therapy is limited to the few hundred cells the vector is capable of transfecting, we consider the possibility of such gene therapy becoming relevant to clinical neurology in the future.

  View details for Web of Science ID 000169864400016

  View details for PubMedID 11474812

• Differential neuroprotection from human heat shock protein 70 overexpression in in vitro and in vivo models of ischemia and ischemia-like conditions EXPERIMENTAL NEUROLOGY Lee, J. E., Yenari, M. A., Sun, G. H., Xu, L. J., Emond, M. R., Cheng, D. Y., Steinberg, G. K., Giffard, R. G. 2001; 170 (1): 129-139

  Abstract

  We previously showed that overexpressing the 70-kDa inducible heat shock protein in primary astrocyte cultures and in a rodent stroke model using viral vectors resulted in protection from ischemia and ischemia-like injury. However, viral transfection could potentially provoke a stress response itself; therefore, we examined whether transgenic mice constitutively expressing human heat shock protein 70 were protected from ischemic insults. Astrocyte cultures from brains of heat shock protein 70 transgenic mice were resistant to hydrogen peroxide injury in a dose-dependent fashion, but were less resistant to hypoglycemia and oxygen-glucose deprivation. Because hydrogen peroxide exposure and glucose deprivation are partially dependent on glutathione levels, we determined whether heat shock protein 70 transgenic cultures had altered glutathione levels under normal growth conditions. However, there was no significant difference in glutathione levels between heat shock protein 70 transgenic and wildtype astrocytes. Hippocampal, but not cortical neuron cultures from these same transgenic mice were also protected against oxygen-glucose deprivation and glutamate toxicity. In an in vivo model of permanent focal cerebral ischemia, there was no significant difference in infarct size assessed 24 h postinsult. These results suggest that heat shock protein 70 protects against some but not all kinds of central nervous system injury. The protective effects may be related to the nature and severity of the insults, as well as subpopulations of brain cells and dose-dependent effects of HSP70 overexpression.

  View details for Web of Science ID 000169840400012

  View details for PubMedID 11421590

• Increased rate of hemorrhage in SOD2-deficient mice after transient focal cerebral ischemia: Effect of mild hypothermia Maier, C. M., Tannous, N., Steinberg, G. K., Chan, P. H. LIPPINCOTT WILLIAMS & WILKINS. 2001: A305–A306

  View details for Web of Science ID 000168270600806

• Calbindin D28K overexpression protects striatal neurons from transient focal cerebral ischemia STROKE Yenari, M. A., Minami, M., Sun, G. H., Meier, T. J., Kunis, D. M., McLaughlin, J. R., Ho, D. Y., Sapolsky, R. M., Steinberg, G. K. 2001; 32 (4): 1028-1035

  Abstract

  Increased intracellular calcium accumulation is known to potentiate ischemic injury. Whether endogenous calcium-binding proteins can attenuate this injury has not been clearly established, and existing data are conflicting. Calbindin D28K (CaBP) is one such intracellular calcium buffer. We investigated whether CaBP overexpression is neuroprotective against transient focal cerebral ischemia.Bipromoter, replication-incompetent herpes simplex virus vectors that encoded the genes for cabp and, as a reporter gene, lacZ were used. Sprague-Dawley rats received bilateral striatal injections of viral vector 12 to 15 hours before ischemia onset. With the use of an intraluminal occluding suture, animals were subjected to 1 hour of middle cerebral artery occlusion followed by 47 hours of reperfusion. Brains were harvested and stained with X-gal (to visualize beta-galactosidase, the gene product of lacZ). The number of remaining virally transfected, X-gal-stained neurons in both the ischemic and contralateral striata were counted and expressed as the percentage of surviving neurons in the ischemic striatum relative to the contralateral nonischemic striatum.Striatal neuron survivorship among cabp-injected animals was 53.5+/-4.1% (n=10) versus 26.8+/-5.4% among those receiving lacZ (n=9) (mean+/-SEM; P<0.001).We conclude that viral vector-mediated overexpression of CaBP leads to neuroprotection in this model of central nervous system injury. This is the first demonstration that CaBP overexpression protects neurons in a focal stroke model.

  View details for Web of Science ID 000167951300038

  View details for PubMedID 11283407

• Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size JOURNAL OF NEUROSURGERY Maier, C. M., Sun, G. H., Kunis, D., Yenari, M. A., Steinberg, G. K. 2001; 94 (1): 90-96

  Abstract

  The goals of this study were to determine the effects of delaying induction of mild hypothermia (33 degrees C) after transient focal cerebral ischemia and to ascertain whether the neuroprotective effects of mild hypothermia induced during the ischemic period are sustained over time.In the first study, rats underwent 2 hours of middle cerebral artery (MCA) occlusion. Animals in one group were maintained under normothermic conditions (N group, 23 rats) throughout the period of ischemia and reperfusion. Rats in four additional groups were exposed to 2 hours of hypothermia, which commenced at ischemia onset (H0 group, 11 rats) or with delays of 90 (H90 group, 10 rats), 120 (H120 group, 10 rats), or 180 (H180 group, five rats) minutes, and allowed to survive for 3 days. In the second study, animals underwent 1.5 hours of MCA occlusion and were maintained under normothermic (48 rats) or hypothermic (44 rats) conditions during the ischemia period, after which they survived for 3 days, 1 week, or 2 months. All animals were evaluated for neurological findings at 24 hours and 48 hours postischemia and before they were killed. Regions of infarct were determined by examining hematoxylin and eosinstained brain slices obtained at six coronal levels.Mild hypothermia conferred significant degrees of neuroprotection in terms of survival, behavioral deficits, and histopathological changes, even when its induction was delayed by 120 minutes after onset of MCA occlusion (p < 0.05) compared with normothermic conditions. Furthermore, the neuroprotective effect of mild hypothermia (2-hour duration) that was induced during the ischemia period was sustained over 2 months. These studies lend further support to the use of mild hypothermia in the treatment of stroke.

  View details for Web of Science ID 000166043900014

  View details for PubMedID 11147904

• Gene therapy for treatment of cerebral ischemia using defective herpes simplex viral vectors 5th International Conference on Neuroprotective Agents Yenari, M. A., Dumas, T. C., Sapolsky, R. M., Steinberg, G. K. NEW YORK ACAD SCIENCES. 2001: 340–357

  Abstract

  Significant advances have been made over the past few years concerning the cellular and molecular events underlying neuron death. Recently, it is becoming increasingly clear that some of genes induced during cerebral ischemia may actually serve to rescue the cell from death. However, the injured cell may not be capable of expressing protein at high enough levels to be protective. One of the most exciting arenas of such interventions is the use of viral vectors to deliver potentially neuroprotective genes at high levels. Neurotropic herpes simplex viral (HSV) strains are an obvious choice for gene therapy to the brain, and we have used bipromoter vectors that are capable of transferring various genes to neurons. Using this system in experimental models of stroke, cardiac arrest, and excitotoxicity, we have found that it is possible to enhance neuron survival against such cerebral insults by overexpressing genes that target various facets of injury. These include energy restoration by the glucose transporter (GLUT-1), buffering calcium excess by calbindin, preventing protein malfolding or aggregation by stress proteins and inhibiting apoptotic death by BCL-2. We show that in some cases, gene therapy is also effective after the onset of injury, and also address whether successful gene therapy necessarily spares function. Although gene therapy is limited to the few hundred cells the vector is capable of transfecting, we consider the possibility of such gene therapy becoming relevant to clinical neurology in the future.

  View details for Web of Science ID 000172028600039

  View details for PubMedID 11462790

• Quantification of the gravity-dependent change in the C-arm image center for image compensation in fluoroscopic spinal neuronavigation Conference on Medicine Meets Virtual Reality 2001 Hariri, S., Abbasi, H. R., Chin, S., Steinberg, G., Shahidi, R. I O S PRESS. 2001: 177–179

  Abstract

  In the quest to develop a viable, frameless spinal navigation system, many researchers are utilizing the C-arm fluoroscope. However, there is a significant problem with the C-arm that must be quantified: the gravity-dependent sag effect resulting from the geometry of the C-arm and aggravated by the inequity of weight at each end of the C-arm. This study quantified the C-arm sag effect, giving researchers the protocol and data needed to develop a program that accounts for this distortion. The development of spinal navigation algorithms that account for the C-arm sag effect should produce a more accurate spinal navigation system.

  View details for Web of Science ID 000169103300035

  View details for PubMedID 11317734

• Diffusion- and perfusion-weighted magnetic resonance imaging of focal cerebral ischemia and cortical spreading depression under conditions of mild hypothermia BRAIN RESEARCH Yenari, M. A., Onley, D., Hedehus, M., deCrespigny, A., Sun, G. H., Moseley, M. E., Steinberg, G. K. 2000; 885 (2): 208-219

  Abstract

  In a model of experimental stroke, we characterize the effects of mild hypothermia, an effective neuroprotectant, on fluid shifts, cerebral perfusion and spreading depression (SD) using diffusion- (DWI) and perfusion-weighted MRI (PWI). Twenty-two rats underwent 2 h of middle cerebral artery (MCA) occlusion and were either kept normothermic or rendered mildly hypothermic shortly after MCA occlusion for 2 h. DWI images were obtained 0.5, 2 and 24 h after MCA occlusion, and maps of the apparent diffusion coefficient (ADC) were generated. SD-like transient ADC decreases were also detected using DWI in animals subjected to topical KCl application (n=4) and ischemia (n=6). Mild hypothermia significantly inhibited DWI lesion growth early after the onset of ischemia as well as 24 h later, and improved recovery of striatal ADC by 24 h. Mild hypothermia prolonged SD-like ADC transients and further decreased the ADC following KCl application and immediately after MCA occlusion. Cerebral perfusion, however, was not affected by temperature changes. We conclude that mild hypothermia is neuroprotective and suppresses infarct growth early after the onset of ischemia, with better ADC recovery. The ADC decrease during SD was greater during mild hypothermia, and suggests that the source of the ADC is more complex than previously believed.

  View details for Web of Science ID 000166026800008

  View details for PubMedID 11102575

• Moyamoya disease CANADIAN JOURNAL OF NEUROLOGICAL SCIENCES Fleetwood, I., Steinberg, G. K. 2000; 27 (4): 325-327

  View details for Web of Science ID 000165302000015

  View details for PubMedID 11097525

• Reply Muscle & nerve Chang, Lopez, Steinberg 2000; 23 (9): 1446-?

  View details for PubMedID 10951453

• AAEM news and comments Muscle & nerve Chang, Lopez, Steinberg 2000; 23 (9): 1450-1451

  View details for PubMedID 10951454

• Institutional peer review can reduce the risk and cost of carotid endarterectomy 71st Annual Session of the Pacific-Coast-Surgical-Association Olcott, C., Mitchell, R. S., Steinberg, G. K., Zarins, C. K. AMER MEDICAL ASSOC. 2000: 939–41

  Abstract

  Surgeon-directed institutional peer review, associated with positive physician feedback, can decrease the morbidity and mortality rates associated with carotid endarterectomy.Case series.Tertiary care university teaching hospital.All patients undergoing carotid endarterectomy at our institution during a 5-year period ending August 1998.Stroke rate decreased from 3.8% (1993-1994) to 0% (1997-1998). The mortality rate decreased from 2.8% (1993-1994) to 0% (1997-1998). Length of stay decreased from 4.7 days (1993-1994) to 2.6 days (1997-1998). The total cost decreased from $13,344 (1993-1994) to $9548 (1997-1998).An objective, confidential peer review process that provides ongoing feedback of performance to surgeons and documents that performance in relationship with that of peers seems to be effective in reducing the morbidity and mortality rate associated with carotid endarterectomy. In addition, the review process lowered the hospital cost of performing carotid endarterectomy.

  View details for Web of Science ID 000088639300017

  View details for PubMedID 10922256

• Cerebral revascularization techniques - Illustrative case TECHNIQUES IN NEUROSURGERY Steinberg, G. K. 2000; 6 (2): 78-79

  View details for Web of Science ID 000088574500002

• Influence of mild hypothermia on Bcl-2/Bax expression and cytochrome c release following experimental stroke Yenari, M. A., Iwayama, S., Maier, C. M., Cheng, D., Sun, G. H., Fujimura, M., Morita-Fujimura, Y., Kunis, D. M., Chan, P. H., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2000: A67–A68

  View details for Web of Science ID 000086557800181

• Increased Bcl-2 protein under conditions of mild hypothermia following global cerebral ischemia Zhang, Z., Yenari, M. A., Kunis, D. M., Sun, G. H., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2000: A66–A67

  View details for Web of Science ID 000086557800178

• Neurosurgical and neuroendovascular management of Takayasu's arteritis NEUROSURGERY Stoodley, M. A., Thompson, R. C., Mitchell, R. S., Marks, M. P., Steinberg, G. K. 2000; 46 (4): 841-851

  Abstract

  The roles of surgical and endovascular treatments for patients with Takayasu's arteritis are not clear. We report our experience in the neurosurgical and/or neuroendovascular treatment of patients with Takayasu's arteritis who exhibited ischemic neurological symptoms.Between 1994 and 1998, seven patients with Takayasu's arteritis and neurological symptoms were treated at the Stanford University Medical Center. All patients were angiographically evaluated and received maximal medical therapy. Cerebral blood flow studies were performed for six patients. Three patients underwent surgical revascularization procedures alone, two underwent combinations of surgical and endovascular procedures, and two underwent endovascular treatment alone.The most common neurological symptoms were dysequilibrium, syncope, and visual disturbances. The characteristic angiographic features of Takayasu's arteritis were identified for all patients. The subclavian arteries and proximal carotid and vertebral arteries were involved in all patients. Two patients exhibited improvement of their symptoms after endovascular treatment alone. There were two deaths after surgery, involving patients with severe global cerebral hypoperfusion. All other surgically treated patients exhibited improvement of their symptoms, with patent grafts, up to 4 years after surgery. Cerebral blood flow improved after treatment.Improvement of symptoms can be achieved with surgical revascularization and/or endovascular treatment. Staged revascularization might be better than one-stage bilateral high-flow grafting for patients with severe global hypoperfusion.

  View details for PubMedID 10764257

• Rewarming from hypothermia leads to elevated plasma lipopolysaccharide concentrations UNDERSEA & HYPERBARIC MEDICINE Gaffin, S. L., Dietz, F. B., Brock-Utne, J. G., Andrews, T. C., Jaffe, R. A., Steinberg, G. K., Wallace, R. F. 2000; 27 (1): 1-7

  Abstract

  Rewarming victims of hypothermia such as divers or immersion victims, participants in winter sports and military operations, and surgical patients on cardiopulmonary bypass (CPB) may lead to vascular instability, multiorgan failure, shock, and even death. While the causes of these rewarming symptoms are unknown, they may be related to bacterial lipopolysaccharide (LPS) translocated from the intestines into the circulation due to splanchnic ischemia. We have determined LPS during the cooling (to 31.5 degrees-34.0 degrees C) and rewarming phases of hypothermic surgery in 11 patients at the Stanford University Medical Center. During rewarming, there was an LPS spike in 6/11, in one more patient there was an LPS spike during surgery but not during rewarming, and in 4/11 there was no rise in LPS, i.e., a temporary endotoxemia occurred in 7/11 (63.6%) patients, usually at the commencement of rewarming. All four patients with no LPS spike received dexamethasone for at least 7 days before surgery. We propose that hypothermia reduced splanchnic blood flow (BF), causing ischemic damage to the gut wall and translocation of LPS from the gut into the vascular space. Upon rewarming, splanchnic BF is restored, the translocated LPS transits from the splanchnic to the systemic circulations as a bolus, and the gut wall is healed. No sequelae occurred in these patients because of their adequately functioning immune systems. However, had they been immunocompromised, symptoms might have occurred. Rewarming of accident victims probably also incurs a similar risk of endotoxemia, and dexamethasone may have protected the gut wall. Further studies are indicated.

  View details for Web of Science ID 000086978900001

  View details for PubMedID 10813433

• Microsurgical resection of brainstem, thalamic, and basal ganglia angiographically occult vascular malformations NEUROSURGERY Steinberg, G. K., Chang, S. D., Gewirtz, R. J., Lopez, J. R. 2000; 46 (2): 260-270

  Abstract

  To evaluate the clinical results for patients who underwent resection of angiographically occult vascular malformations (AOVMs) of the brainstem, thalamus, or basal ganglia, successfully resected after it exhibited rebleeding and presented to a pial surface.Between January 1990 and May 1998, 56 patients with 57 deep AOVMs underwent 63 operations, at Stanford University Medical Center, to treat AOVMs of the brainstem (42 AOVMs), thalamus (5 AOVMs), or basal ganglia (10 AOVMs). The surgical approach was suboccipital midline (27 operations), far lateral suboccipital (10 operations), transsylvian (9 operations), interhemispheric transcallosal or infracallosal (8 operations), infratentorial supracerebellar (6 operations), or subtemporal (3 operations). Four patients experienced recurrent bleeding from the same lesion after surgical resection, requiring a second operation. One patient required a planned second operation, using a different approach, to completely resect the lesion, and one patient underwent two surgical procedures to resect two separate brainstem AOVMs. One patient initially underwent exploration but not resection of her AOVM, because it did not present to a pial or ependymal surface. The AOVM was successfully resected after it exhibited rebleeding and presented to a pial surface.The immediate outcomes after surgery were unchanged for 31 patients (55%), worsened for 16 (29%), and improved for 9 (16%). The long-term outcomes were unchanged for 24 patients (43%), compared with their presenting grade, worse for 3 (5%), and improved for 29 (52%). Patients who had undergone previous radiotherapy or radiosurgery to treat these lesions experienced more difficult postoperative courses, and radiation necrosis was observed for two patients.AOVMs of the brainstem, thalamus, and basal ganglia can be safely removed, with a long-term neurological morbidity rate of only 5% and a complete lesion resection rate of 93% after the initial planned resection. The use of cranial base surgical approaches and intraoperative electrophysiological monitoring contributes to successful clinical outcomes.

  View details for Web of Science ID 000085191800002

  View details for PubMedID 10690715

• Planned direct dual-modality treatment of complex broad-necked intracranial aneurysms: Four technical case reports NEUROSURGERY Cockroft, K. M., Marks, M. P., Steinberg, G. K. 2000; 46 (1): 226-230

  Abstract

  Treatment of complex, broad-based intracranial aneurysms with either microsurgical clipping or endovascular coiling alone is sometimes impossible. In this study, we report the planned combined endovascular and microsurgical treatment of four complex, wide-necked aneurysms in four patients.Three of the four patients presented with subarachnoid hemorrhage. The fourth patient presented with a progressive neurological deficit secondary to an associated arteriovenous malformation. Three of the aneurysms were located in the posterior circulation (two broad-necked basilar apex aneurysms and one bilobed vertebrobasilar junction aneurysm with a wide-necked ventral component). The fourth aneurysm was a broad-based paraclinoid/cavernous-carotid lesion.One of the patients with a basilar apex aneurysm and the patient with the paraclinoid aneurysm underwent surgery intended to create a narrow neck that would be amenable to future coiling. The patient with the bilobed vertebrobasilar junction aneurysm underwent surgery to treat the broad-necked ventral lobe, whereas the dorsal lobe, with the neck partially buried in the brainstem, was treated endovascularly. The second patient with a basilar apex aneurysm was in poor clinical condition after subarachnoid hemorrhage and was therefore treated with coil embolization to reduce the risk of rebleeding. After the patient made a good clinical recovery, the residual aneurysm was surgically clipped. Angiographic follow-up documented the complete obliteration of all four aneurysms. Clinically, all patients had good to excellent outcomes after a follow-up period of 6 to 30 months.Complex, broad-necked aneurysms that may be difficult to treat with a single mode of therapy can be safely and successfully treated with a combination of endovascular and microsurgical techniques. For patients with broad-based aneurysms that are difficult to access surgically without incurring significant morbidity, microsurgical clipping may be used as the initial procedure to create a smaller neck. Alternatively, for patients who are in poor clinical condition after subarachnoid hemorrhage and who harbor a broad-necked aneurysm in a surgically formidable location, partial coiling may be used initially to reduce the short-term risk of rebleeding.

  View details for PubMedID 10626956

• Gene therapy using viral vectors for acute neurologic insults NEUROLOGY Sapolsky, R. M., Steinberg, G. K. 1999; 53 (9): 1922-1931

  Abstract

  Enormous knowledge has emerged concerning the cellular and molecular events underlying necrotic neuron death after seizure, hypoxia-ischemia, or hypoglycemia. This has allowed the design of rational therapies to protect neurons at such times. One of the most exciting arenas of such interventions is the use of viral vectors to deliver neuroprotective genes. This review considers the progress in this nascent discipline. Neuroprotection has been demonstrated against a variety of in vitro and in vivo rodent models of necrotic insults with vectors overexpressing genes that target various facets of injury. These have included the energetic components, calcium excess, accumulation of reactive oxygen species, protein malfolding, inflammation, and triggering of apoptosis (i.e., programmed cell death) in a subset of cells. A number of caveats, subtleties, and pressing questions concerning this literature then are considered. These include whether these gene therapy interventions actually prevent, rather than merely delay, neuron death; the extent to which the effects of such vectors on neuronal cell biology is actually understood; the potential adverse effects of the use of such vectors; and whether sparing a neuron from death with one of these interventions spares function as well. Finally, we consider the likelihood of such gene therapy becoming relevant to clinical neurology in the near future.

  View details for Web of Science ID 000084255300005

  View details for PubMedID 10599759

• The neuroprotective potential of heat shock protein 70 (HSP70) MOLECULAR MEDICINE TODAY Yenari, M. A., Giffard, R. G., Sapolsky, R. M., Steinberg, G. K. 1999; 5 (12): 525-531

  Abstract

  In response to many metabolic disturbances and injuries, including stroke, neurodegenerative disease, epilepsy and trauma, the cell mounts a stress response with induction of a variety of proteins, most notably the 70-kDa heat shock protein (HSP70). Whether stress proteins are neuroprotective has been hotly debated, as these proteins might be merely an epiphenomenon unrelated to cell survival. Only recently, with the availability of transgenic animals and gene transfer, has it become possible to overexpress the gene encoding HSP70 to test directly the hypothesis that stress proteins protect cells from injury. A few groups have now shown that overproduction of HSP70 leads to protection in several different models of nervous system injury. This review will cover these studies, along with the potential mechanisms by which HSP70 might mediate cellular protection.

  View details for Web of Science ID 000083729600007

  View details for PubMedID 10562718

• Long-term outcomes after carotid stent placement for treatment of carotid artery dissection NEUROSURGERY Liu, A. Y., Paulsen, R. D., Marcellus, M. L., Steinberg, G. K., Marks, M. P. 1999; 45 (6): 1368-1373

  Abstract

  To assess the long-term outcomes after stent placement for the treatment of carotid artery dissections.Between 1992 and 1998, seven patients underwent stenting procedures for treatment of extracranial carotid artery dissections resulting from various causes, including trauma (n = 2), iatrogenesis (n = 2), spontaneous development (n = 2), and fibromuscular dysplasia (n = 1). Stenting procedures were performed for large, nonhealing, dissection-induced pseudoaneurysms (four cases) or severe preocclusive stenosis (three cases). A total of 11 stents were placed (Palmaz stents, n = 8; Wallstents, n = 3). Radiological follow-up examinations were performed after a mean period of 17.7 months (range, 1-67 mo), using conventional or computed tomographic angiography. Clinical follow-up data were obtained after a mean period of 42.9 months (range, 13-72 mo).All stent placements resulted in complete resolution of dissection-induced stenosis. For two of the four patients with aneurysms, the lesions occluded spontaneously at the time of the procedure. The third patient required coil embolization of the pseudoaneurysm. One patient exhibited progressive shrinkage of the aneurysm in serial follow-up examinations, with healing after 18 months. No clinical complications were associated with the procedures. One patient exhibited progression to asymptomatic occlusion 3 months after stenting. The remaining six patients exhibited no significant changes in luminal diameters. All patients remained in clinically stable condition, with no ischemic symptoms, during more than 3.5 years (mean period) of follow-up monitoring.This experience suggests that stents placed for treatment of extracranial carotid artery dissections remain patent and patients remain free of symptoms on a long-term basis. Additional studies will be required to determine the optimal types of stents and intervals for follow-up monitoring using imaging.

  View details for PubMedID 10598705

• The usefulness of electrophysiological monitoring during resection of central nervous system vascular malformations. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Chang, S. D., Lopez, J. R., Steinberg, G. K. 1999; 8 (6): 412-422

  Abstract

  Goal: The purpose of this study was to evaluate the usefulness of electrophysiological monitoring during the resection of vascular malformations. Methods: Between September 1994 and April 1996, we surgically resected vascular malformations (31 arteriovenous malformations, 22 angiographically occult vascular malformations) from 53 patients (56 procedures) and used intraoperative evoked potential monitoring. Somatosensory evoked potentials (SSEPs) were monitored in 54 procedures (96%), and brain stem auditory evoked potentials (BAEPs) in 17 (30%). The neurological status of the patients was evaluated before and after surgery. Findings: Five of the 54 patients (9%) monitored with SSEPs had SSEP changes (4 transient, 1 persistent) coinciding with new clinical neurological deficits in 4 patients (all transient). In all 4 patients who had transient SSEP changes, the changes resolved with adjustment or removal of clips on feeding vessels (2 patients) or with elevating mean arterial pressure (MAP) (2 patients). Forty-seven patients (91%) had neither SSEP or neurological examination alterations. One of 17 patients (6%) monitored with BAEPs had neurological and persistent BAEP changes, 15 (88%) had neither BAEP or neurological changes, and 1 (6%) had a neurological change despite no change in BAEP (false negative). The sensitivity of SSEP and BAEP for predicting a new postoperative deficit (transient or prolonged) in this series was 86% (6/7); specificity was 98% (55/56). Clinical outcome was excellent in 41 patients, good in 11 and poor in 1 (no patients died) and was largely related to pretreatment grade. Conclusion: SSEPs and BAEPs predict the likelihood of clinical neurological injury during resection of vascular malformations with high sensitivity and specificity and may prove a useful adjunct in treating these lesions.

  View details for PubMedID 17895195

• Intraoperative electrical stimulation for identification of cranial nerve nuclei 45th Annual Meeting of the American-Association-for-Electrodiagnostic-Medicine Chang, S. D., Lopez, J. R., Steinberg, G. K. JOHN WILEY & SONS INC. 1999: 1538–43

  Abstract

  The purpose of this study was to evaluate the feasibility and usefulness of cranial nerve nuclei monitoring during resection of brainstem cavernous malformations. Eleven patients with brainstem cavernous malformations underwent resection of their malformations utilizing cranial nerve nuclei monitoring. Cranial nerves V and VII were monitored by placing electrodes in muscle groups innervated by these nerves and recording manipulation-induced neurotonic discharges and triggered electromyographic (EMG) activity, after electrical stimulation of the corresponding brainstem nuclei. Seven of 11 procedures (64%) with cranial nerve nuclei monitoring were noted to have cranial nerve nuclei activity corresponding to manipulation of the nuclei. The cavernous malformation was completely resected in 5 of 7 cases with cranial nerve nuclei activity and in all 4 cases without activity. In the remaining 2 cases, the cavernous malformation was not resected due to the proximity of the monitored cranial nerve nuclei to the cavernous malformation and to increasing neurotonic activity as the cavernous malformation was approached. None of the 11 patients had new permanent postoperative deficits corresponding to the cranial nerve nuclei monitored; 1 patient had a transient partial facial palsy lasting 2 days. Preliminary results indicate that cranial nerve nuclei monitoring proves useful in preserving neurologic function and reducing surgical morbidity during resection of brainstem cavernous malformations, particularly indicating when lesion resection places these nuclei at risk.

  View details for Web of Science ID 000083306000008

  View details for PubMedID 10514231

• Direct and combined revascularization in pediatric moyamoya disease NEUROSURGERY Golby, A. J., Marks, M. P., Thompson, R. C., Steinberg, G. K. 1999; 45 (1): 50-58

  Abstract

  Surgical revascularization of moyamoya disease can improve neurological outcomes, compared with the natural history of the disease or the results of medical treatment. Controversy exists regarding whether direct or indirect revascularization yields better outcomes. This study involves a single-center experience with direct anastomosis and is the first North American series using direct revascularization for pediatric patients with moyamoya disease.Twelve patients (age range, 5-17 yr; mean age, 10.2 yr) underwent direct revascularization of 21 hemispheres. Two patients had experienced failure of previous indirect revascularization procedures, with continued clinical deterioration. Superficial temporal artery-middle cerebral artery anastomosis was performed in 19 hemispheres (with concurrent encephaloduroarteriosynangiosis in 6). Middle meningeal artery-middle cerebral artery anastomosis and omental transposition were each performed in one hemisphere. Follow-up periods ranged from 12 to 65 months (mean, 35 mo), and monitoring included neurological examinations, angiography, magnetic resonance imaging, and cerebral blood flow studies.The neurological conditions of all patients were stable or improved after surgery. None of the patients developed new strokes, and no new ischemic lesions were seen in magnetic resonance imaging scans. All grafts evaluated by follow-up angiography were patent. Postoperative cerebral blood flow studies showed significantly improved blood flow (54.4 versus 42.5 ml/100 g/min; P = 0.017, n = 4) and hemodynamic reserve (70.3 versus 43.9 ml/100 g/min; P = 0.009, n = 4), compared with preoperative studies.Surgical revascularization by direct anastomosis in pediatric patients is technically feasible, is well tolerated, and can improve the progressive natural history, the angiographic appearance, and the cerebral blood flow abnormalities associated with the disease. Direct revascularization has the advantage of providing immediate and high-flow revascularization and is particularly useful for patients who have experienced failure of previous indirect revascularization procedures.

  View details for PubMedID 10414566

• Correlation of magnetic resonance characteristics and histopathological type of angiographically occult vascular malformations Neurosurgery Vanefsky, M. A., Cheng, M. L., Chang, S. D., Norbash, A., Snipe, J., Marks, M. P., Steinberg, G. K. 1999; 44 (6): 1174-80; discussion 1180-1

  Abstract

  OBJECTIVE: Histological and radiological classification of vascular malformations has previously been attempted in an effort to understand their nature and predict their biological behavior. There exists a subgroup of vascular malformations that are angiographically occult and share a common magnetic resonance imaging (MRI) appearance but may differ in their behavior. We sought to determine any correlation between MRI features and final histopathological diagnosis. METHODS: We reviewed our series of 72 patients with angiographically occult vascular malformations operated on at Stanford University Medical Center between 1988 and 1993. Radiographic magnetic resonance images and histopathological specimens were retrospectively evaluated for various diagnostic features. RESULTS: Our data indicate that lesions exhibiting a ring of hemosiderin are associated with the presence of a cavernous malformation (CM) component (86% of CMs versus 33% of non-CM lesions). A lesion associated with edema, mass effect, or a single prominent blood product on MRI correlates with the presence of an arteriovenous malformation (AVM) component. Sixty-three percent of AVMs and 80% of lesions with partial AVM components showed edema, compared with 8% of CMs and 0% of venous malformations. Sixty percent of AVMs and 63% of lesions with partial AVM components showed a single prominent blood product, compared with 8% of CMs and 0% of venous malformations. Finally, 60% of AVMs exhibited mass effect, compared with 20% of CMs. Additionally, an expansile hemorrhage is suggestive of an AVM. CONCLUSION: This study is the first to demonstrate that a particular MRI appearance of an angiographically occult vascular malformation is suggestive of an AVM component. This may have important implications with regard to the behavior of the lesion and planning of future treatment.

  View details for PubMedID 10371616

• Outcome of angioplasty for atherosclerotic intracranial stenosis STROKE Marks, M. P., Marcellus, M., Norbash, A. M., Steinberg, G. K., Tong, D., Albers, G. W. 1999; 30 (5): 1065-1069

  Abstract

  We sought to assess the long-term outcome and efficacy of percutaneous transluminal angioplasty in the treatment of symptomatic intracranial atherosclerotic stenoses.Twenty-three patients with fixed symptomatic intracranial stenoses were treated over a 5-year period with percutaneous transluminal angioplasty. Patients who underwent successful angioplasty were followed up for 16 to 74 months (mean, 35.4 months).An angioplasty that resulted in decreased stenosis was performed in 21 of 23 patients (91.3%). In 1 case a stenosis could not be safely crossed, and in another balloon dilatation resulted in vessel rupture. This vessel rupture resulted in the 1 periprocedural death in the series. In follow-up there was 1 stroke in the same vascular territory as the angioplasty and 2 strokes in the series overall. This yielded an annual stroke rate of 3.2% for strokes in the territory appropriate to the site of angioplasty.Intracranial angioplasty can be performed with a high degree of technical success. The long-term clinical follow-up available in this series suggests that it may reduce the risk of future stroke in patients with symptomatic intracranial stenoses.

  View details for PubMedID 10229745

• Embolization of basal ganglia and thalamic arteriovenous malformations NEUROSURGERY Paulsen, R. D., Steinberg, G. K., Norbash, A. M., Marcellus, M. L., Marks, M. P. 1999; 44 (5): 991-996

  Abstract

  Basal ganglia and thalamic arteriovenous malformations (AVMs) show a poor natural history and have proven difficult to treat. We report the safety and efficacy of presurgical and preradiosurgical embolization of these deep central lesions and describe the contribution of embolization to multimodality treatment.Thirty-eight patients with basal ganglia and/or thalamic AVMs underwent embolization in a total of 69 sessions. Seven of the 38 patients (18.4%) presented with hemorrhage, and 23 of 38 (60.5%) exhibited neurological deficits before therapy. Thirty patients (78.9%) underwent embolization with a liquid adhesive (cyanoacrylate), and five of these patients also underwent embolization with polyvinyl alcohol. Five patients (13.2%) were treated with polyvinyl alcohol or polyvinyl alcohol and silk. One patient (2.6%) underwent embolization alone, 19 (50.0%) underwent embolization followed by radiosurgery, 5 (13.2%) underwent embolization plus microsurgical resection, and 13 (34.2%) patients were treated using all three modalities.Three patients did not undergo embolization because of the morphological features of the AVMs and poor endovascular access. The patients who underwent embolization achieved AVM volume reductions of 10 to 100% (mean, 49.7%). Fifteen patients (39.5%) achieved complete obliteration of their AVMs, one with embolization alone, three with embolization followed by radiosurgery, five with embolization plus microsurgical resection, and six with a combination of all three modalities. At the time of the last follow-up imaging session, embolization combined with radiosurgery (19 patients) yielded a mean volume reduction of 81.1%, and all three modalities (13 patients) yielded a mean reduction of 84.6%. Four permanent neurological deficits resulted from embolization (5.8% of procedures, 10.5% of patients). The embolization-related complication rate was higher in the earlier years (1984-1989) of this series.Endovascular embolization plays an important role in multimodality treatment of AVMs involving the basal ganglia and/or thalamus. Embolization can result in obliteration of a significant volume of the AVM and may allow complete obliteration of the AVM when combined with microsurgical resection and/or stereotactic radiosurgery.

  View details for PubMedID 10232532

• Recanalization and rupture of a giant vertebral artery aneurysm after Hunterian ligation: Case report NEUROSURGERY Chang, S. D., Marks, M. P., Steinberg, G. K. 1999; 44 (5): 1117-1120

  Abstract

  Recanalization and subsequent rupture of giant aneurysms of the posterior circulation after Hunterian ligation is an extremely rare event that has been noted to occur with basilar apex, basilar trunk, and vertebrobasilar junction aneurysms. We report the case of a giant, previously unruptured right vertebral artery aneurysm, which recanalized from the contralateral vertebral artery and subsequently ruptured after previously performed angiography showed complete thrombosis of the aneurysm.A 72-year-old woman presented with headaches, ataxia, and lower extremity weakness. A giant 3-cm right vertebral artery aneurysm was found during the patient evaluation.Because of the size of the aneurysm and the absence of a discrete neck, Hunterian ligation was performed. After treatment, angiograms showed no filling of the aneurysm from either the right or left vertebral artery. Nine days later, after the patient developed lethargy and nausea, repeat angiography showed that a small portion of the aneurysmal base had recanalized. The next day, the patient had a massive subarachnoid hemorrhage and subsequently died.We think that this is a previously undescribed complication associated with direct arterial ligation of giant vertebral artery aneurysms. Patients with aneurysms treated using Hunterian ligation need to be followed up closely. Even aneurysms that have minimal recanalization are at risk for subarachnoid hemorrhage.

  View details for PubMedID 10232546

• Embolization of rolandic cortex arteriovenous malformations NEUROSURGERY Paulsen, R. D., Steinberg, G. K., Norbash, A. M., Marcellus, M. L., Lopez, J. R., Marks, M. P. 1999; 44 (3): 479-484

  Abstract

  To evaluate the safety and efficacy of preradiosurgical and presurgical embolization of arteriovenous malformations (AVMs) involving the rolandic cortex.Seventeen consecutive patients with rolandic AVMs seen during a 31-month period (December 1994-July 1997) were evaluated. All patients underwent superselective sodium amobarbital testing to determine any changes in the results of the neurological examinations before undergoing embolization. In 16 of 17 patients (94.1%), somatosensory evoked potentials augmented physical examinations. Patients were embolized with N-butyl cyanoacrylate (Histoacryl; B. Braun, Melsungen, Germany) and iophendylate (Ethiodol; Savage Labs, Melville, NY). Rigid control of the mean arterial pressure (65-75 mm Hg) was maintained in all patients for 24 to 48 hours after embolization.Twenty-three embolization sessions were performed in 17 patients (mean, 1.5 sessions/patient), and a total of 40 feeding arteries were embolized. Two patients were unable to undergo embolization because of positive results of the amobarbital testing despite repeated attempts to reposition a microcatheter in the AVM circulation. In one case, somatosensory evoked potentials and the results of the physical examination were both positive; in the other case, only the somatosensory evoked potentials were used (in a pediatric patient under general anesthesia). All patients with AVMs that were embolized experienced a significant size reduction of their lesions (range, 20-95%; mean, 63%). There were no permanent complications. Four procedures (10% of the procedures, 23% of the patients) resulted in minor transient neurological deficits, with patients' conditions returning to baseline. Thirteen patients subsequently underwent radiosurgery, three underwent surgical resection, and one underwent combined surgery and radiosurgery. Complete obliteration of the lesions has been achieved in four patients to date (three who underwent surgery and one who underwent radiosurgery), with the remainder undergoing further follow-up.When properly evaluated before treatment, rolandic AVMs can be embolized with a high success rate (measured by completed embolization and size reduction) and a low complication rate.

  View details for PubMedID 10069584

• Moyamoya syndrome in children with Alagille syndrome: Additional evidence of a vasculopathy PEDIATRICS Woolfenden, A. R., Albers, G. W., Steinberg, G. K., Hahn, J. S., Johnston, D. C., Farrell, K. 1999; 103 (2): 505-508

  View details for Web of Science ID 000078437800023

  View details for PubMedID 9925853

• The use of electrophysiological monitoring in the intraoperative management of intracranial aneurysms JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Lopez, J. R., Chang, S. D., Steinberg, G. K. 1999; 66 (2): 189-196

  Abstract

  Somatosensory evoked potentials (SSEPs) and brainstem auditory evoked potentials (BAEPs) have been increasingly utilised during surgery for intracranial aneurysms to identify cerebral ischaemia. Between July 1994 and April 1996, we surgically treated 70 aneurysms in 49 consecutive patients (58 operations) with the aid of intraoperative evoked potential monitoring. This study sought to evaluate the usefulness of SSEP and BAEP monitoring during intracranial aneurysm surgery.Mean patient age was 51.9 (range 18-79) years. The sizes of the aneurysms were 3-4 mm (15), 5-9 mm (26), 10-14 mm (11), 15-19 mm (seven), 20-24 mm (six), and >25 mm (five). SSEPs were monitored in 58 procedures (100%) and BAEPs in 15 (26%). The neurological status of the patients was evaluated before and after surgery.Thirteen of the 58 procedures (22%) monitored with SSEPs had SSEP changes (12 transient, one persistent); 45 (78%) had no SSEP changes. Three of 15 patients (20%) monitored with BAEPs had changes (two transient, one persistent); 12 (80%) had no BAEP changes. Of the 14 patients with transient SSEP or BAEP changes, these changes resolved with adjustment or removal of aneurysm clips (nine), elevating MAP (four), or retractor adjustment (one). Mean time from precipitating event to electrophysiological change was 8.9 minutes (range 3-32), and the mean time for recovery of potentials in patients with transient changes was 20.2 minutes (range 3-60). Clinical outcome was excellent in 39 patients, good in five, and poor in three (two patients died), and was largely related to pretreatment grade.SSEPs and BAEPs are useful in preventing clinical neurological injury during surgery for intracranial aneurysms and in predicting which patients will have unfavourable outcomes.

  View details for Web of Science ID 000078450800011

  View details for PubMedID 10071098

  View details for PubMedCentralID PMC1736209

• Remote-rendered 3D CT angiography (3DCTA) as an intraoperative aid in cerebrovascular neurosurgery. Computer aided surgery Wilkinson, E. P., Shahidi, R., Wang, B., Martin, D. P., Adler, J. R., Steinberg, G. K. 1999; 4 (5): 256-263

  Abstract

  To assess the viability and utility of network-based rendering in the treatment of patients with cerebral aneurysms, we implemented an intraoperative rendering system and protocol using both three-dimensional CT angiography (3DCTA) and perspective volume rendering (PVR).A Silicon Graphics InfiniteReality engine was connected via a Fast Ethernet network to a workstation in the neurosurgical operating room. A protocol was developed to isolate bone and vessels using an appropriate transfer function. Three-dimensional CT angiogram images were volume rendered and transmitted to the workstation using a bandwidth-conserving remote rendering system, and were rotated, cut using clipping planes, and viewed using normal and perspective views. Twelve patients with intracranial aneurysms were examined at surgery using this system.Rendering performance at optimal operating bandwidths (50-60 Mb/s) was excellent, with regeneration of a high-resolution image in less than 1 s. Network performance varied in two cases, slowing image regeneration. Surgeons found the images to be useful as an adjunct to conventional imaging in understanding the morphology of complex aneurysms and their relationship to the skull base.Intraoperative volume rendering using 3DCTA is achievable over a network, can reduce hardware costs by amortizing hardware among multiple users, and provides useful imaging information during the surgical treatment of cerebral aneurysms. Future operating suites may incorporate network-transmitted three-dimensional images as additional sources of imaging information.

  View details for PubMedID 10581523

• Reliance on TCD during carotid endarterectomy may lend to overshunting: A comparison of EEG, SSEP and TCD monitoring during carotid endarterectomy. Cockroft, K. M., Lee, J. A., Loper, Tong, D. C., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 1999: 270

  View details for Web of Science ID 000077934200282

• Diagnosing cerebral vasospasm: The correlation rate between cerebral angiograms and transcranial Doppler Chang, S. D., Bell, T., Ceranski, J., Tong, D., Marks, M. P., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 1999: 259

  View details for Web of Science ID 000077934200215

• Transgenic mice which overexpress HSP70 are protected against some but not all central nervous system insults Yenari, M. A., Lee, J. E., Sun, G. H., Giffard, R. G., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 1999: 233

  View details for Web of Science ID 000077934200063

• Long-term effects of mild hypothermia on SOD2 expression following transient focal ischemia Maier, C. M., Onley, D., Yenari, M. A., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 1999: 275

  View details for Web of Science ID 000077934200312

• Unruptured intracranial aneurysms - Risk of rupture and risks of surgical intervention NEW ENGLAND JOURNAL OF MEDICINE Wiebers, D., Whisnant, J., Forbes, G., Meissner, I., Brown, R., Piepgras, D., Huston, J., Nichols, D., O'Fallon, W., Peacock, J., Jaeger, L., Kassell, N., Kongable-Beckman, G., Torner, J., Rajput, M., Drake, C., Kurtzke, J., Marler, J., Walker, M., Meyer, F., Atkinson, J., Marsh, W., Thielen, K., Ferguson, G., Barr, H., Lownie, S., Hachinski, V., Fox, A., Sahjpaul, R., Parrent, A., Mayer, C., Lindsay, K., Teasdale, E., Bone, I., Fatukasi, J., Lindsay, M., Cail, W., Sagher, O., Davis, M., Sengupta, R., Bates, D., Gholkar, A., Murdy, J., Wilson, S., Praharaj, S., Partridge, G., Reynolds, C., Hind, N., Ogilvy, C., Crowell, R., Gress, D., Schaefer, P., Choi, I., Buckley, D., Sloan, K., King, D., Giannotta, S., Ameriso, S., Teitelbaum, T., Thomson, E., Fishback, D., Vajda, J., Nyary, I., Czirjak, S., Horvath, M., Szikora, I., Pasztor, E., Varady, P., Erdos, A., Edner, G., Wahlgren, N., Lindqvist, M., Antonsson, A., Da Pian, R., Pasqualin, A., Chioffi, F., Beltramello, A., Zampieri, G., Benati, A., Rossi, G., Ronkainen, A., Hernesniemi, J., Vapalahti, M., Rinne, J., Luukkonen, M., Vihavainen, M., Savolainen, S., Koivisto, T., Leivo, S., Helin, K., Steinberg, G., Marks, M., Vanefsky, M., Norbash, A., Thompson, R., Bell, T., Marcellus, M., Meyer, A., Kerr, R., Adams, C., Molyneux, A., Vinden, S., Bacon, F., Shrimpton, J., Parker, S., Day, A., Nadeau, S., Stachniak, J., Friedman, W., Fessler, R., Peters, K., Jacob, R., Roper, S., Smith, A., LaFrentz, P., Howard, M., Loftus, C., Adams, H., Crosby, D., Rogers, M., Broderick, J., Tew, J., Brott, T., van Loveren, H., Yeh, H., Zuccarello, M., Tomsick, T., Gaskill-Shipley, M., Minneci, L., McMahon, N., Castel, J., Orgogozo, J., Loiseau, H., Bourgeois, P., Berge, J., Dousset, V., Cuny, E., RICHARD, M., Agbi, C., Hugenholtz, H., Benoit, B., Morrish, W., Wee, R., Grahovac, S., Pratt, L., Mortensen, M., Andreoli, A., Testa, C., Comani, V., Trevisan, C., Limoni, P., Carlucci, F., Leonardi, M., Sturiale, C., Pendl, G., Eder, H., Klein, G., Eder, M., Leber, K., Horner, T., Leipzig, T., Payner, T., DeNardo, A., Scott, J., Redelman, K., Fisher, W., Rosner, M., Vitek, G., Hand, M., Flack, W. F., Sichez, J., Pertuiset, B., Fohanno, D., Marsault, C., Casasco, A., Biondi, A., Capelle, L., Duffau, H., Winn, H., Grady, M., NEWELL, D., Longstreth, W., Thompson, P., Bybee, H., Jones, D., Findlay, J., Petruk, K., Steinke, D., Ashforth, R., Stenerson, P., Schindel, D., Vanderhoven, H., Neves, J., Zager, E., Flamm, E., Raps, E., Hurst, R., Parrott, S., Sellers, M., Torchia, M., Anderson, B., West, M., Fewer, D., Hill, N., Sutherland, G., Ross, I., McClarty, B., Brownstone, R., Williams, O., Narotam, P., Christane, L., McGinn, G., Gladish, D., Kirkpatrick, P., Pickard, J., Antoun, N., Simpson, D., Higgins, N., Turner, C., Tebbs, S., Holness, R., Malloy, D., Phillips, S., Maloney, W., Molina-de-Orozco, V., Baxter, B., Connolly-Campbell, K., MacDougall, A., Gentili, F., Wallace, M., ter Brugge, K., Willinsky, R., Tymianski, M., Rickards, L., Tucker, W., Lambert, C., Montanera, W., Rychlewski, C., Flood, C., Villani, R., Sganzerla, E., Tomei, G., Bettinelli, A., Leonardi, M., Ceccarelli, G., Righini, A., Bello, L., Marras, C., Nelson, R., Lewis, T., Renowden, C., Clarke, Y., Varian, L., Chyatte, D., Sila, C., Perl, J., Masaryk, T., Porterfield, R., Shaw, M., Foy, P., Nixon, T., Dunn, L., Clitheroe, N., Smith, T., Eldridge, P., Humphrey, P., Wiseman, J., Hawkins, K., Owen, L., Ost, K., Saminaden, S., Mohr, G., Schondorf, R., Carlton, J., Maleki, M., Just, N., Brien, S., Entis, S., Tampieri, D., Simons, N., Mooij, J., Metzemackers, J., Hew, J., Beks, J., Van der Veen, A., Bosma, I., Sprengers, M., Rinkel, G., van Gijn, J., Ramos, L., Tulleken, C., Greebe, P., Van Vliet, F., Borgesen, S., Jespersen, B., Boge-Rasmussen, T., Willumsen, L., Homer, D., Eller, T., Carpenter, J., Meyer, J., Munson, R., Small, B., Nussbaum, E., Heros, R., Latchaw, R., Camarata, P., Lundgren, J., Mattsen, N., Whittle, I., Sellar, R., O'Sullivan, M., Steers, A., Statham, P., Malcolm, G., Price, R., Hoffman, B., Yonas, H., Wechsler, L., Thompson-Dobkin, J., Jungreis, C., Kassam, A., Kirby, L., Parent, A., Lewis, A., Azordegan, P., Smith, R., Alexander, L., GORDON, D., Russell, W., Brown, R., Benashvili, G., Perry, R., Scalzo, D., Mandybur, G., Morgan, C., Karanjia, P., Madden, K., Kelman, D., Gallant, T., Vanderspek, H., Choucair, A., Neal, J., Mancl, K., Saveland, H., Brandt, L., Holtas, S., Trulsson, B., MacDonald, R., Weir, B., Mojtahedi, S., Amidei, C., Vermeulen, M., Bosch, D., Hulsmans, F., Albrecht, K., Roos, Y., Vet, A., Gorissen, A., Mechielsen, M., Martin, N., Gobin, Y., Saver, J., Vinuela, F., Duckwiler, G., Kelly, D., Frazee, J., da Graca, R., Gravori, T., Illingworth, R., Richards, P., Wade, J., Colquhoun, I., Bashir, E., Shortt, S., Weaver, J., Fisher, M., Stone, B., Chaturvedi, S., Davidson, R., Davidson, K., Giombini, S., Solero, C., Boiardi, A., Cimino, C., Valentini, S., Silvani, A., Alberts, M., Friedman, A., Gentry, A., Hoffman, K., Hughes, R., Lillihei, K., Earnest, M., Nichols, J., Kindt, G., Anderson, A., Levy, S., Nichols, J., Smith, R., Breeze, R., Noonan, V., Gress, D., Dowd, C., Vanwestrop, J., Wilson, C., Berger, M., Hannegan, L., Heros, R., Marcos, J., Ugarte, L., Kitchen, N., Taylor, W., Kumar, M., Grieve, J., Durity, F., Boyd, M., Fairholm, D., Griesdale, D., Honey, C., Redekop, G., Toyota, B., Turnbull, I., Woodhurst, W., Zwimpfer, T., Teal, P., Grabe, D., Brevner, A., Piepgras, A., Schmiedek, P., Schwartz, A., Weber, T., Biller, J., Brem, S., Cybulski, G., Chadwick, L., Bronstein, K., Pietila, T., Brock, M., Krug, D., Krznaric, I., Hernesniemi, J., Kivisaari, R. 1998; 339 (24): 1725-1733

  Abstract

  The management of unruptured intracranial aneurysms requires knowledge of the natural history of these lesions and the risks of repairing them.A total of 2621 patients at 53 participating centers in the United States, Canada, and Europe were enrolled in the study, which had retrospective and prospective components. In the retrospective component, we assessed the natural history of unruptured intracranial aneurysms in 1449 patients with 1937 unruptured intracranial aneurysms; 727 of the patients had no history of subarachnoid hemorrhage from a different aneurysm (group 1), and 722 had a history of subarachnoid hemorrhage from a different aneurysm that had been repaired successfully (group 2). In the prospective component, we assessed treatment-related morbidity and mortality in 1172 patients with newly diagnosed unruptured intracranial aneurysms.In group 1, the cumulative rate of rupture of aneurysms that were less than 10 mm in diameter at diagnosis was less than 0.05 percent per year, and in group 2, the rate was approximately 11 times as high (0.5 percent per year). The rupture rate of aneurysms that were 10 mm or more in diameter was less than 1 percent per year in both groups, but in group 1, the rate was 6 percent the first year for giant aneurysms (> or =25 mm in diameter). The size and location of the aneurysm were independent predictors of rupture. The overall rate of surgery-related morbidity and mortality was 17.5 percent in group 1 and 13.6 percent in group 2 at 30 days and was 15.7 percent and 13.1 percent, respectively, at 1 year. Age independently predicted surgical outcome.The likelihood of rupture of unruptured intracranial aneurysms that were less than 10 mm in diameter was exceedingly low among patients in group 1 and was substantially higher among those in group 2. The risk of morbidity and mortality related to surgery greatly exceeded the 7.5-year risk of rupture among patients in group 1 with unruptured intracranial aneurysms smaller than 10 mm in diameter.

  View details for Web of Science ID 000077459700001

• Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia - Effects on neurologic outcome, infarct size, apoptosis, and inflammation STROKE Maier, C. M., Ahern, K. V., Cheng, M. L., Lee, J. F., Yenari, M. A., Steinberg, G. K. 1998; 29 (10): 2171-2180

  Abstract

  Mild hypothermia is possibly the single most effective method of cerebroprotection developed to date. However, many questions regarding mild hypothermia remain to be addressed before its potential implementation in the treatment of human stroke. Here we report the results of 2 studies designed to determine the optimal depth and duration of mild hypothermia in focal stroke and its effects on infarct size, neurological outcome, programmed cell death, and inflammation.Rats underwent a 2-hour occlusion of the left middle cerebral artery. In the first study (I) animals were kept (intraischemically) at either 37 degreesC (n=8), 33 degreesC (n=8), or 30 degreesC (n=8). Study II consisted of 4 groups: (1) controls (37 degreesC, n=10), (2) 30 minutes of hypothermia started at ischemic onset (33 degreesC, n=9), (3)1 hour (33 degreesC, n=8), and (4) 2 hours (33 degreesC, n=8). Brain temperature was measured by a thermocouple probe placed in the contralateral cortex. After suture removal, all animals were rewarmed and reperfused for 22 hours (I) or 70 hours (II).Mild hypothermia to 33 degreesC or 30 degreesC was neuroprotective (17+/-7% and 27+/-6%, respectively) relative to controls (53+/-8%, P<0.02), but 33 degreesC was better tolerated and recovery from anesthesia was faster. The neurological score of hypothermic animals was significantly better than that of controls (I & II) at both 24 and 72 hours postischemia except for the 30-minute group (II), which showed no improvement. In Study II, 2 hours of hypothermia reduced injury by 59%, 1 hour reduced injury by 84% whereas 30 minutes did not reduce injury. Normalized for infarct size, 2 hours of mild hypothermia decreased neutrophil accumulation by 57% whereas both 1 hour and 30 minutes had no effect. At 72 hours, 1 and 2 hours of mild hypothermia decreased transferase dUTP nick-end labeling (TUNEL) staining by 78% and 99%, respectively, and 30 minutes of hypothermia had no effect.Intraischemic mild hypothermia must be maintained for 1 to 2 hours to obtain optimal neuroprotection against ischemic cell death due to necrosis and apoptosis.

  View details for Web of Science ID 000076198600033

  View details for PubMedID 9756600

• Gene therapy with HSP72 is neuroprotective in rat models of stroke and epilepsy ANNALS OF NEUROLOGY Yenari, M. A., Fink, S. L., Sun, G. H., Chang, L. K., Patel, M. K., Kunis, D. M., Onley, D., Ho, D. Y., Sapolsky, R. M., Steinberg, G. K. 1998; 44 (4): 584-591

  Abstract

  Brain areas damaged by stroke and seizures express high levels of the 72-kd heat shock protein (HSP72). Whether HSP72 represents merely a marker of stress or plays a role in improving neuron survival in these cases has been debated. Some induced tolerance experiments have provided correlative evidence for a neuroprotective effect, and others have documented neuroprotection in the absence of HSP72 synthesis. We report that gene transfer therapy with defective herpes simplex virus vectors overexpressing hsp72 improves neuron survival against focal cerebral ischemia and systemic kainic acid administration. HSP72 overexpression improved striatal neuron survival from 62.3 to 95.4% in rats subjected to 1 hour of middle cerebral artery occlusion, and improved survival of hippocampal dentate gyrus neurons after systemic kainic acid administration, from 21.9 to 64.4%. We conclude that HSP72 may participate in processes that enhance neuron survival during transient focal cerebral ischemia and excitotoxin-induced seizures.

  View details for Web of Science ID 000076316300002

  View details for PubMedID 9778256

• Mild hypothermia: an alternative to deep hypothermia for achieving neuroprotection. journal of cardiovascular nursing Bell, T. E., Kongable, G. L., Steinberg, G. K. 1998; 13 (1): 34-44

  Abstract

  The role of excitotoxins in the ischemic cascade that results in ischemic neuronal death has been clearly defined and has brought about attempts to halt the progression of neurologic damage. Improved understanding of this process has allowed for the development of interventions to optimize neurologic outcome following periods of ischemia. Deep hypothermia (15-22 degrees C) has long been recognized as one method of achieving neuroprotection, but is not without serious implications and risks to the patient. Mild hypothermia (32-34 degrees C) is evolving as an alternative neuroprotective measure that has been shown to improve neurologic outcome in experimental models of ischemia and head injury, as well as in recent head injury clinical trials. It has been safely used intraoperatively in a large series of patients undergoing craniotomy. Mild hypothermia is a technique that may soon be commonly employed alone or in conjunction with other methods of neuroprotection. Nurses caring for patients undergoing this technique must be aware of the practice implications associated with this procedure and adapt their care accordingly.

  View details for PubMedID 9785204

• Microsurgical resection of incompletely obliterated intracranial arteriovenous malformations following stereotactic radiosurgery NEUROLOGIA MEDICO-CHIRURGICA Chang, S. D., Steinberg, G. K., Levy, R. P., Marks, M. P., Frankel, K. A., Shuster, D. L., Marcellus, M. L. 1998; 38: 200-207

  Abstract

  Radiosurgery is effective in obliterating small arteriovenous malformations (AVMs), but less successful in thrombosing larger AVMs. This study reviewed patients who underwent surgical resection of their large AVMs following failed radiosurgical obliteration. AVMs from 36 patients (aged 7 to 64 years, mean 29.9) were surgically resected 1 to 11 years after radiosurgery. Initial AVM volumes were 0.7 to 117 cm3 (mean 21.6 cm3), and radiosurgical doses ranged from 4.6 to 45 Gray equivalent (GyE) (mean 21.1 GyE). Thirty AVMs (83%) were located in eloquent tissue. Venous drainage was deep (14), superficial (13), or both (9). Spetzler grades were II (2), III (12), IV (18), and V (4). Nine patients suffered rehemorrhage after radiosurgery but prior to surgery, while three patients developed radiation necrosis. Twenty-seven patients underwent endovascular embolization prior to surgery. During microsurgical resection, the AVMs were found to be significantly less vascular and more easily resected, compared to AVMs in patients who had not received radiosurgery. Histology showed endothelial proliferation with hyaline and mineralization in vessel walls. Partial or complete thrombosis of some AVM vessels, and evidence of vessel and brain necrosis were noted in many cases. Clinical outcome was excellent or good in 34 cases, with two patients dying of rebleeding from residual AVM. Five patients were neurologically worse following microsurgical resection. Final outcome was largely related to the pretreatment grade. Radiosurgery several years prior to surgical resection appears useful in treating unusually large and complex AVMs.

  View details for PubMedID 10235006

• Hu23F2G, an antibody recognizing the leukocyte CD11/CD18 integrin, reduces injury in a rabbit model of transient focal cerebral ischemia EXPERIMENTAL NEUROLOGY Yenari, M. A., Kunis, D., Sun, G. H., Onley, D., Watson, L., Turner, S., Whitaker, S., Steinberg, G. K. 1998; 153 (2): 223-233

  Abstract

  Neutrophils are known to mediate injury in acute ischemic stroke especially during reperfusion. Migration of neutrophils into regions of ischemic injury involves binding to the endothelial cell's intercellular adhesion molecule (ICAM-1) through the leukocyte integrin, CD11/CD18. We studied the potential for neuroprotection with a humanized antibody that binds to and blocks the functions of the CD11/CD18 integrin in a rabbit model of transient focal ischemia. Fifteen New Zealand White rabbits underwent transorbital occlusion of the left middle cerebral, anterior cerebral, and internal carotid arteries using aneurysm clips for 2 h, followed by 6 h of reperfusion. Treatment with a maximally saturating dose (4 mg/kg) of a humanized CD11/CD18 monoclonal antibody (Hu23F2G, ICOS Corp., Bothell, WA) (n = 8) or placebo (n = 7) was administered 20 min after occlusion and given as a single intravenous bolus. Hemispheric ischemic neuronal damage (IND) as seen on hematoxylin- and eosin-stained sections was significantly reduced in Hu23F2G-treated animals by 57% (Hu23F2G: 15 +/- 6.9%; placebo: 35 +/- 5%; mean +/- SEM, P < 0.05, t-test). Immunohistochemical staining with neutrophil elastase confirmed the presence of neutrophils within regions of IND in control brains. Treatment with Hu23F2G resulted in marked reduction of neutrophil infiltration. (No. of neutrophils/IND area: Hu23F2G 36.1 +/- 36.7 cm-2, placebo 460.6 +/- 101.8 cm-2, P = 0.001. ) Antagonism of neutrophil migration at the level of the CD11/CD18 integrin reduces ischemic injury in experimental stroke.

  View details for Web of Science ID 000076771200006

  View details for PubMedID 9784282

• The management of patients with arteriovenous malformations and associated intracranial aneurysms NEUROSURGERY Thompson, R. C., Steinberg, G. K., Levy, R. P., Marks, M. P. 1998; 43 (2): 202-211

  Abstract

  Few published studies have focused specifically on the unique management issues encountered in treating patients with arteriovenous malformations (AVMs) and associated intracranial aneurysms. The primary objective of this study was to retrospectively review the clinical and radiographic features of these patients.Medical records of all patients seen at Stanford University Hospital between 1988 and 1996 with a diagnosis of AVMs were retrospectively reviewed. Aneurysms were identified by conventional angiography and characterized by size, number, and location relative to the AVMs. AVMs were graded according to the Spetzler-Martin scale. Odds ratios were calculated for the risk of intracranial hemorrhage. Variables included age, sex, number of aneurysms, and AVM grade.Forty-five of 600 patients (7.5%) were identified as having coexisting intracranial aneurysms. All 45 patients had high-flow malformations, and 58% had AVMs of Spetzler-Martin Grade IV or higher. A majority of patients had multiple aneurysms. There was a statistically significant increase in AVM hemorrhage in female patients (odds ratio, 8.53 [1.87-38.98]; P < 0.005). There was no statistically significant correlation between the development of hemorrhage and either age, AVM grade, or the number of aneurysms. Twenty-three patients (51%) presented with intracranial hemorrhage: bleeding occurred from the AVMs in 15 and from ruptured aneurysms in 5, and the source of the bleeding could not be determined in 3. Overall, nine patients (20%) bled from ruptured aneurysms: five at presentation, two during or within 3 weeks of AVM treatment, and two from new aneurysms. Two of these nine patients died as a direct result of aneurysmal subarachnoid hemorrhage. Five patients (11%) developed new aneurysms.Aneurysms associated with AVMs are at risk for rupture before, during, and immediately after treatment of the AVMs. New aneurysms may arise in patients with high-flow AVMs. The risk of intracranial hemorrhage from either source is higher in female patients. To reduce the complications of intracranial hemorrhage in these patients, we recommend a management protocol designed to treat the aneurysms by surgical or endovascular means before administering definitive therapy for the AVMs. Meticulous intraoperative blood pressure control and fluid management during aneurysm surgery is critical to avoid hemorrhage from the AVMs.

  View details for PubMedID 9696071

• Stereotactic radiosurgery of angiographically occult vascular malformations: 14-year experience NEUROSURGERY Chang, S. D., Levy, R. P., Adler, J. R., Martin, D. P., Krakovitz, P. R., Steinberg, G. K. 1998; 43 (2): 213-220

  Abstract

  Radiosurgery is generally effective in obliterating true arteriovenous malformations, but less is known about its effects on angiographically occult vascular malformations (AOVMs). Since July 1983, 57 patients with surgically inaccessible AOVMs of the brain were treated using helium ion (47 patients) or linear accelerator (10 patients) radiosurgery. This study retrospectively evaluates the response of these AOVMs to treatment.All patients presented with previous hemorrhage. The mean patient age was 35.6 years (range, 13-71 yr). The mean AOVM volume was 2.25 cm3 (range, 0.080-15.2 cm3), treated with a mean of 18.0 Gy equivalent (physical dose x relative biological effectiveness, which is 1.3 for helium ion Bragg peak) (range, 7.0-40 Gy equivalent). The Drake scale scores before treatment were as follows: excellent (25 patients), good (26 patients), and poor (6 patients). The mean follow-up period was 7.5 years (range, 9 mo-13.8 yr).Eighteen patients (32%) bled symptomatically (20 hemorrhages) after radiosurgery. Sixteen hemorrhages occurred within 36 months after radiosurgery (9.4% annual bleed rate; 16 hemorrhages/171 patient yr); 4 hemorrhages occurred more than 36 months after treatment (1.6% annual bleed rate; 4 hemorrhages/257 patient yr) (P < 0.001). Complications included symptomatic radiation edema (four patients, 7%), necrosis (one patient, 2%), and increased seizure frequency (one patient, 2%). Eight patients underwent surgical resection of their AOVMs 8 to 59 months after radiosurgery because of subsequent hemorrhage. The Drake scale scores after treatment were as follows: excellent (25 patients), good (24 patients), poor (3 patients), and dead (5 patients, 3 of whom died as a result of causes unrelated to the AOVMs or radiosurgery).Radiosurgery may be useful for AOVMs located in surgically inaccessible regions of the brain. A significant decrease in bleed rate exists more than 3 years after treatment compared with the bleed rate within 3 years of treatment. Because current neuroradiological techniques are not able to image obliterative response in these slow-flow vascular lesions, longer term clinical follow-up is required.

  View details for Web of Science ID 000074979500010

  View details for PubMedID 9696072

• Aneurysms and arteriovenous malformations NEUROSURGERY CLINICS OF NORTH AMERICA Cockroft, K. M., Thompson, R. C., Steinberg, G. K. 1998; 9 (3): 565-?

  Abstract

  Patients with arteriovenous malformation (AVM)-associated aneurysms are a well-recognized subset of the cerebrovascular disease population. The origin of these dual lesions is likely multifactorial, with hemodynamic stresses having a dominant influence. In most patients who present with hemorrhage, the aneurysm is the usual source. Since aneurysm rupture continues to carry a more significant morbidity and mortality when compared to AVM hemorrhage, the authors recommend that the aneurysm be treated first or simultaneously with the AVM in the majority of cases. Treatment of the AVM first is primarily reserved for patients who have suffered bleeds from resectable AVMs.

  View details for Web of Science ID 000074837400013

  View details for PubMedID 9668188

• Thrombolysis with reteplase, an unglycosylated plasminogen activator variant, in experimental embolic stroke. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Yenari, M. A., Lee, L. K., Beaulieu, C., Sun, G. H., Kunis, D., Chang, D., Albers, G. W., Moseley, M. E., Steinberg, G. K. 1998; 7 (3): 179-186

  Abstract

  We incorporated diffusion-weighted magnetic resonance imaging (MRI) (DWI) and perfusion-weighted MRI (PWI) to evaluate the efficacy of thrombolysis in experimental embolic stroke using a plasminogen activator, reteplase. Reteplase (rPA) is an unglycosylated plasminogen activator with enhanced fibrinolytic potency. Right internal carotid arteries of 34 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans 0.5 hours after embolization confirmed successful embolization among 32. Intravenous treatment with rPA (n=11; 1 mg/kg bolus), recombinant tissue plasminogen activator (rt-PA) (n=11; 6 mg/kg bolus over 1 hour), or placebo (n=10) commenced 1 hour after stroke induction. MRIs were performed at 1.75, 3, and 5 hours after embolization. Six hours after embolization, brains were harvested and examined for hemorrhage. Posttreatment areas of diffusion abnormality and perfusion delay were graded using both a semiquantitative scale and percent areas expressed as a ratio of the baseline values. Improved perfusion was seen among the rt-PA, and rPA-treated groups compared with placebo, using a semiquantitative scale (P<.01 rt-PA v controls, P<.05, rPA v controls). DWI scans, however, were not improved with thrombolysis. Cerebral hemorrhage was not increased with thrombolytic treatment, although the incidence of wound site hemorrhage was higher with either rPA or rt-PA. One fatal systemic hemorrhage was observed in each of the thrombolytic-treated groups. Cerebral perfusion was equally improved with either rt-PA or rPA without causing excess cerebral hemorrhage. An advantage of rPA is single-bolus dosing rather than continuous infusion. Use of rPA for stroke treatment should be further explored.

  View details for PubMedID 17895078

• Pathological changes in surgically resected angiographically occult vascular malformations after radiation NEUROSURGERY Gewirtz, R. J., Steinberg, G. K., Crowley, R., Levy, R. P. 1998; 42 (4): 738-742

  Abstract

  The goal of this study was to evaluate the pathological changes associated with radiation treatment (stereotactic radiosurgery or conventional irradiation) of angiographically occult vascular malformations (AOVMs).Eleven patients underwent surgical resection of an AOVM in the mesial temporal lobe, brain stem, thalamus, or basal ganglia after previous radiation treatment. The indications for surgery were recurrent symptomatic bleeding from the lesion in 10 patients and recurrent intractable seizures in 1 patient. Radiation was used as the initial therapy because the risk of surgical resection was deemed too high. Three patients received conventional radiation therapy of 3000 to 5400 rads at an outside institution. One patient received radiosurgery with the gamma knife at another institution using a dose of 15 Gy to the margin. The remaining 7 patients received stereotactic radiosurgery with a helium-ion particle beam. The dose range was from 18 to 26 Gy equivalents. The interval from radiation to surgical resection ranged from 1 to 10 years, with a mean of 3.5 years. These lesions were compared with 10 nonirradiated cavernous malformations.One irradiated lesion was identified pathologically as a true arteriovenous malformation despite being angiographically occult. This lesion did not demonstrate significant changes in the vasculature but did have radiation necrosis of the surrounding brain 5 years after 25 Gy equivalents of helium-ion radiosurgery. Two other specimens were too small to identify the type of vascular malformation adequately. Of the remaining eight malformations identified as cavernous malformations, six showed a combination of marked fibrosis of the vascular channels, fibrinoid necrosis, and ferrugination. However, the fibrinoid necrosis was the only finding unique to the irradiated lesions compared with nonirradiated controls. All the irradiated lesions still had patent vascular channels; none were completely thrombosed.Radiosurgery or conventional radiation therapy did not cause histologic vascular obliteration in intracranial AOVMs evaluated 1 to 10 years (mean 3.5 yr) after radiation delivery. It should be recognized that these patients are irradiation failures who may not be representative of all irradiated patients. However, recurrent bleeding from AOVMs may relate to poor radiation response in some patients.

  View details for Web of Science ID 000073318600029

  View details for PubMedID 9574637

• Neuropsychological recovery from childhood moyamoya disease BRAIN & DEVELOPMENT Bowen, M., Marks, M. P., Steinberg, G. K. 1998; 20 (2): 119-123

  Abstract

  These reports describe mental recovery from childhood moyamoya disease wherein comprehensive and valid neuropsychological testing is administered in serial fashion. Two young children diagnosed with moyamoya disease underwent procedures to achieve bilateral revascularization. Neuropsychological studies were administered pre-operatively in one case and in serial fashion post-operatively through longer-term follow-up in both cases. Results indicated a trend of gradual improvements in both cases. The disease process and its postulated neuroanatomical and hemodynamic relationship to the psychometric findings are discussed.

  View details for PubMedID 9545184

• Management of intracranial aneurysms. Vascular medicine Chang, S. D., Steinberg, G. K. 1998; 3 (4): 315-326

  Abstract

  Intracranial aneurysms are lesions commonly encountered by neurosurgeons, usually as a result of subarachnoid hemorrhage. The preferred treatment of these aneurysms is either surgical clipping or endovascular coiling, both of which eliminate the aneurysm from the normal circulation to prevent aneurysmal enlargement or additional hemorrhage. Despite advances over the last several decades in the understanding of intracranial aneurysms, morbidity from treatment of these lesions remains significant. This review will discuss the epidemiology, anatomy and pathophysiology, clinical and radiographic diagnosis, various treatment options, and potential complications from aneurysm treatment.

  View details for PubMedID 10102672

• Multi-modality management of high flow AVMs in pediatric patients Cockroft, K. M., Marcellus, M. L., Marks, M. P., Huhn, S. L., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 1998: 335

  View details for Web of Science ID 000071417100334

• In vivo imaging of apoptotic cell death associated with cerebral hemispheric ischemia using Tc-99m radiolabeled annexin V. Blankenberg, F. G., Busch, E., Yenari, M. A., Davis, R. E., Sun, G. H., Tait, J. F., Kopiwada, S., Ohtsuki, K., Steinberg, G. K., Strauss, H. W. LIPPINCOTT WILLIAMS & WILKINS. 1998: 330

  View details for Web of Science ID 000071417100304

• Direct revascularization for Moyamoya disease in pediatric patients Golby, A. J., Thompson, R. C., Huhn, S., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 1998: 335

  View details for Web of Science ID 000071417100335

• Dose escalation safety and tolerance study of the competitive NMDA antagonist Selfotel (CGS 19755) in neurosurgery patients CLINICAL NEUROPHARMACOLOGY Yenari, M. A., Bell, T. E., Kotake, A. N., Powell, M., Steinberg, G. K. 1998; 21 (1): 28-34

  Abstract

  Selfotel (CGS 19755), a competitive N-methyl-D-aspartate antagonist, is neuroprotective in experimental models of ischemic cerebral injury. We studied the safety and tolerability of a single intravenous dose (0.5 to 2.0 mg/kg) of selfotel in neurosurgery patients. Thirty-two neurosurgical patients undergoing intracranial surgery were given ascending doses of selfotel 2 to 14 h before surgery. Serum selfotel levels were measured over a period of 24 h. Cerebrospinal fluid (CSF) levels were measured 1.5 to 18 h after dosing. Frequent side effects included psychomimetic symptoms such as hallucinations, abnormal dreaming, agitation, and paranoia among 20 (66%) patients. Ataxia was seen among five (16%) and dizziness among eight (25%). Symptoms occurred 38 min to 40 h from administration and persisted 5 min to 4 days. Symptom severity worsened with increasing area under the curve measurements and doses above 1.0 mg/kg. All symptoms were reversible and easily treated with intravenous haloperidol. Modest elevations of hepatic enzymes were observed among four patients. No patient had severe adverse reactions. Maximum selfotel levels attained were 143 mumol (serum) and 4.76 mumol (CSF). Peak serum levels among six patients were within potentially neuroprotective ranges. CSF levels remained detectable up to 18 h after dosing. No obvious relationship was seen between CSF drug levels and symptoms. Selfotel in doses of 0.5 to 2.0 mg/kg can be administered safely to neurosurgical patients. Maximum serum levels attained were within the range shown to be neuroprotective in experimental studies. Side effects even at the highest levels are tolerable and reversible. Selfotel use in patients at risk for cerebral injury should be further explored.

  View details for Web of Science ID 000073319400004

  View details for PubMedID 9579282

• SNX-111, a novel, presynaptic N-type calcium channel antagonist, is neuroprotective against focal cerebral ischemia in rabbits JOURNAL OF THE NEUROLOGICAL SCIENCES Perez-Pinzon, M. A., Yenari, M. A., Sun, G. H., Kunis, D. M., Steinberg, G. K. 1997; 153 (1): 25-31

  Abstract

  Cytosolic Ca2+ overload has been proposed as a main cause of neuronal injury during cerebral ischemia. SNX-111, a synthetic product of the naturally occurring omega-conotoxin MVIIA, is a novel, presynaptic N-type Ca2+ channel antagonist and has been reported to be neuroprotective against cerebral ischemia. We studied the neuroprotective effects of SNX-111 in a rabbit model of focal cerebral ischemia. New Zealand white male rabbits (2.5-3.5 kg) were given 1 mg/kg/h i.v. SNX-111 (n=8) or normal saline (n=8) 10 min after onset of a 2-h period of transient focal cerebral ischemia induced by occlusion of the left middle cerebral, anterior cerebral and internal carotid arteries followed by 4 h reperfusion. SNX-111 significantly attenuated overall cortical ischemic neuronal damage by 44% (saline, 38.7+/-3.0%; SNX-111, 21.5+/-6.0%, P<0.05) and regions of hyperintensity on T2-weighted MRI by 30% (saline, 70.6+/-4.0%; SNX-111, 49.3+/-11.0%, P<0.05). No significant difference in (regional cerebral blood flow) rCBF or MAP (mean arterial blood pressure) was found between SNX-111- and saline-treated rabbits suggesting that neuroprotection is due to a cellular effect. We conclude that SNX-111 reduces ischemic injury in this model. Its use as a clinical neuroprotective agent for cerebrovascular surgery or stroke should be investigated further.

  View details for Web of Science ID 000071162000005

  View details for PubMedID 9455974

• Diffusion-weighted magnetic resonance imaging characteristics of hemorrhagic transformation in experimental embolic stroke JOURNAL OF NEUROIMAGING Yenari, M. A., Beaulieu, C., Steinberg, G. K., Moseley, M. E. 1997; 7 (4): 227-231

  Abstract

  Diffusion-weighted magnetic resonance imaging (MRI) can detect ischemia within minutes of onset, but its ability to reliably detect hyperacute cerebral hemorrhage is unknown. The present study characterized diffusion-weighted, T2-weighted, and contrast-enhanced T1-weighted MRI appearances of hemorrhagic transformation within 5 hours of onset in experimental embolic stroke. Apparent diffusion coefficients and MRI signal characteristics were noted within corresponding regions of hemorrhage observed on gross pathology. Apparent diffusion coefficients were significantly increased within hemorrhagic lesions, but were still within the expected range for bland ischemia. The appearance of the hemorrhagic lesions on diffusion-weighted MRI was also very heterogeneous and not very useful for clinical screening. Other MRI modalities should be investigated, but computed tomography remains the only widely available clinical method of reliably detecting cerebral hemorrhage.

  View details for Web of Science ID A1997YA94200006

  View details for PubMedID 9344005

• Herpes simplex viral vectors expressing Bcl-2 are neuroprotective when delivered after a stroke JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Lawrence, M. S., McLaughlin, J. R., Sun, G. H., Ho, D. Y., McIntosh, L., Kunis, D. M., Sapolsky, R. M., Steinberg, G. K. 1997; 17 (7): 740-744

  Abstract

  Considerable interest has focused on the possibility of using viral vectors to deliver genes to the central nervous system for the purpose of decreasing necrotic neuronal injury. To that end, we have previously shown that a herpes simplex virus (HSV) vector expressing Bcl-2 could protect neurons from ischemia. In that study, vector was delivered before the ischemia. However, for such gene therapy to be of clinical use, vectors must be protective even if delivered after the onset of the insult. In the present study, we show that an HSV vector expressing Bcl-2 protects striatal neurons when delivered after focal ischemia. Rats were exposed to middle cerebral artery occlusion for 1 hour, followed by reperfusion, and damage was assessed 48 hours later. Delivery of the Bcl-2 vector 30 minutes after reperfusion (i.e., 1.5 hours after ischemia onset) prevented any significant loss of virally-targeted neurons in the striatum. In contrast, in rats microinfused with a vector only expressing a reporter gene, a highly significant loss of neurons occurred. By 4 hours into the reperfusion period (5 hours after ischemia onset), delivery of the Bcl-2 vector was no longer protective. These data show the efficacy of postinsult gene therapy strategies for the brain, underline the finite length of this temporal therapeutic window, and support the growing evidence attesting to the neuroprotective potential of Bcl-2.

  View details for Web of Science ID A1997XR34500003

  View details for PubMedID 9270490

• Improved perfusion with rt-PA and hirulog in a rabbit model of embolic stroke JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Yenari, M. A., deCrespigny, A., Palmer, J. T., Roberts, S., Schrier, S. L., Albers, G. W., Moseley, M. E., Steinberg, G. K. 1997; 17 (4): 401-411

  Abstract

  We conducted a study using diffusion-weighted (DWI) and perfusion-weighted (PWI) magnetic resonance imaging (MRI) to evaluate the efficacy of thrombolysis in an embolic stroke model with recombinant tissue plasminogen activator (rt-PA) and hirulog, a novel direct-acting antithrombin. DWI can identify areas of ischemia minutes from stroke onset, while PWI identifies regions of impaired blood flow. Right internal carotid arteries of 36 rabbits were embolized using aged heterologous thrombi. Baseline DWI and PWI scans were obtained to confirm successful embolization. Four animals with no observable DWI lesion on the initial scan were excluded; therefore, a total of 32 animals were randomized to one of three treatment groups: rt-PA (n = 11), rt-PA plus hirulog (n = 11), or placebo (n = 10). Treatment was begun 1 h after stroke induction. Intravenous doses were as follows: rt-PA, 5 mg/kg over 0.5 h with 20% of the total dose given as a bolus; hirulog, 1 mg/kg bolus followed by 5 mg/kg over 1 h. MRI was performed at 2, 3, and 5 h following embolization. Six hours after embolization, brains were harvested, examined for hemorrhage, then prepared for histologic analysis. The rt-PA decreased fibrinogen levels by 73%, and hirulog prolonged the aPTT to four times the control value. Posttreatment areas of diffusion abnormality and perfusion delay were expressed as a ratio of baseline values. Significantly improved perfusion was seen in the rt-PA plus hirulog group compared with placebo (normalized ratios of the perfusion delay areas were as follows: placebo, 1.58, 0.47-3.59; rt-PA, 1.12, 0.04-3.95; rt-PA and hirulog, 0.40, 0.02-1.08; p < 0.05). Comparison of diffusion abnormality ratios measured at 5 h showed trends favoring reduced lesion size in both groups given rt-PA (normalized ratios of diffusion abnormality areas were as follows: placebo, 3.69, 0.39-15.71; rt-PA, 2.57, 0.74-5.00; rt-PA and hirulog, 1.95, 0.33-6.80; p = 0.32). Significant cerebral hemorrhage was observed in one placebo, two rt-PA, and three rt-PA plus hirulog treated animals. One fatal systemic hemorrhage was observed in each of the rt-PA groups. We conclude that rt-PA plus hirulog improves cerebral perfusion but does not necessarily reduce cerebral injury. DWI and PWI are useful methods for monitoring thrombolysis.

  View details for Web of Science ID A1997WW73800005

  View details for PubMedID 9143222

• Mixed arteriovenous malformation and capillary telangiectasia: A rare subset of mixed vascular malformations - Case report JOURNAL OF NEUROSURGERY Chang, S. D., Steinberg, G. K., Rosario, M., Crowley, R. S., Hevner, R. F. 1997; 86 (4): 699-703

  Abstract

  In this report, the authors discuss the case of a patient with a mixed cerebrovascular malformation in which an arteriovenous malformation (AVM) was associated with a capillary telangiectasia. Recent reports have contained reviews of various subsets of mixed malformations. To the authors' knowledge, however, this is the first report of a mixed vascular malformation with both arterial and capillary components. The patient underwent complete resection of the AVM after presenting with a clinical hemorrhage. She required a second operation to resect the capillary telangiectasia after new symptoms developed several months following the first procedure. The authors conclude that a mixed AVM-capillary telangiectasia is a rare but distinct entity.

  View details for Web of Science ID A1997WP02000017

  View details for PubMedID 9120635

• Stereotactic radiosurgery of arteriovenous malformations: Pathologic changes in resected tissue CLINICAL NEUROPATHOLOGY Chang, S. D., Shuster, D. L., Steinberg, G. K., Levy, R. P., Frankel, K. 1997; 16 (2): 111-116

  Abstract

  Both stereotactic radiosurgery and microsurgery are treatment modalities for arteriovenous malformations (AVM), and more recently, multimodality treatment using these approaches has been utilized. We surgically resected AVMs from 33 patients (ages 7-64 years old, mean age 30.4) 1-11 years after radiosurgery. AVM volumes were 0.8-117 cm3 (mean 21.6 cm3), and doses ranged from 4.6-45 GyE (mean 21.2 GyE). AVMs resected were submitted for pathologic review. Each AVM was evaluated for the following radiation changes, and the number of AVMs demonstrating these changes were noted: endothelial proliferation (27), hyaline (18) and calcium (10) in AVM vessel walls, partial (9) or complete (24) thrombosis of some AVM vessels, and necrosis of vessels (15) and adjacent brain tissue (11). A semiquantitative scale (mild, moderate, severe) incorporating the aforementioned changes present in each case classified the extent of radiation-induced change. There was a significant correlation (r = 0.624, p < 0.01) between extent of radiation change and dose of radiation received. There was no absolute radiation dose threshold below which radiation-induced changes were absent. However, all but one patient receiving greater than 20 GyE developed moderate to severe radiation vascular changes and the 3 patients treated with greater than 30 GyE all had severe radiation-induced changes. Radiation changes in AVMs following stereotactic radiosurgery appear to be dose-related. The correlation of dose to extent of radiation change may allow the determination of the optimal dose of radiation to treat AVMs.

  View details for Web of Science ID A1997WR10700012

  View details for PubMedID 9101115

• Antibodies against the leukocyte CD11/CD18 integrin reduces injury in a model of transient focal cerebral ischemia Yenari, M., Kunis, D., Sun, G. H., Onley, D., Wu, A., Cosgrove, S., Steinberg, G. AMER HEART ASSOC. 1997: 132

  View details for Web of Science ID A1997WB81400183

• Time-course and treatment response with SNX-111, an N-type calcium channel blocker, in a rodent model of focal cerebral ischemia using diffusion-weighted MRI BRAIN RESEARCH Yenari, M. A., Palmer, J. T., Sun, G. H., deCrespigny, A., Moseley, M. E., Steinberg, G. K. 1996; 739 (1-2): 36-45

  Abstract

  Diffusion-weighted magnetic resonance imaging (DWI) is capable of noninvasively imaging acute cerebral ischemia. We demonstrate the utility of this technique by evaluating SNX-111, a novel N-type calcium channel blocker with potential neuroprotective properties, in a rodent model of transient focal ischemia. Twenty-four Sprague-Dawley rats weighing between 310-350 g underwent occlusion of the middle cerebral artery (MCAO) for 105 min followed by 22.5 h of reperfusion. Thirty minutes following MCAO, animals were randomized to receive SNX-111 5 mg/kg intravenously over 1 h vs. placebo. DWI and T2-weighted MRIs (T2W) were performed at 0.5, 1.5 and 24 h after the onset of ischemia. Area fractions of increased signal intensity on the DWI and T2W images were measured. DWI area fractions at 1.5 and 24 h were also normalized to the initial, pre-treatment scans. Apparent diffusion coefficients (ADC) were calculated from fitted maps. Tri-phenyl tetrazolium chloride (TTC) staining was performed on brains at 24 h and infarct area fractions were measured. SNX-111 treated animals showed significantly improved 1.5-h DWI scan ratios compared to controls (ratios of 1.06 +/- 0.25 vs. 2.98 +/- 0.78 SNX vs. controls respectively, P < 0.05). A trend toward improved DWI ratios was seen by 24 h in the SNX-111 group (2.5 +/- 0.75 vs. 4.12 +/- 1.6, N.S.) DWI, T2W and TTC area fractions at 24 h also showed trends favoring a neuroprotective effect of SNX-111. Bright areas on DWI corresponded to ADC decreases of about 30% compared to the non-ischemic hemisphere. These decreases were the same in both treatment groups and at each time point. DWI, T2W and TTC area fractions at 24 h were strongly correlated (r = 0.98, DWI and TTC; r = 0.99, T2W and TTC; r = 0.97, T2W and DWI, P < 0.0001). We conclude that in this ischemic model, SNX-111 provides early neuroprotection and that serial DWI is a useful way of demonstrating this.

  View details for Web of Science ID A1996VV25300005

  View details for PubMedID 8955922

• Phenytoin-related chorea in children with deep hemispheric vascular malformations JOURNAL OF CHILD NEUROLOGY Koukkari, M. W., Vanefsky, M. A., Steinberg, G. K., Hahn, J. S. 1996; 11 (6): 490-491

  View details for Web of Science ID A1996VW88600015

  View details for PubMedID 9120230

• CGS 19755 (Selfotel): A Novel Neuroprotective Agent Against CNS Injury. CNS drug reviews Pérez-Pinzón, M. A., Steinberg, G. K. 1996; 2 (3): 257-268

  Abstract

  The hypothesis that excitoxicity is a mechanism of damage following different types of cerebral injury including global and focal ischemia (34), and head and spinal cord trauma (6,7,9,25) has been supported by numerous findings. During ischemia for example, glutamate neurotoxicity is mediated in part through N-methyl-D-aspartate (NMDA) receptors, since selective antagonists to this receptor protect against hypoxic-ischemic injury (10,35,41). In the last few years, different NMDA antagonists have been developed and tested; they can be divided into competitive and noncompetitive antagonists. Noncompetitive NMDA antagonists are extremely lipophilic and reach high levels in the brain after systemic administration. Various studies have demonstrated that these agents provide neuroprotection against hypoxic-ischemic injury (for review see ref. 29). Many competitive NMDA antagonists are hydrophilic and require direct cerebral administration to obtain high brain levels. Newer competitive NMDA blockers, such as cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755, selfotel), provide neuroprotection against global ischemia, focal ischemia, and trauma when given systemically (2,3,32,33). Selfotel is currently being studied in multicenter safety and efficacy trials for stroke (17) and head trauma (6).

  View details for PubMedID 23766625

• Surgical resection of large incompletely treated intracranial arteriovenous malformations following stereotactic radiosurgery JOURNAL OF NEUROSURGERY Steinberg, G. K., Chang, S. D., Levy, R. P., Marks, M. P., Frankel, K., Marcellus, M. 1996; 84 (6): 920-928

  Abstract

  Although radiosurgery is effective in obliterating small arteriovenous malformations (AVMs), it has a lower success rate for thrombosing larger AVMs. The authors surgically resected AVMs from 33 patients ranging in age from 7 to 64 years (mean 30.4 years) 1 to 11 years after radiosurgery. Initial AVM volumes were 0.8 to 117 cm3 (mean 21.6 cm3), and doses ranged from 4.6 to 45 GyE (mean 21.2 GyE). Of 27 AVMs in eloquent or critical areas, 10 were located in language, motor, sensory, or visual cortex, 11 in the basal ganglia/thalamus, one each in the brainstem, hypothalamus, and cerebellum, and three in the corpus callosum. Venous drainage was deep in 13, superficial in 12, or both in eight lesions. Spetzler-Martin grades were II in one, III in 12, IV in 16, and V in four patients. Eight patients experienced rebleeding after radiosurgery but prior to surgery. Three patients developed radiation necrosis and 25 underwent endovascular embolization prior to surgery. At surgery the AVMs were found to be markedly less vascular, partially thrombosed, and more easily resected, compared to those seen in patients who had not undergone radiosurgery. Pathological investigation showed endothelial proliferation with hyaline and calcium in vessel walls. There was partial or complete thrombosis of some AVM vessels and evidence of vessel and brain necrosis in many cases. Complete resection was achieved in 28 patients and partial resection in five. Clinical outcome was excellent or good in 31 cases, and two patients died of rebleeding from residual AVM. Four patients' conditions worsened following microsurgical resection. Final clinical outcome was largely related to the pretreatment grade. Radiosurgery several years prior to open microsurgery may prove to be a useful adjunct in treating unusually large and complex AVMs.

  View details for PubMedID 8847585

• Vertebral artery stenting following percutaneous transluminal angioplasty - Technical note JOURNAL OF NEUROSURGERY Storey, G. S., Marks, M. P., Dake, M., Norbash, A. M., Steinberg, G. K. 1996; 84 (5): 883-887

  Abstract

  The authors report initial results and follow up using stent placement to treat atherosclerotic stenosis in vertebral arteries. Three patients with severe atherosclerotic vascular disease underwent vertebral artery stent placement using a balloon expandable stent. Medical therapy (aspirin and warfarin) and conventional percutaneous angioplasty failed to resolve the disease and the patients developed symptomatic restenosis within 3 months of angioplasty. Two patients had symptoms of anterior circulation ischemia with carotid artery occlusions and reduced supply to the anterior circulation from the stenosed vertebral arteries. One patient had recurrent posterior circulation symptoms. Stents were successfully placed in all three, resulting in immediate reversal of stenosis and resolution of symptoms. Clinical follow-up study (mean 9 months) has shown no recurrent symptoms in the patient with posterior circulation symptoms, but the two patients with anterior circulation ischemia did develop recurrent symptoms. Angiographic follow up in these two patients at 3 months and 1 year, however, demonstrated continued patency of vertebral artery lumina. They underwent extracranial-intracranial bypass surgery to relieve their symptoms. This experience suggests stents can be placed without complication in the proximal vertebral arteries and may have an adjunctive role in the treatment of atherosclerotic cerebrovascular disease following unsuccessful angioplasty.

  View details for PubMedID 8622166

• Dose escalation safety and tolerance study of the N-methyl-D-aspartate antagonist dextromethorphan in neurosurgery patients JOURNAL OF NEUROSURGERY Steinberg, G. K., Bell, T. E., Yenari, M. A. 1996; 84 (5): 860-866

  Abstract

  Experimental studies have shown that dextromethorphan, a noncompetitive N-methyl-D-aspartate antagonist is neuroprotective in experimental models of ischemic cerebral injury. The authors studied the safety and tolerability of oral dextromethorphan (DM) in humans, and correlated serum levels of this drug with cerebrospinal fluid (CSF) and brain levels. Neurosurgical patients undergoing intracranial surgery or endovascular procedures were given ascending doses of oral DM prior to and 24 hours after surgery. Serum, CSF, and brain levels of DM and its active metabolite, dextrorphan, were measured. One hundred eighty-one patients received a total of 212 courses of DM treatment in dose ranges of 0.8 to 9.64 mg/kg. Serum DM levels correlated highly with CSF and brain DM levels. Brain levels were 68-fold higher than serum levels, whereas CSF levels were fourfold lower than serum levels. The maximum DM levels attained were 1514 ng/ml (serum) 118 ng/ml (CSF), and 92,700 ng/g (brain). The maximum dextrorphan levels were 501 ng/ml (serum), 167 ng/ml (CSF), and 6840 ng/g (brain). In 11 patients, brain and plasma levels of DM were comparable to levels that have been shown to be neuroprotective in animal studies. Frequent side effects occurring at neuroprotective levels of DM included nystagmus (64%), nausea and vomiting (27%) distorted vision (27%), feeling "drunk" (27%), ataxia (27%), and dizziness (27%). All symptoms were reversible and no patient suffered severe adverse reactions. This study demonstrates that potentially neuroprotective doses of DM can be administered safely to neurosurgical patients. Brain and CSF levels of DM can be estimated from serum levels of the drug. Side effects, even at the highest levels, proved to be tolerable and reversible. Administration of DM to patients at risk for cerebral injury should be further explored.

  View details for Web of Science ID A1996UG54000023

  View details for PubMedID 8622162

• Rapid and near-complete resolution of moyamoya vessels in a patient with moyamoya disease treated with superficial temporal artery middle cerebral artery bypass PEDIATRIC NEUROSURGERY Wang, M. Y., Steinberg, G. K. 1996; 24 (3): 145-150

  Abstract

  Several groups have reported partial resolution of moyamoya vessels following surgical revascularization in pediatric patients, but angiographic documentation of near-complete resolution has been poor. We report here a case of a 5-year-old boy who underwent bilateral superficial temporal artery-middle cerebral artery bypass combined with unilateral encephaloduroarteriosynangiosis who demonstrated near-complete resolution of moyamoya vessels and a dramatic improvement in cerebral perfusion as measured by xenon-enhanced CT. The resolution of moyamoya networks may serve as an indicator of successful surgical revascularization.

  View details for Web of Science ID A1996VC15800007

  View details for PubMedID 8870018

• Overexpression of the glucose transporter gene with a Herpes simplex viral vector protects striatal neurons against stroke JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Lawrence, M. S., Sun, G. H., Kunis, D. M., Saydam, T. C., Dash, R., Ho, D. Y., Sapolsky, R. M., Steinberg, G. K. 1996; 16 (2): 181-185

  Abstract

  Herpes simplex virus vectors bearing a glucose transporter (GT) gene and a marker gene were found to protect neurons against a 1-h focal ischemic insult. Rats receiving the GT vector v alpha22beta gal alpha4GT exhibited a 67.4 +/- 35.3% survival of virally targeted neurons in the ischemic hemisphere compared with the contralateral control (n = 7), whereas rats receiving a control vector exhibited only 32.8 +/- 17.9% survival (n = 9). This significant improvement in survival (105%, p=0.022) suggests that energy failure is an important contributor to the neuropathology of ischemic damage in the striatum, and that it can be alleviated by gene transfer. This is the first demonstration of protection against ischemic cerebral injury by the direct transfer of GT genes to neurons.

  View details for Web of Science ID A1996TW39300001

  View details for PubMedID 8594048

• Cost-effectiveness of endovascular therapy in the surgical management of cerebral arteriovenous malformations AMERICAN JOURNAL OF NEURORADIOLOGY Jordan, J. E., Marks, M. P., Lane, B., Steinberg, G. K. 1996; 17 (2): 247-254

  Abstract

  To determine the economic effect of endovascular therapy in conjunction with surgery for cerebral arteriovenous malformations.Twenty-five patients with arteriovenous malformations treated with embolization and surgical excision or embolization alone were compared with reported results in 475 patients who underwent surgery only. Respective mean morbidity and mortality rates were calculated and a cost-effectiveness analysis was performed in terms of costs of hospitalization, professional fees, and other direct procedural and indirect costs. Quality-adjusted life-years saved were also calculated.The net effective treatment cost per cure was $71 366 (in 1992 dollars) for embolization and surgery compared with $78 506 for surgery alone. This resulted in a 9% average savings per treated patient. Cost per quality-adjusted life-year calculations resulted in a cost of $6734 for embolization and surgery and $9814 for surgical treatment alone, with savings as high as 34% when endovascular therapy was used.Endovascular therapy in conjunction with surgery resulted in significant economic benefits for treatment of cerebral arteriovenous malformations.

  View details for Web of Science ID A1996TW23400015

  View details for PubMedID 8938294

• MR and cerebrospinal fluid enzymes as sensitive indicators of subclinical cerebral injury after open-heart valve replacement surgery AMERICAN JOURNAL OF NEURORADIOLOGY Steinberg, G. K., Delapaz, R., Mitchell, R. S., Bell, T. E., Albers, G. W. 1996; 17 (2): 205-212

  Abstract

  To evaluate MR imaging and lumbar cerebrospinal fluid enzymes as potential sensitive indicators of cerebral injury after open-heart valve replacement surgery.Thirty-four patients with cardiac valvular disease were prospectively entered into this study and then underwent valve replacement or repair under cardiopulmonary bypass using a membrane oxygenator. In 26 patients, MR head images were obtained 12 to 24 hours before surgery; repeat MR images were obtained between 1 and 2 weeks after surgery. In 18 patients, lumbar puncture cerebrospinal fluid was analyzed 24 to 48 hours after surgery; the analyses included measurement of lactic dehydrogenase, creatine phosphokinase, adenylate kinase, and neuron-specific enolase.After surgery, MR imaging showed new ischemic lesions in 15 (58%) of 26 patients: 7 with deep white matter hyperintense lesions; 5 with brain stem, caudate, cerebellar, or thalamic/basal ganglia infarcts; 1 with intraparenchymal hemorrhage; 1 with a subdural hematoma and cortical infarct; and 1 with a corpus callosum lesion consistent with calcium or air. These new ischemic lesions seen on MR images were associated with a focal neurologic deficit in only 4 (27%) of the 15 patients. Neuron-specific enolase and lactic dehydrogenase were abnormally elevated after surgery in 5 (28%) of 18 patients. Adenylate kinase and creatine phosphokinase (brain isozymes) were elevated in one (67%) of the patients. Two (40%) of the five patients with abnormally high neuron-specific enolase or lactic dehydrogenase after surgery also showed a new focal neurologic deficit.MR imaging is a sensitive measure of subclinical cerebral ischemia after cardiac valve replacement under cardiopulmonary bypass. Cerebrospinal fluid neuron-specific enolase and lactic dehydrogenase are less sensitive than MR imaging for detecting subclinical cerebral ischemia, but these values were elevated after surgery more frequently than was adenylate kinase in our patients.

  View details for Web of Science ID A1996TW23400001

  View details for PubMedID 8938287

• Overexpression of bcl-2 with herpes simplex virus vectors protects CNS neurons against neurological insults in vitro and in vivo JOURNAL OF NEUROSCIENCE Lawrence, M. S., Ho, D. Y., Sun, G. H., Steinberg, G. K., Sapolsky, R. M. 1996; 16 (2): 486-496

  Abstract

  Previous studies have demonstrated that overexpression of the proto-oncogene bcl-2 can protect neuron and neuron-like cell lines from growth factor deprivation, calcium ionophores, glutamate excitotoxicity, hypoglycemia, free radicals, and lipid peroxidation. To determine whether Bcl-2 exhibits a similar protective effect in CNS neurons, we generated defective herpes simplex virus (HSV) vectors capable of overexpressing Bcl-2 in primary cultures and in the intact brain. Infection of hippocampal cultures with Bcl-2 vectors enhanced neuron survivorship after exposure to adriamycin, a potent oxygen radical generator. Furthermore, dichlorofluorescein measurements indicated that there was a significant reduction in the accumulation of oxygen radicals associated with this insult. Bcl-2 vectors also enhanced survival in cultured neurons after exposure to glutamate and hypoglycemia. Most significantly, the in vivo delivery of the vector protected neurons against adriamycin toxicity in the dorsal horn of the dentate gyrus and focal ischemia in the striatum.

  View details for Web of Science ID A1996TP51900007

  View details for PubMedID 8551333

• Herpes simplex virus mediated gene transfer protects against focal ischemia Lawrence, M., Sun, G. H., Sapolsky, R., Steinberg, G. AMER HEART ASSOC. 1996: 43

  View details for Web of Science ID A1996TN25400087

• Surgical obliteration for vein of galen malformation: A case report SURGICAL NEUROLOGY Moriarity, J. L., Steinberg, G. K. 1995; 44 (4): 365-369

  Abstract

  Vein of Galen aneurysm is a relatively rare vascular malformation, often resulting in high morbidity or mortality. Outcome is particularly poor in the neonatal population.We report staged surgical treatment of a vein of Galen aneurysm in a neonate who presented in congestive heart failure.Cerebral angiography 6 months following staged surgical treatment revealed complete obliteration of the aneurysm. The patient tolerated surgery well, and at 6 years of age is free of neurologic or cardiovascular impairment.While the endovascular approach is the procedure of first choice, aggressive medical management followed by staged surgical clipping of aneurysm feeders produced excellent results in this case of neonatal vein of Galen aneurysm. Staged surgical obliteration of arterial feeders should be considered as a therapy when endovascular methods are unsuccessful in safely curing these difficult vascular lesions.

  View details for Web of Science ID A1995TR43500019

  View details for PubMedID 8553256

• CORRELATION OF CGS-19755 NEUROPROTECTION AGAINST IN-VITRO EXCITOTOXICITY AND FOCAL CEREBRAL-ISCHEMIA JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM PEREZPINZON, M. A., Maier, C. M., Yoon, E. J., Sun, G. H., Giffard, R. G., Steinberg, G. K. 1995; 15 (5): 865-876

  Abstract

  The in vivo neuroprotective effect and brain levels of cis-4-phosphonomethyl-2-piperidine carboxylic acid (CGS 19755), a competitive N-methyl-D-aspartate (NMDA) antagonist, were compared with its in vitro neuroprotective effects. The dose-response for in vitro neuroprotection against both NMDA toxicity and combined oxygen-glucose deprivation (OGD) was determined in murine neocortical cultures. Primary cultures of neocortical cells from feta mice were injured by exposure to 500 microM NMDA for 10 min or to OGD for 45 min. The effect of CGS 19755 in both injury paradigms was assessed morphologically and quantitated by determination of lactate dehydrogenase release. Near complete neuroprotection was found at high doses of CGS 19755. The ED50 for protection against NMDA toxicity was 25.4 micro M, and against OGD the ED50 was 15.2 microM. For the in vivo paradigm rabbits underwent 2 h of left internal carotid, anterior cerebral, and middle cerebral artery occlusion followed by 4 h reperfusion; ischemic injury was assessed by magnetic resonance imaging and histopathology. The rabbits were treated with 40 mg/kg i.v. CGS 19755 or saline 10 min after arterial occlusion. CSF and brain levels of CGS 19755 were 12 microM and 5 microM, respectively, at 1 h, 6 microM and 5 microM at 2 h, and 13 microM and 7 microM at 4 h. These levels were neuroprotective in this model, reducing cortical ischemic edema by 48% and ischemic neuronal damage by 76%. These results suggest that a single i.v. dose penetrates the blood-brain barrier, attaining sustained neuroprotective levels that are in the range for in vitro neuroprotection.

  View details for Web of Science ID A1995RQ02000017

  View details for PubMedID 7673380

• NEUROPROTECTION BY THE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST CGP-40116 - IN-VIVO AND IN-VITRO STUDIES JOURNAL OF NEUROCHEMISTRY Maier, C. M., Sun, G. H., Kunis, D. M., Giffard, R. G., Steinberg, G. K. 1995; 65 (2): 652-659

  Abstract

  The goal of this study was to evaluate the effects of a novel competitive N-methyl-D-aspartate (NMDA) receptor antagonist, D-(E)-2-amino-4-methyl-5-phosphono-3-pentoic acid (CGP 40116), on neuronal damage in vivo and in vitro. We studied 20 rabbits that underwent a 2-h occlusion of the left internal carotid, anterior cerebral, and middle cerebral arteries followed by 4 h of reperfusion. Ten minutes after occlusion the animals were treated with either normal saline (n = 7) or CGP 40116 at two different doses (20 mg/kg, n = 6; 40 mg/kg, n = 7) administered over a 5-min period. Somatosensory evoked potentials were used to confirm adequate ischemia and neuronal injury was assessed by histopathology and magnetic resonance imaging. CGP 40116 decreased cortical ischemic neuronal damage by 74 and 77% (control, 37.8 +/- 13.1%; CGP 20 mg/kg, 9.9 +/- 3.6%; CGP 40 mg/kg, 8.7 +/- 3.7%; p < 0.01) and reduced cortical ischemic edema by 52 and 35% (control, 42.3 +/- 10.4%; CGP 20 mg/kg, 20.1 +/- 6.7%; CGP 40 mg/kg, 27.5 +/- 13.3%; p < 0.05) but did not protect against striatal injury. We performed a second study using primary cell cultures from mouse neocortex to determine the effects of CGP 40116 on neuronal death induced by a 10-min exposure to 500 microM NMDA or by 45 min of oxygen-glucose deprivation (OGD). Our results demonstrate that CGP 40116 was effective at attenuating neuronal death in a concentration-dependent manner (ED50 of 3.2 microM against NMDA toxicity and 23.1 microM against OGD) as measured by lactate dehydrogenase levels 24 h after the insult.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995RJ65700022

  View details for PubMedID 7616221

• IMAGING STUDIES OF CEREBRAL HYPERPERFUSION AFTER CAROTID ENDARTERECTOMY - CASE-REPORT JOURNAL OF NEUROSURGERY Penn, A. A., Schomer, D. F., Steinberg, G. K. 1995; 83 (1): 133-137

  Abstract

  A case is reported of severe unilateral hemispheric edema and localized hemorrhage associated with seizures following endarterectomy of an ipsilateral high-grade carotid stenosis. Imaging studies including angiography, computerized tomography (CT), magnetic resonance imaging/angiography, and xenon-CT, suggested postoperative ipsilateral cerebral hyperperfusion. Cerebral hyperperfusion syndromes caused by a probable failure of vascular autoregulation are rare but potentially serious complications after endarterectomy. The literature on this type of complication is briefly reviewed, and the role of various imaging modalities in identification of the syndrome and in guiding management decisions is emphasized.

  View details for Web of Science ID A1995RE60900023

  View details for PubMedID 7782830

• A RANDOMIZED TRIAL OF INTRAOPERATIVE, INTRACISTERNAL TISSUE-PLASMINOGEN ACTIVATOR FOR THE PREVENTION OF VASOSPASM NEUROSURGERY FINDLAY, J. M., KASSELL, N. F., WEIR, B. K., HALEY, E. C., KONGABLE, G., GERMANSON, T., TRUSKOWSKI, L., ALVES, W. M., HOLNESS, R. O., KNUCKEY, N. W., YONAS, H., STEINBERG, G. K., WEST, M., WINN, H. R., FERGUSON, G. 1995; 37 (1): 168–76

  Abstract

  A multicenter, randomized, blinded, placebo-controlled trial was conducted to study the possible role of intracisternally administered fibrinolytic agent recombinant tissue plasminogen activator (rt-PA) in preventing delayed onset cerebral vasospasm following aneurysmal subarachnoid hemorrhage (SAH). The target population was patients with ruptured saccular aneurysms causing severe SAH, placing them at high risk for vasospasm. Treatment consisted of a single 10 ml intraoperative injection of either vehicle buffer solution or rt-PA (1 mg/ml) into the opened basal subarachnoid cisterns immediately following aneurysm clipping. The major efficacy endpoint in this trial was angiographic vasospasm, and the major safety concern was intracranial hemorrhage. One hundred patients were randomized, 49 to placebo and 51 to rt-PA treatment. Baseline population characteristics were similar between the two groups. Severity of intracranial hemorrhage on computed tomographic scans was also similar between groups: 87.2% of both placebo and rt-PA treated patients had thick subarachnoid clots, and the rates for intracerebral and intraventricular hemorrhage were, respectively, 16.3% and 22.5% for placebo and 23.5% and 21.6% for rt-PA. Nine randomized patients did not receive treatment in the operating room, and in 8 this was due to conditions felt unsafe for the administration of a fibrinolytic agent. The overall incidence of angiographic vasospasm measured between the seventh and eleventh day following SAH was similar between the two groups, with arterial narrowing detected in 74.4% of dosed placebo patients and 64.6% of rt-PA treated patients. However, there was a trend toward lesser degrees of vasospasm in the rt-PA treated group. The rates for no or mild, moderate, and severe vasospasm were 69%, 16% and 15% in the rt-PA treated group, versus 42%, 35% and 23% in the placebo group (P = 0.07). When only those patients with thick subarachnoid clots were considered at the treating centers, there was a 56% relative risk reduction of severe vasospasm in the rt-PA treated group, which was significant (P = 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for DOI 10.1227/00006123-199507000-00041

  View details for Web of Science ID A1995RE54500085

  View details for PubMedID 8587685

• NARROW TEMPORAL THERAPEUTIC WINDOW FOR NMDA ANTAGONIST PROTECTION AGAINST FOCAL CEREBRAL-ISCHEMIA NEUROBIOLOGY OF DISEASE Steinberg, G. K., Panahian, N., PEREZPINZON, M. A., Sun, G. H., Modi, M. W., SEPINWALL, J. 1995; 2 (2): 109-118

  Abstract

  N-methyl-d-aspartate (NMDA) receptor antagonists have been shown to protect against focal cerebral ischaemia when administered either before or soon after the onset of ischaemia. However, the precise therapeutic window for protection using these drugs remains to be defined. We studied dextrorphan administration delayed for 2 or 4 h after transient middle cerebral focal ischaemia in a rabbit model. With a 2h delay, the mid (12.5 mg kg-1 h-1) and high doses (17.5 mg kg-1 h-1) provided significant cortical neuroprotection (50% and 58% reduction, respectively), and the low dose (7.5 mg kg-1 h-1) protected against ischaemic damage in the basal ganglia (52% reduction). Animals having steady-state serum dextrorphan concentrations greater than 2000 ng ml-1 showed 50% cortical neuroprotection for the 2-h-delay group. No significant neuroprotection was seen in the 4-h-delay group, and the 4 h delay animals with dextrorphan levels greater than 2000 ng ml-1 had more severe ischaemic oedema than the saline controls. These results suggest a narrow temporal therapeutic window for neuroprotection, where delivery of drug delayed by 2 h was efficacious but treatment at 4 h after ischaemia onset was not beneficial and possibly harmful. These findings may have important implications for the treatment of clinical stroke.

  View details for Web of Science ID A1995TA63500005

  View details for PubMedID 8980014

• THROMBOLYSIS WITH TISSUE-PLASMINOGEN ACTIVATOR (TPA) IS TEMPERATURE-DEPENDENT THROMBOSIS RESEARCH Yenari, M. A., Palmer, J. T., Bracci, P. M., Steinberg, G. K. 1995; 77 (5): 475-481

  Abstract

  Thrombolysis with tissue plasminogen activator (tPA) and hypothermia are two potential treatment modalities for acute ischemic stroke. Many investigators are studying these modalities both in the laboratory and in clinical trials. Because these modalities each appear to show benefit in animal models, there is considerable interest in studying combined therapy with both thrombolysis and hypothermia. However, it is known that alterations in the coagulation system can occur with decreased body temperature. Clinicians have frequently observed bleeding problems when patients are subjected to hypothermia for a variety of reasons. Hypothermia induced coagulopathy has been attributed to a variety of factors. Hypothermia can cause platelet dysfunction, inhibition of clotting factors, increased fibrinolysis and endogenous production of a heparin-like factor. Groups who studied fibrinolysis and temperature, however, found the opposite to be the case. Clot lysis studies with streptokinase showed increased fibrinolysis at higher temperatures. Data by Mumme suggested that the peak fibrinolytic activity of streptokinase was at 40 degrees C, but at 43 degrees C fibrinolytic activity was decreased. Rijken et al studied plasminogen activation with tissue plasminogen activator (tPA), urokinase and streptokinase at extremely low temperatures. They found less plasminogen activation and fibrinogen degradation at 25 degrees C compared to 37 degrees C, but negligible differences at 10 degrees C, 0 degrees C and -8 degrees C. To our knowledge, there is no data studying the fibrinolytic activity of tissue plasminogen activator (tPA) at temperature ranges between 25-37 degrees C which is the range of temperatures used clinically for therapeutic purposes.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995QJ05000009

  View details for PubMedID 7778062

• NEUROPROTECTION BY N-METHYL-D-ASPARTATE ANTAGONISTS IN FOCAL CEREBRAL-ISCHEMIA IS DEPENDENT ON CONTINUED MAINTENANCE DOSING NEUROSCIENCE Steinberg, G. K., Yoon, E. J., Kunis, D. M., Sun, G. H., Maier, C. M., Grant, G. A. 1995; 64 (1): 99-107

  Abstract

  While N-methyl-D-aspartate antagonists have been shown to attenuate neuronal damage in focal cerebral ischemia, few studies have examined whether continuous or multiple dose treatment is necessary for maximum efficacy. We studied the effect of a loading dose only or load plus maintenance infusion using several non-competitive N-methyl-D-aspartate antagonists (dextromethorphan, dextrorphan, MK-801) and the levorotatory enantiomer of dextromethorphan (levomethorphan) in a rabbit model of focal cerebral ischemia. Forty-seven anesthetized rabbits underwent occlusion of the left internal carotid, anterior cerebral and middle cerebral arteries for 2 h followed by 4 h of reperfusion. Drugs were administered 10 min after occlusion. Dextromethorphan and dextrorphan protected against ischemic edema only when given as load plus maintenance (29% and 31% reduction, respectively), while both load only and load plus maintenance of MK-801 protected against edema (26% and 31% reduction, respectively). Levomethorphan load plus maintenance also protected against ischemic edema (25% reduction). However, dextromethorphan and dextrorphan both required maintenance infusion to protect against ischemic neuronal damage (24% and 27% reduction in area of ischemic neuronal damage, respectively), while levomethorphan failed to protect against neuronal injury even when given as load plus maintenance. Administration of MK-801 as load plus maintenance reduced ischemic neuronal damage by 23%, but this difference was not quite statistically significant. These results suggest that processes of ischemic damage, such as excitotoxic injury, continue for several hours beyond the initial period of focal ischemia, and that non-competitive N-methyl-D-aspartate antagonists require more prolonged administration to achieve neuroprotection.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1995QC34300010

  View details for PubMedID 7708219

• ANGIOPLASTY OF INTRACRANIAL CIRCULATION STENOSIS MARKS, M., NORBASH, A., CLARK, J., ALBERS, G., STEINBERG, G. AMER HEART ASSOC. 1995: 159

  View details for Web of Science ID A1995PZ89600053

• CURRENT SURGICAL-MANAGEMENT OF MOYA-MOYA DISEASE VANEFSKY, M. A., STEINBERG, G. K. AMER HEART ASSOC. 1995: 172

  View details for Web of Science ID A1995PZ89600113

• CGS-19755 - CORRELATION OF IN-VITRO NEUROPROTECTION, PROTECTION AGAINST EXPERIMENTAL-ISCHEMIA AND CSF LEVELS IN CEREBROVASCULAR SURGERY PATIENTS PEREZPINZON, M. A., MAIER, C. M., SUN, G. H., YOON, E., BELL, T. E., POWELL, M., KOTAKE, A., GIFFARD, R. G., STEINBERG, G. K. AMER HEART ASSOC. 1995: 182

  View details for Web of Science ID A1995PZ89600174

• COMBINED USE OF ENDOVASCULAR COILS AND SURGICAL CLIPPING FOR INTRACRANIAL ANEURYSMS AMERICAN JOURNAL OF NEURORADIOLOGY Marks, M. P., Steinberg, G. K., Lane, B. 1995; 16 (1): 15-18

  Abstract

  We report two cases in which combined surgical clipping and endovascular coils have been used to treat intracranial aneurysms. In one case, a 59-year-old woman with multiple episodes of subarachnoid hemorrhage had an anterior communicating artery aneurysm, which was initially treated with coils and then clipped to occlude the aneurysm securely. In the second case, a broad-based cavernous aneurysm could not be completely surgically occluded, but surgical clipping did decrease the aneurysm neck size, allowing it to be successfully treated with coils.

  View details for PubMedID 7900585

• CEREBRAL-DAMAGE CAUSED BY INTERRUPTED, REPEATED ARTERIAL-OCCLUSION VERSUS UNINTERRUPTED OCCLUSION IN A FOCAL ISCHEMIC MODEL JOURNAL OF NEUROSURGERY Steinberg, G. K., Panahian, N., Sun, G. H., Maier, C. M., Kunis, D. 1994; 81 (4): 554-559

  Abstract

  Temporary intracranial arterial occlusion is often utilized during the surgical treatment of intracranial aneurysms. Although numerous experimental studies have suggested that repetitive, brief periods of global ischemia cause more severe cerebral injury than a similar single period of global ischemia, this issue has not been extensively studied in relation to focal ischemia. It remains controversial whether it is safer to use brief periods of interrupted, temporary occlusion separated by reperfusion periods, or a more prolonged, single temporary occlusion. This question is addressed in studies on a rabbit model of transient, focal cerebral ischemia. Sixteen anesthetized rabbits underwent transorbital occlusion of the left internal carotid, middle cerebral, and anterior cerebral arteries, with one of two paradigms:uninterrupted occlusion (1 hour of temporary occlusion followed by 5 hours of reperfusion in eight rabbits), or interrupted occlusion (three separate 20-minute periods of occlusion, with 10 minutes of reperfusion between occlusions, followed by 4 hours, 40 minutes of reperfusion in eight rabbits). Histopathological evaluation for ischemic neuronal damage and magnetic resonance imaging studies for ischemic edema were conducted 6 hours after the initial arterial occlusion. The animals in the interrupted, repeated occlusion group showed a 59% decrease in the area of cortical ischemic neuronal damage (mean +/- standard error of the mean 10.0% +/- 1.7%) compared with the uninterrupted occlusion group (24.4% +/- 5%, p = 0.016). There was no difference between the groups in the extent of striatal ischemic damage or area of ischemic edema. These results suggest that interrupted, repeated focal ischemia causes less cortical ischemic injury than uninterrupted transient ischemia of a similar total duration. Although caution should be exercised in extrapolating from these results to the clinical situation, they may have important implications for temporary arterial occlusion during intracranial surgery.

  View details for Web of Science ID A1994PJ91900008

  View details for PubMedID 7931589

• THE ANATOMY OF THE POSTERIOR COMMUNICATING ARTERY AS A RISK FACTOR FOR ISCHEMIC CEREBRAL INFARCTION NEW ENGLAND JOURNAL OF MEDICINE Schomer, D. F., Marks, M. P., Steinberg, G. K., Johnstone, I. M., Boothroyd, D. B., Ross, M. R., Pelc, N. J., Enzmann, D. R. 1994; 330 (22): 1565-1570

  Abstract

  After the occlusion of an internal carotid artery the principal source of collateral flow is through the arteries of the circle of Willis, but the size and patency of these arteries are quite variable. Study of the anatomy of the collateral pathways in patients with internal-carotid-artery occlusion with or without infarction in the watershed area of the deep white matter may identify patterns that afford protection from ischemic infarction.Using conventional magnetic resonance imaging and three-dimensional phase-contrast magnetic resonance angiography, we evaluated 29 consecutive patients (32 hemispheres at risk) with angiographically proved occlusion of the internal carotid artery. Four collateral pathways to the occluded vessel were evaluated: the proximal segment of the anterior cerebral artery, the posterior communicating artery, the ophthalmic artery, and leptomeningeal collateral vessels from the posterior cerebral artery.Only features of the ipsilateral posterior communicating artery were related to the risk of watershed infarction. The presence of posterior communicating arteries measuring at least 1 mm in diameter was associated with the absence of watershed infarction (13 hemispheres, no infarcts; P < 0.001). Conversely, there were 4 watershed infarcts in the 6 hemispheres with posterior communicating arteries measuring less than 1 mm in diameter and 10 infarcts in the 13 hemispheres with no detectable flow in the ipsilateral posterior communicating artery.A small (< 1 mm in diameter) or absent ipsilateral posterior communicating artery is a risk factor for ischemic cerebral infarction in patients with internal-carotid-artery occlusion.

  View details for PubMedID 8177246

• A MECHANICALLY DETACHABLE COIL FOR THE TREATMENT OF ANEURYSMS AND OCCLUSION OF BLOOD-VESSELS AMERICAN JOURNAL OF NEURORADIOLOGY Marks, M. P., CHEE, H., Liddell, R. P., Steinberg, G. K., Panahian, N., Lane, B. 1994; 15 (5): 821-827

  Abstract

  To evaluate mechanically detachable coil designs capable of controlled and instantaneous release within an aneurysm or vascular space.Three mechanically detachable coil designs, clamped ball, looped ribbon, and interlocking cylinder, were evaluated using in vitro and in vivo testing to study reliability of coil release, retractability, and coil behavior in a microcatheters. In vitro tests were performed using a glass side-wall aneurysm model and conventional microcatheters. In vivo experiments in rabbits included aneurysm models (side-wall and bifurcation) and arterial occlusions (carotid and renal).All three designs deployed coils easily and were able to retract coils after partial deployment. Motion was seen in previously released coils and in the catheter when using the clamped ball and looped ribbon designs. The interlocking cylinder design did not cause similar motion. When compared with the other two designs, the interlocking cylinder had significantly greater separation forces between coil pusher and coil while in the catheter. Frictional forces within the catheter were lower for the interlocking cylinder mechanically detachable coil design than for a commercially available conventional coil and coil pusher system. During in vivo testing, the mechanically detachable coil design operated smoothly in the catheter, providing good release and retraction in aneurysms and straight vessels.The interlocking cylinder mechanically detachable coil design is superior to the other two tested designs. The mechanically detachable coil was reliably delivered and detached in in vivo testing for the treatment of aneurysms and for the occlusion of blood vessels.

  View details for PubMedID 8059648

• STENT PLACEMENT FOR ARTERIAL AND VENOUS CEREBROVASCULAR-DISEASE - PRELIMINARY EXPERIENCE RADIOLOGY Marks, M. P., Dake, M. D., Steinberg, G. K., Norbash, A. M., Lane, B. 1994; 191 (2): 441-446

  Abstract

  To report initial clinical experience with stent placement in the cerebrovascular circulation.Four patients underwent arterial or venous stent placement. Two patients had cervical internal carotid artery dissections, with aneurysms and stenoses of the distal cervical carotid artery. Two patients had venous occlusive disease involving the major dural sinuses, with substantial pressure gradients across the stenoses.Immediately after stent placement, the true arterial lumina returned to normal diameter and both carotid aneurysms were more than 90% occluded. Follow-up angiography demonstrated continued improvement in the arterial aneurysms. Both patients with dural sinus venous occlusive disease showed substantial improvement of the sinus stenoses and substantial reversal of the pressure gradients after venous stent placement. At follow-up, these patients have done well.This preliminary experience suggests there may be a role for stents in the management of arterial and venous cerebrovascular disease, including carotid artery dissection and venous occlusive disease.

  View details for PubMedID 8153318

• FAILURE OF INTRACISTERNAL TISSUE-PLASMINOGEN ACTIVATOR TO PREVENT VASOSPASM IN CERTAIN PATIENTS WITH ANEURYSMAL SUBARACHNOID HEMORRHAGE NEUROSURGERY Steinberg, G. K., Vanefsky, M. A., Marks, M. P., Adler, J. R., KOENIG, G. H. 1994; 34 (5): 809-813

  Abstract

  Recent experimental and clinical reports suggest that the intracisternal administration of recombinant tissue plasminogen activator (tPA) within 72 hours of subarachnoid hemorrhage decreases the incidence of severe angiographic and clinical vasospasm. In this report, we present four of eight patients with aneurysmal subarachnoid hemorrhage who developed angiographic and clinical vasospasm with delayed neurological deterioration, despite the use of intracisternal tPA after early aneurysm clipping. One patient did not clear her massive subarachnoid hemorrhage with tPA; one patient had extremely poor collateral flow with occlusion of one cervical internal carotid artery and 80% stenosis of the other cervical internal carotid artery; the other two patients had a subarachnoid hemorrhage 7 to 12 days after their sentinel hemorrhage. Three patients ultimately made excellent or good recoveries, and one was left with hemiparesis. The four other patients treated by this protocol did not develop vasospasm. We conclude that intracisternal tPA may not prevent vasospasm in certain patients. This may relate to inadequate clearing of the subarachnoid clot, pre-existing poor collateral supply, or the occurrence of prior subarachnoid hemorrhage.

  View details for PubMedID 8052377

• NEURONAL PROTECTION TO FOCAL CEREBRAL-ISCHEMIA BY THE COMPETITIVE NMDA RECEPTOR ANTAGONIST CGS-19755 IN RABBITS PEREZPINZON, M. A., SUN, G. H., YOON, E., STEINBERG, G. K., LUTZ, P. FEDERATION AMER SOC EXP BIOL. 1994: A654

  View details for Web of Science ID A1994ND19700401

• PROTECTION AGAINST FOCAL CEREBRAL-ISCHEMIA FOLLOWING EXPOSURE TO A PULSED ELECTROMAGNETIC-FIELD BIOELECTROMAGNETICS GRANT, G., Cadossi, R., Steinberg, G. 1994; 15 (3): 205-216

  Abstract

  There is evidence that electromagnetic stimulation may accelerate the healing of tissue damage following ischemia. We undertook this study to investigate the effects of low frequency pulsed electromagnetic field (PEMF) exposure on cerebral injury in a rabbit model of transient focal ischemia (2 h occlusion followed by 4 h of reperfusion). PEMF exposure (280 V, 75 Hz, IGEA Stimulator) was initiated 10 min after the onset of ischemia and continued throughout reperfusion (six exposed, six controls). Magnetic resonance imaging (MRI) and histology were used to measure the degree of ischemic injury. Exposure to pulsed electromagnetic field attenuated cortical ischemia edema on MRI at the most anterior coronal level by 65% (P < 0.001). On histologic examination, PEMF exposure reduced ischemic neuronal damage in this same cortical area by 69% (P < 0.01) and by 43% (P < 0.05) in the striatum. Preliminary data suggest that exposure to a PEMF of short duration may have implications for the treatment of acute stroke.

  View details for Web of Science ID A1994NQ25900004

  View details for PubMedID 8074737

• A MULTIVARIATE-ANALYSIS OF MAGNETIC-RESONANCE CHARACTERISTICS AND HISTOPATHOLOGY OF ANGIOGRAPHICALLY OCCULT VASCULAR MALFORMATIONS VANEFSKY, M., NORBASH, A., SNIPES, J., MARKS, M., STEINBERG, G. AMER HEART ASSOC. 1994: 252

  View details for Web of Science ID A1994MP10600069

• SURGICAL RESECTION OF BRAIN-STEM AND THALAMIC ANGIOGRAPHICALLY OCCULT VASCULAR MALFORMATIONS - ADVANTAGES AND LIMITATIONS STEINBERG, G. K. AMER HEART ASSOC. 1994: 248

  View details for Web of Science ID A1994MP10600045

• Migraine and vertebrobasilar dissection: Case reports. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Yenari, M. A., Steinberg, G. K., Marks, M. P. 1994; 4 (1): 36-41

  Abstract

  We report two patients with chronic migraine headaches who developed vertebrobasilar arterial dissections. In both cases, there was a change in both the character and location of the headaches, which prompted further evaluation with magnetic resonance imaging and angiography, which led to the diagnosis. Other possible risk factors for dissection in these patients included hypertension, exercise, and chiropractic manipulation. Both patients were treated with anticoagulation and recovered with little to no neurologic deficit. A review of the literature relating migraine and arterial dissection suggests that there may be an association. Although more extensive controlled studies are needed to demonstrate the significance of this association, we suggest that the diagnosis of cervicocranial arterial dissection be strongly considered in migraine patients who develop an abrupt change in the nature of their headaches.

  View details for DOI 10.1016/S1052-3057(10)80144-2

  View details for PubMedID 26487533

• Neuropsychological improvements following endovascular embolization of arteriovenous malformation. Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association Bowen, M., Steinberg, G. K., Marks, M., ACOSTA, Y. 1994; 4 (3): 194-199

  Abstract

  Two right-handed patients with large, left-hemisphere arteriovenous malformations (AVM) underwent serial endovascular embolization and neuropsychological testing procedures. One patient presented with hemorrhage, hemiplegia, and aphasia; the other patient presented with a seizure only with multiple cognitive impairments. Case 1 was assessed for motor-sensory skills in the left hand and for visual recall (nondominant hemisphere). Case 2 was administered a more global assessment of cognitive functions. Both patients demonstrated significant improvements in neuropsychological functions 1 month following endovascular embolization with >50% reduction in AVM volume. The nature and extent of these improvements are discussed with respect to intervention-related, reversed impairments.

  View details for DOI 10.1016/S1052-3057(10)80186-7

  View details for PubMedID 26486060

• STEREOTAXIC RADIOSURGICAL ABLATION - AN ALTERNATIVE TREATMENT FOR RECURRENT AND MULTIFOCAL HEMANGIOBLASTOMAS - A REPORT OF 4 CASES SURGICAL NEUROLOGY Page, K. A., WAYSON, K., Steinberg, G. K., Adler, J. R. 1993; 40 (5): 424-428

  Abstract

  Craniotomy and resection is usually a safe and effective treatment for hemangioblastoma. However, since the surgical removal of recurrent and multifocal tumors can be associated with greater risks, stereotaxic radiosurgery was used to ablate hemangioblastomas in four patients with von Hippel-Lindau disease. In two of these cases a symptomatic lesion was surgically resected just prior to radiosurgery. The 11 radiosurgically treated tumors (four patients) were spherical and varied in diameter from 0.75 to 2.0 cm with a mean of 1.25 cm. Dose ranged from 30 to 75 Gy with a mean of 35 Gy. After a mean clinical and radiologic follow-up of greater than 1 1/2 years, tumor size and/or cyst formation was controlled in all cases. Nevertheless, it was necessary to temporarily shunt a tumor cyst in one patient. In another case, aggressive treatment resulted in symptomatic radiation necrosis. Despite such potential problems we believe that radiosurgical tumor ablation is a reasonable alternative to craniotomy and/or radiation therapy in poor risk patients. This report is believed to be the first published description of the use of radiosurgery in the treatment of hemangioblastoma.

  View details for Web of Science ID A1993ME16400012

  View details for PubMedID 8211662

• NEUROPROTECTION BY THE ALPHA-2-ADRENOCEPTOR AGONIST DEXMEDETOMIDINE IN A FOCAL MODEL OF CEREBRAL-ISCHEMIA ANESTHESIOLOGY Maier, C., Steinberg, G. K., Sun, G. H., ZHI, G. T., Maze, M. 1993; 79 (2): 306-312

  Abstract

  Dexmedetomidine, a highly selective alpha 2-adrenoreceptor agonist, decreases central sympathetic activity and reduces the anesthetic requirement of halothane. Preliminary studies show that dexmedetomidine improves the outcome from ischemic injury and, therefore, may have potential therapeutic value.The authors studied 14 rabbits that underwent a 2-h occlusion of the left internal carotid, anterior cerebral, and middle cerebral arteries, followed by 4 h of reperfusion. Ten minutes after occlusion, the animals were treated with either normal saline (n = 7) or dexmedetomidine (n = 7) using a computer-controlled infusion rate calculated to maintain a steady state plasma concentration. Halothane concentration was reduced by 50% for dexmedetomidine-treated animals to maintain a comparable level of anesthesia. Somatosensory evoked potentials were used to confirm adequate ischemia, and injury was assessed by histopathology.There were significant differences in the area of ischemic neuronal damage between the groups in the cortex (halothane alone, 38.2 +/- 6.0% SEM vs. halothane plus dexmedetomidine, 20.0 +/- 2.7% SEM, P = 0.018), but not in the striatum (halothane alone, 68.7 +/- 12.6% SEM vs. halothane plus dexmedetomidine, 43.5 +/- 15.9% SEM, P = 0.24), nor in physiologic parameters. Dexmedetomidine plasma levels obtained every 90 min showed a mean of 4.0 +/- 0.15 ng/ml.Results from this study indicate that postischemic administration of dexmedetomidine, in a dose that reduces the anesthetic requirements by 50%, has a neuroprotective effect in this model of focal cerebral ischemia.

  View details for Web of Science ID A1993LP76100015

  View details for PubMedID 8102042

• DELIBERATE BASILAR OR VERTEBRAL ARTERY-OCCLUSION IN THE TREATMENT OF INTRACRANIAL ANEURYSMS - IMMEDIATE RESULTS AND LONG-TERM OUTCOME IN 201 PATIENTS JOURNAL OF NEUROSURGERY Steinberg, G. K., Drake, C. G., Peerless, S. J. 1993; 79 (2): 161-173

  Abstract

  Deliberate occlusion of the basilar or vertebral arteries was performed in 201 patients with intracranial aneurysms, where the aneurysmal neck could not be clipped directly. The aneurysms arose from the basilar apex in 83 cases, the basilar trunk in 46, the vertebrobasilar junction in 35, and the vertebral artery in 37; 87% of the aneurysms were classified as giant lesions (> 2.5 cm). There were 85 upper basilar occlusions, 41 lower basilar occlusions, 29 bilateral vertebral occlusions, and 48 unilateral vertebral artery occlusions. The clinical follow-up period varied from 1 to 23 years, with a mean of 9.5 years. Overall long-term results were excellent in 68% of the patients, good in 5%, and poor in 3%; 24% died. Clinical outcome varied according to aneurysm site; excellent or good results were achieved in 64% of the patients with basilar apex, 76% with basilar trunk, 74% with vertebrobasilar junction, and 87% with vertebral artery aneurysms. Clinical outcome also varied depending on preoperative grade: 86% of the patients with an excellent presenting grade achieved excellent results. The size of the posterior communicating arteries was a good predictor of tolerance to basilar artery occlusion (p < 0.05). Successful aneurysm thrombosis was achieved in 78% of the patients. The neurological status in 26 patients (13%) deteriorated due to vertebrobasilar ischemia occurring within the 1st postoperative week, and thrombosis or embolism was implicated much more frequently than hemodynamic insufficiency. Subarachnoid hemorrhage (SAH) in 14 patients, vasospasm in five patients, and surgical trauma in seven patients accounted for additional morbidity in the 1st month following operation; however, many of these patients ultimately made an excellent recovery. Late vertebrobasilar ischemic complications or neurological deterioration from persistent mass effect occurred in 4% of patients with successful aneurysm thrombosis 6 weeks to 18 months after arterial ligation. Among the 43 patients with incompletely thrombosed aneurysms, 67% developed early or late neurological deterioration from SAH, progressive brain-stem compression, or brain-stem stroke, with 86% of the complications proving fatal.

  View details for Web of Science ID A1993LP27600001

  View details for PubMedID 8331396

• PROFILES OF EXTRACELLULAR AMINO-ACID CHANGES IN FOCAL CEREBRAL-ISCHEMIA - EFFECTS OF MILD HYPOTHERMIA NEUROLOGICAL RESEARCH Lo, E. H., Steinberg, G. K., Panahian, N., Maidment, N. T., Newcomb, R. 1993; 15 (4): 281-287

  Abstract

  Mild hypothermia has been recently proposed as a therapeutic approach for ameliorating ischaemic cerebral damage. The protective potential of mild hypothermia, however, may be dependent on its ability to reduce the efflux of potentially excitotoxic amino acids and the severity of ischaemia. In this study, we examined the effects of mild brain hypothermia (33 degrees C) in a rabbit model of permanent focal ischaemia. In vivo microdialysis was used to measure extracellular amino acids in central and peripheral regions of the ischaemic cortex. In normothermic ischaemia (n = 7), glutamate, alanine, taurine, and phosphoethanolamine increased above baseline levels by about 2 h post-ischaemia. Mild hypothermia (n = 7) reduced glutamate efflux only in the central regions and increased alanine efflux in the peripheral regions of ischaemia. There were no significant differences in other amino acid levels between the two temperature groups. Haematoxylin-eosin histology did not demonstrate hypothermic protection in the ischaemic hemisphere. The lack of neuroprotection in this study may correspond with the sustained release of glutamate in the peripheral regions of ischaemia even with lowered brain temperature. These results suggest that hypothermic reduction of excitotoxic perturbations may be more important in the ischaemic periphery than the core.

  View details for Web of Science ID A1993LT09100010

  View details for PubMedID 8105409

• INTRAARTERIAL PAPAVERINE FOR THE TREATMENT OF VASOSPASM AMERICAN JOURNAL OF NEURORADIOLOGY Marks, M. P., Steinberg, G. K., Lane, B. 1993; 14 (4): 822-826

  Abstract

  The authors describe the use of intraarterial papaverine to treat vasospasm following subarachnoid hemorrhage. Two cases are reported: a 40-year-old woman with a posterior communicating artery aneurysm and a 67-year-old man with a posterior cerebral artery aneurysm. Both patients developed symptomatic, angiographically demonstrated vasospasm that responded to papaverine infusion.

  View details for PubMedID 8352152

• NEUROPROTECTION FOLLOWING FOCAL CEREBRAL-ISCHEMIA WITH THE NMDA ANTAGONIST DEXTROMETHORPHAN, HAS A FAVORABLE DOSE-RESPONSE PROFILE NEUROLOGICAL RESEARCH Steinberg, G. K., Kunis, D., Delapaz, R., Poljak, A. 1993; 15 (3): 174-180

  Abstract

  Although N-methyl-D-Aspartate (NMDA) antagonists protect against focal cerebral ischaemia, there is concern that the high doses necessary for neuroprotection may cause unacceptable adverse effects. We studied the dose response characteristics of the clinically available NMDA antagonist dextromethorphan in a rabbit model of transient focal ischaemia. Thirty-three anaesthetized rabbits underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h followed by 4.5 h of reperfusion. One hour after the onset of ischaemia, they were treated with an i.v. infusion of varying doses of dextromethorphan or normal saline. Seventeen additional unanaesthetized, nonischaemic rabbits received similar infusions of dextromethorphan to correlate brain with blood levels and to evaluate adverse effects. Rabbits with plasma dextromethorphan levels 500-1500 ng ml-1 had a 64% reduction in ischaemic neuronal damage (p < 0.05); those with levels > 1500 ng ml-1 showed 92% attenuation of neuronal damage and 65% decrease in ischaemic oedema (p < 0.01). Drug levels suggest that dextromethorphan's neuroprotection is not mediated by its active metabolite dextrorphan. Unanaesthetized rabbits with plasma levels > 2500 ng ml-1 demonstrated severe gait ataxia. These results demonstrate that systemic treatment with dextromethorphan after 1 h of focal ischaemia can significantly protect against cerebral damage if adequate plasma and brain levels are achieved. Dextromethorphan was concentrated 7-30 x in brain compared with plasma, and brain levels were highly correlated with plasma levels (r = 0.89). Neuroprotective doses of dextromethorphan were tolerated with only transient side effects.

  View details for Web of Science ID A1993LF50400005

  View details for PubMedID 8103583

• ENDOVASCULAR TREATMENT OF CEREBRAL ARTERIOVENOUS-MALFORMATIONS FOLLOWING RADIOSURGERY AMERICAN JOURNAL OF NEURORADIOLOGY Marks, M. P., Lane, B., Steinberg, G. K., FABRIKANT, J. I., Levy, R. P., Frankel, K. A., Phillips, M. H. 1993; 14 (2): 297-303

  Abstract

  Previous reports of embolization of cerebral arteriovenous malformations (AVMs) have evaluated the technique as adjunctive therapy prior to surgery or radiosurgery; our aim is to assess the role of embolization following radiosurgery.Six patients previously treated with radiosurgery and showing no response as judged by cerebral angiography were embolized 24 to 55 months (mean 34.3 months) after initial radiosurgery.In five of six, a significant volume reduction was achieved ranging from 60%-100% (mean 74%). One patient was treated with embolization alone and the AVM has remained fully thrombosed 2 years after treatment. Three patients underwent surgical resection for cure after embolization, and two patients had repeat radiosurgery to a significantly smaller AVM volume. One patient had an asymptomatic carotid dissection at embolization; however, no clinically apparent complications occurred in the treatment group.Embolization can be used after radiosurgery to assist in the management of those AVMs that have not responded to initial treatment.

  View details for PubMedID 8456702

• LOCALIZED HYPERTROPHIC MONONEUROPATHY OF THE TRIGEMINAL NERVE ARCHIVES OF PATHOLOGY & LABORATORY MEDICINE Chang, Y., Horoupian, D. S., Jordan, J., Steinberg, G. 1993; 117 (2): 170-176

  Abstract

  We report a case of localized hypertrophic mononeuropathy that involved the trigeminal nerve in a 61-year-old woman with a 5-year history of progressive drooping of the left eyelid, double vision, and left-sided temporal and retro-orbital pain. A mass that occupied the patient's left cavernous sinus was found to display localized hypertrophic mononeuropathy characterized by "onion bulbs" that were formed of concentrically proliferating Schwann cell processes around intact axons. This contrasted to the majority of previously reported cases of localized hypertrophic mononeuropathy, predominantly found in peripheral nerves, where the proliferating cell processes have been shown to be of a perineurial cell origin. Differences in architectural arrangement and degree of cellularity between the perineurial and schwannian forms of localized hypertrophic mononeuropathy were noted. These findings suggest important fundamental differences in the pathogenesis of various forms of onion-bulb mononeuropathies.

  View details for Web of Science ID A1993KK44500013

  View details for PubMedID 8427566

• Transcranial Doppler: correlation of blood velocity measurement with clinical status in subarachnoid hemorrhage. journal of neuroscience nursing Bell, T. E., LaGrange, K. M., Maier, C. M., Steinberg, G. K. 1992; 24 (4): 215-219

  Abstract

  Subarachnoid hemorrhage affects approximately 30,000 people each year in North America. Up to 50% of patients who survive the initial hemorrhage experience cerebral vasospasm, often resulting in permanent disability or death. Early detection allows interventions which may prevent catastrophic complications. Diagnosing vasospasm has always been dependent on invasive testing and correlation of the clinical picture. Alterations in neurological assessment, including Glasgow Coma Scale score changes, merely reflect poor cerebral perfusion secondary to the vasospasm, and may not be apparent for days. Transcranial Doppler (TCD) ultrasonography is an exciting diagnostic alternative. This noninvasive test may be done daily at the bedside, and may accurately predict impending vasospasm.

  View details for PubMedID 1517668

• CLINICALLY DOCUMENTED HEMORRHAGE IN CEREBRAL ARTERIOVENOUS-MALFORMATIONS - MR CHARACTERISTICS RADIOLOGY CHAPPELL, P. M., Steinberg, G. K., Marks, M. P. 1992; 183 (3): 719-724

  Abstract

  This study assessed the ability of magnetic resonance (MR) imaging to identify vascular characteristics of cerebral arteriovenous malformations (AVMs) which are predictive of hemorrhage. The study also evaluated the sensitivity and specificity of spin-echo (SE) and gradient-recalled-echo (GRE) imaging in the detection of prior clinical hemorrhage on the basis of location of the hemorrhage (parenchymal, intraventricular, or subarachnoid). Fifty patients with high-flow AVMs were evaluated. Twenty-four (48%) patients had prior clinical hemorrhage documented at computed tomography or MR imaging at the time of bleeding. Central venous drainage (P less than .001), central AVM location (P less than .001), and peri- or intraventricular AVM location (P less than .01) correlated positively with prior clinical hemorrhage. Intranidus aneurysms and angiomatous change could not be detected with MR. Nineteen of the 24 patients with prior hemorrhage underwent both SE and GRE imaging. Hypointensity, indicating the presence of iron from prior hemorrhage, was demonstrated in 14 of 19 T2-weighted SE images (sensitivity, 74%) and in 18 of 19 GRE images (sensitivity, 95%). No patient without a prior episode of clinical bleeding demonstrated evidence of iron deposition at MR imaging (specificity, 100%).

  View details for Web of Science ID A1992HV57800026

  View details for PubMedID 1584926

• EFFECTS OF HYPOTHERMIA ON EVOKED-POTENTIALS, MAGNETIC-RESONANCE-IMAGING, AND BLOOD-FLOW IN FOCAL ISCHEMIA IN RABBITS STROKE Lo, E. H., Steinberg, G. K. 1992; 23 (6): 889-893

  Abstract

  Mild hypothermia has been shown to ameliorate neuronal damage due to cerebral ischemia. In our study, the influence of mild-to-moderate hypothermia was examined in a rabbit model of focal cerebral ischemia.After 4 hours of permanent ischemia induced by occlusion of the anterior and middle cerebral and internal carotid arteries, somatosensory evoked potentials and regional cerebral blood flow were measured. Ex vivo magnetic resonance imaging scans were also obtained to determine the degree of ischemic brain injury. Three temperature (temporalis muscle) groups were studied: 37 degrees C, 33 degrees C, and 30 degrees C (n = 5 per group). An additional two animals were used to confirm that temporalis muscle temperatures were well correlated with brain temperature. Rectal temperatures were kept constant (37.5 degrees C) in all groups.After 4 hours of focal ischemia, evoked potentials in the normothermic animals remained depressed (2.2 +/- 2.1% [mean +/- SEM] preocclusion values). Recovery of potentials was significantly enhanced in both hypothermic groups (p less than 0.05): 18.2 +/- 6.5% (33 degrees C) and 43.6 +/- 12.2% (30 degrees C). Quantitative magnetic resonance measurements showed that T1 and T2 relaxation times were increased in the core ischemic regions within the cortex (20.4 +/- 4.0% and 25.3 +/- 5.9%, respectively). These elevations in T1 and T2 were reduced by hypothermia. However, blood flow was not improved by lowered temperature; in fact, flow in the 30 degrees C group was significantly decreased compared with the other groups (p less than 0.01). There was no statistically significant correlation between specific cerebral blood flow values and T1 or T2 elevations.These results demonstrate that hypothermia can improve evoked potentials and magnetic resonance parameters in permanent focal ischemia. However, moderate hypothermia (30 degrees C) appears to also significantly decrease blood flow in the ischemic brain.

  View details for Web of Science ID A1992HW86000018

  View details for PubMedID 1595110

• INTRANIDAL ANEURYSMS IN CEREBRAL ARTERIOVENOUS-MALFORMATIONS - EVALUATION AND ENDOVASCULAR TREATMENT RADIOLOGY Marks, M. P., Lane, B., Steinberg, G. K., Snipes, G. J. 1992; 183 (2): 355-360

  Abstract

  Patients with cerebral arteriovenous malformations (AVMs) have an increased risk of hemorrhage if an intranidal aneurysm is present. Angiograms from 125 patients with cerebral AVMs were evaluated, and 15 (12%) had intranidal aneurysms. All 15 patients had a history of bleeding. Five patients underwent particulate or liquid embolization before surgical excision of or radiation therapy for the AVM. All aneurysms were thrombosed at the time of embolization. Ten patients underwent radio-surgery alone. Eight of the 10 underwent angiographic follow-up (mean, 33 months); seven patients showed complete obliteration of the AVM without residual aneurysm. Histologic evaluation showed intranidal aneurysms to be thin-walled vascular structures, and they are the likely site for AVM hemorrhage. Embolization is an effective method for achieving thrombosis of the intranidal aneurysm and may be beneficial in patients undergoing radiation therapy because of a long latency period between treatment and thrombosis of the AVM.

  View details for Web of Science ID A1992HQ88400012

  View details for PubMedID 1561335

• Stereotactic, angiography-guided clipping of a distal, mycotic intracranial aneurysm using the Cosman-Roberts-Wells system: technical note. Neurosurgery Steinberg, G. K., GUPPY, K. H., Adler, J. R., Silverberg, G. D. 1992; 30 (3): 408-411

  Abstract

  We describe the use of stereotactic, angiographic guidance for localization and clipping of a small, distal intracranial bacterial aneurysm. The technique uses the commercially available Suetens-Gybels-Vandermeulen angiographic localizer with the widely used Cosman-Roberts-Wells stereotactic system. This method is simple and easy to use and significantly decreased the operative time. It may be quite useful for surgically treating mycotic and other peripheral aneurysms.

  View details for PubMedID 1620306

• HIGH-DOSE SINGLE-FRACTION BRAIN IRRADIATION - MRI, CEREBRAL BLOOD-FLOW, ELECTROPHYSIOLOGICAL, AND HISTOLOGICAL STUDIES INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lo, E. H., Frankel, K. A., Steinberg, G. K., DeLaPaz, R. L., FABRIKANT, J. I. 1992; 22 (1): 47-55

  Abstract

  Radiation-induced alterations in cerebrovascular and metabolic function form the basis for the radiosurgical treatment of selected intracranial vascular malformations and tumors in human patients. However, the underlying mechanisms, temporal progression, and modifying factors involved in the radiosurgical obliteration of these intracranial lesions as well as the risks of delayed radiation injury to surrounding normal brain remain poorly understood. In this report, the rabbit brain was used as an animal model to examine the effects of high-dose single-fraction X-irradiation on magnetic resonance imaging (MRI) appearance, neurophysiologic function, and histological integrity. At approximately 10 weeks following left-hemisphere irradiation with 60 Gy (225 kVp) X rays, MRI studies showed radiation-induced changes including blood-brain barrier (BBB) perturbations in the white matter regions and the hippocampus. Significant reductions in regional cerebral blood flow (rCBF) ratios were found in the hippocampus and certain regions of the cortex in irradiated animals. However, no changes in somatosensory evoked potentials (SEP) were observed. Histological studies demonstrated telangiectatic vessels, spreading edema in the white matter, and focal regions of necrosis and hemorrhage in the irradiated cortices and hippocampi. These results demonstrate that the irradiated rabbit brain may be used as an experimental model to correlate the spatiotemporal pattern of functional changes with radiologic and histological changes in delayed radiation injury.

  View details for Web of Science ID A1992GU93200007

  View details for PubMedID 1727129

• Charged-particle radiosurgery for intracranial vascular malformations. Neurosurgery clinics of North America FABRIKANT, J. I., Levy, R. P., Steinberg, G. K., Phillips, M. H., Frankel, K. A., Lyman, J. T., Marks, M. P., Silverberg, G. D. 1992; 3 (1): 99-139

  Abstract

  Heavy charged-particle radiation has unique physical characteristics that offer several advantages over photons and protons for stereotactic radiosurgery of intracranial AVMs. These include improved dose distributions with depth in tissue, small angle of lateral scattering, and sharp distal fall-off of dose in the Bragg ionization peak. Under multi-institutionally approved clinical trials, we have used stereotactic helium-ion Bragg peak radiosurgery to treat approximately 400 patients with symptomatic, surgically inaccessible vascular malformations at the UCB-LBL 184-in synchrocyclotron and bevatron. Treatment planning for stereotactic heavy charged-particle radiosurgery for intracranial vascular disorders integrates anatomic and physical information from the stereotactic cerebral angiogram and stereotactic CT and MR imaging scans for each patient, using computerized treatment-planning calculations for optimal isodose contour distribution. The shape of an intracranial AVM is associated strongly with its treatability and potential clinical outcome. In this respect, heavy charged-particle radiosurgery has distinct advantages over other radiosurgical methods; the unique physical properties allow the shaping of individual beams to encompass the contours of large and complexly shaped AVMs, while sparing important adjacent neural structures. We have had a long-term dose-searching clinical protocol in collaboration with SUMC and UCSF and have followed up over 300 patients for more than 2 years. Initially, treatment doses ranged from 45 GyE to 35 GyE. Currently, total doses up to 25 GyE are delivered to treatment volumes ranging from 0.1 cm3 to 70 cm3. This represents a relatively homogeneous dose distribution, with the 90% isodose surface contoured to the periphery of the lesion; there is considerable protection of normal adjacent brain tissues, and most of the brain receives no radiation exposure. Dose selection depends on the volume, shape, and location of the AVM and several other factors, including the volume of normal brain that must be traversed by the plateau portion of the charged-particle beam. The first 230 patients have been evaluated clinically to the end of 1989. Using the clinical grading of Drake, about 90% of the patients had an excellent or good neurologic grade, about 5% had a poor grade, and about 5% had progression of disease and died, or died as a result of unrelated intercurrent illness. Neuroradiologic follow-up to the end of 1989 indicated the following rates of complete angiographic obliteration 3 years after treatment: 90% to 95% for AVM treatment volumes less than 4 cm3, 90% to 95% for volumes 4 to 14 cm3, and 60% to 70% for volumes greater than 14 cm3.(ABSTRACT TRUNCATED AT 400 WORDS)

  View details for PubMedID 1633456

• DEXTROMETHORPHAN ALTERS CEREBRAL BLOOD-FLOW AND PROTECTS AGAINST CEREBRAL INJURY FOLLOWING FOCAL ISCHEMIA NEUROSCIENCE LETTERS Steinberg, G. K., Lo, E. H., Kunis, D. M., Grant, G. A., Poljak, A., Delapaz, R. 1991; 133 (2): 225-228

  Abstract

  The effects of the N-methyl-D-aspartate (NMDA) antagonist dextromethorphan (DM) on regional cerebral blood flow (rCBF) and cerebral injury were studied in a rabbit model of transient focal ischemia. Anesthetized rabbits underwent 2 h occlusion of the left internal carotid, middle cerebral and anterior cerebral artery, followed by 4 h of reperfusion. Ten minutes after the onset of ischemia they were treated with either i.v. DM 20 mg/kg followed by 10 mg/kg/h (n = 6) or normal saline (NS, n = 5). Control rabbits received DM (n = 3) or NS (n = 2) infusion without arterial occlusion. DM attenuated the sharp, post-ischemic rise in rCBF seen during reperfusion within the ischemic core of NS controls (DM 31% pre-ischemic value, NS 92%). DM also improved the delayed post-ischemic hypoperfusion compared with controls. DM infusion without arterial occlusion did not change rCBF values. Compared with NS controls, DM treated animals demonstrated recovery of the somatosensory evoked potential (DM 96% pre-ischemic values, NS 24%), 76% reduction in cortical edema and 92% decrease in cortical ischemic neuronal damage. We conclude that DM's effect on CBF may contribute to its neuroprotective action.

  View details for Web of Science ID A1991GX48400019

  View details for PubMedID 1816501

• PROTECTION AFTER TRANSIENT FOCAL CEREBRAL-ISCHEMIA BY THE N-METHYL-D-ASPARTATE ANTAGONIST DEXTRORPHAN IS DEPENDENT UPON PLASMA AND BRAIN LEVELS JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Steinberg, G. K., Kunis, D., Saleh, J., Delapaz, R. 1991; 11 (6): 1015-1024

  Abstract

  Dextrorphan is a dextrorotatory morphinan and a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. We studied the dose response characteristics of dextrorphan's neuroprotective efficacy and side effects, correlating these beneficial and adverse responses with plasma and brain levels in a rabbit model of transient focal cerebral ischemia. Thirty-three rabbits, anesthetized with halothane, underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h, followed by 4.5 h of reperfusion. One hour after the onset of ischemia, they were treated with an i.v. infusion of varying dextrorphan doses or normal saline. After killing, the brains were analyzed for ischemic high signal intensity using magnetic resonance imaging (MRI) and for ischemic neuronal damage with histopathology. A separate group of 12 anesthetized ischemic rabbits received similar doses of dextrorphan, correlating plasma with brain dextrorphan levels. Twenty-six additional dextrorphan unanesthetized, nonischemic rabbits received infusions of dextrorphan to correlate behavioral side effects with dextrorphan dose and levels. Compared with controls, dextrorphan 15 mg/kg group had significantly less cortical ischemic neuronal damage (5.3 versus 33.2%, p = 0.01) and a reduction in cortical MRI high signal area (9.1 versus 41.2%, p = 0.02). The dextrorphan 10 mg/kg rabbits showed less cortical ischemic neuronal damage (27.2%) and less MRI high signal (34.8%) but this was not statistically significant (p = 0.6). Dextrorphan 5 mg/kg had no benefit on either neocortical ischemic neuronal damage (35.8%) or MRI high signal (42.9%). The protective effect of dextrorphan was correlated with plasma free dextrorphan levels (r = -0.50, p less than 0.02 for ischemic neuronal damage; r = -0.66, p less than 0.001 for ischemic MRI high signal). All the rabbits with plasma levels greater than 2,000 ng/ml had less than 12% cortical ischemic neuronal damage and less than 34% MRI high signal. All rabbits with plasma levels greater than 3,000 ng/ml showed less than 7% ischemic neuronal damage and less than 11% MRI high signal. Plasma levels of approximately 2,500 ng/ml correlated with brain dextrorphan levels of approximately 6,000 ng/g. Unanesthetized rabbits with plasma levels of approximately 2,500 ng/ml demonstrated loss of the righting reflex. These results demonstrate that systemic treatment with dextrorphan after 1 h focal ischemia can significantly protect against cerebral damage if adequate plasma and brain levels of dextrorphan are achieved. The brain levels necessary to obtain in vivo protection are similar to concentrations that prevent glutamate or NMDA-induced injury in neuronal culture.

  View details for Web of Science ID A1991GL51500017

  View details for PubMedID 1939379

• MEDULLOBLASTOMA - FREEDOM FROM RELAPSE LONGER THAN 8 YEARS - A THERAPEUTIC CURE JOURNAL OF NEUROSURGERY BELZA, M. G., Donaldson, S. S., Steinberg, G. K., Cox, R. S., Cogen, P. H. 1991; 75 (4): 575-582

  Abstract

  Seventy-seven patients presenting with medulloblastoma between 1958 and 1986 were treated at Stanford University Medical Center and studied retrospectively. Multimodality therapy utilized surgical extirpation followed by megavoltage irradiation. In 15 cases chemotherapy was used as adjunctive treatment. The 10- and 15-year actuarial survival rates were both 41% with an 18-year maximum follow-up period (median 4.75 years). There were no treatment failures after 8 years of tumor-free survival. Gross total removal of tumor was achieved in 22 patients (32%); the surgical mortality rate was 3.9%. No significant difference was noted in the incidence of metastatic disease between shunted and nonshunted patients. The classical form of medulloblastoma was present in 67% of cases while the desmoplastic subtype was found in 16%. Survival rates were best for patients presenting after 1970, for those with desmoplastic tumors, and for patients receiving high-dose irradiation (greater than or equal to 5000 cGy) to the posterior fossa. Although early data on freedom from relapse suggested a possible beneficial effect from chemotherapy, long-term follow-up results showed no advantage from this modality of treatment. The patterns of relapse and survival were examined; 64% of relapses occurred within the central nervous system, and Collins' rule was applicable in 83% of cases beyond the period of risk. Although patients treated for recurrent disease could be palliated, none were long-term survivors. The study data indicate that freedom from relapse beyond 8 years from diagnosis can be considered as a cure in this disease. Long-term follow-up monitoring is essential to determine efficacy of treatment and to assess survival patterns accurately.

  View details for Web of Science ID A1991GG76500010

  View details for PubMedID 1885975

• GLIOFIBROMA - CASE-REPORT JOURNAL OF NEUROSURGERY Snipes, G. J., Steinberg, G. K., Lane, B., Horoupian, D. S. 1991; 75 (4): 642-646

  Abstract

  The case history of an infant with a large gliofibroma is presented. Gliofibromas are rare mixed glialmesenchymal tumors that have been poorly characterized. The computerized tomography appearance and a detailed light and electron microscopic description are presented, along with immunoperoxidase studies of this tumor. This case is compared with gliofibromas described elsewhere in the literature.

  View details for Web of Science ID A1991GG76500020

  View details for PubMedID 1885984

• EFFECTS OF NMDA AND CALCIUM-CHANNEL ANTAGONISTS ON REGIONAL CEREBRAL BLOOD-FLOW NEUROSCIENCE LETTERS Lo, E. H., Sun, G. H., Steinberg, G. K. 1991; 131 (1): 17-20

  Abstract

  N-Methyl-D-aspartate (NMDA) antagonists and voltage-dependent calcium channel antagonists were tested to determine potential effects on regional cerebral blood flow in the normal rabbit brain. Ketamine had no effects on cortical or hippocampal blood flow, but was found to significantly decrease blood flow in the inferior colliculus. MK-801 decreased blood flow in almost all regions of the brain tested. On the other hand, nimodipine significantly increased flow in the cortex, hippocampus, and tegmentum. Dextromethorphan and dextrorphan, which have been shown to act at the NMDA receptor as well as the dihydropyridine calcium channel, decreased blood flow in the inferior colliculus, but showed no effects in the cortex or hippocampus. These results suggest that the neuroprotective NMDA antagonists do not increase blood flow primarily in the normal brain.

  View details for Web of Science ID A1991GK15300005

  View details for PubMedID 1791974

• EFFECTS OF DEXTROMETHORPHAN ON REGIONAL CEREBRAL BLOOD-FLOW IN FOCAL CEREBRAL-ISCHEMIA JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM Lo, E. H., Steinberg, G. K. 1991; 11 (5): 803-809

  Abstract

  Dextromethorphan (DM), a noncompetitive NMDA antagonist, has been demonstrated to reduce ischemic neuronal damage and edema, but DM's influence on cerebral blood flow has not been extensively studied. In this investigation, it is shown that DM has significant effects on regional cerebral blood flow (rCBF) patterns in a rabbit model of focal cerebral ischemia. rCBF was measured using radioactive microspheres following a 1 h permanent occlusion of the left internal carotid, anterior cerebral, and middle cerebral arteries in rabbits. Somatosensory evoked potentials (SEPs) were used to assess the degree of ischemia; only animals where SEPs were completely abolished were used for a frequency distribution analysis of rCBF. It was found that there were significantly more regions with lower flows in animals treated with normal saline (NS) (n = 7) compared to animals treated with DM (n = 7) (p less than 0.05, ipsilateral left side; p less than 0.001, contralateral right side). The frequency distribution medians were 27.5 ml 100 g-1 min-1 (left) and 70.0 ml 100 g-1 min-1 (right) in the NS group vs. 34.5 ml 100 g-1 min-1 (left) and 80.5 ml 100 g-1 min-1 (right) in the DM group. The left and right hemispheric regional means were 29.4 +/- 20 and 74.3 +/- 23 ml 100 g-1 min-1, respectively, in the NS group vs. 34.4 +/- 16 and 91.0 +/- 28 ml 100 g-1 min-1, respectively, in the DM group.(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1991GD34400012

  View details for PubMedID 1874811

• VASCULAR CHARACTERISTICS OF INTRACEREBRAL ARTERIOVENOUS-MALFORMATIONS IN PATIENTS WITH CLINICAL STEAL AMERICAN JOURNAL OF NEURORADIOLOGY Marks, M. P., Lane, B., Steinberg, G., Chang, P. 1991; 12 (3): 489-496

  Abstract

  In patients with intracerebral arteriovenous malformations (AVMs), symptoms attributed to steal can lead to progressive debilitating deficits. This study was undertaken to determine which morphologic features of the AVM could be correlated with clinical symptoms of steal. Over a 4-year period, 65 patients with intracranial AVMs were evaluated with angiography supplemented by MR (46 cases) and CT (19 cases). Eleven characteristics of AVM vascular architecture were studied; these included size, lobar location, periventricular/intraventricular location, arterial stenosis, arteriovenous fistulae, angiomatous change (the presence of dilated transcortical collateral circulation), venous drainage pattern (central, cortical, mixed), venous stenosis, venous aneurysm or ectasia, venous variation, and delayed drainage. These characteristics were correlated with a history of clinical steal, which was seen in nine (14%) of 65 patients. Three characteristics were found to correlate highly with steal: angiomatous change (p less than .0001), size (p less than .0001), and peripheral venous drainage (p = .045). The mean size of the AVM nidus was 31.3 cm3 for the entire group of patients, 105.0 cm3 for patients with steal, and 19.5 cm3 for those without steal symptoms. Angiomatous change was seen in six (9%) of 65 patients; all six of these had clinical steal. The association of clinical steal with AVM size, angiomatous change, and peripheral venous drainage may contribute to establishing a prognosis and treatment planning. When a patient's symptoms are caused by steal, treatment with subtotal excision or partial embolization may be beneficial.

  View details for Web of Science ID A1991FJ90400022

  View details for PubMedID 2058499

• MRI AND PET OF DELAYED HEAVY-ION RADIATION-INJURY IN THE RABBIT BRAIN INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Lo, E. H., DeLaPaz, R. L., Frankel, K. A., Poljak, A., Phillips, M. H., Brennan, K. M., WOODRUFF, K. H., Valk, P. E., Steinberg, G. K., FABRIKANT, J. I. 1991; 20 (4): 689-696

  Abstract

  Magnetic resonance imaging (MRI) and positron emission tomography (PET) techniques were used to obtain in vivo scans of delayed (30 GyE helium ion, 230 MeV/u) radiation injury in rabbit brain. T2-weighted (T2W) MRI scans demonstrated alterations that were restricted primarily to the white matter tracts and the deep perithalamic and thalamic regions. Quantitative measurements of T2 and T1 values demonstrated wide variations in absolute values. However, paired comparisons in hemibrain-irradiated rabbits revealed significant increases in T2 (p less than 0.001) and T1 (p less than 0.01) in irradiated versus unirradiated brain. Gadolinium DTPA (GdDTPA) enhanced MRI and 82Rubidium (82Rb) PET detected focal regions of blood-brain barrier (BBB) disruption restricted to the deep white matter and thalamic regions. Sequential GdDTPA enhanced MRI scans showed the spreading of the tracer from the initial site of contrast enhancement. 18Fluorodeoxyglucose (18FDG) PET studies demonstrated the markedly depressed metabolic profiles of irradiated brain. Histological findings of tissue edema and necrosis correlated well with the in vivo imaging abnormalities. These initial studies demonstrate that the irradiated rabbit brain is a suitable animal model for examining the delayed effects of radiation injury in the brain.

  View details for Web of Science ID A1991FC80600007

  View details for PubMedID 2004945

• STEREOTAXIC HELIUM ION BRAGG PEAK RADIOSURGERY FOR INTRACRANIAL ARTERIOVENOUS-MALFORMATIONS - DETAILED CLINICAL AND NEURORADIOLOGICAL OUTCOME HARVARD RADIOSURGERY UPDATE COURSE ON RADIOSURGERY : ENHANCEMENT OF CLINICAL EXCELLENCE Steinberg, G. K., FABRIKANT, J. I., Marks, M. P., Levy, R. P., Frankel, K. A., Phillips, M. H., Shuer, L. M., Silverberg, G. D. KARGER. 1991: 36–49

  Abstract

  89 patients with angiographically documented arteriovenous malformations were treated with helium ion Bragg peak radiation. The rate of complete angiographic obliteration 2 years after radiation was 94% in those lesions smaller than 4 cm3 (2.0 cm in diameter), 75% for those 4-25 cm3 and 39% for those larger than 25 cm3 (3.7 cm in diameter); at 3 years after radiation, the corresponding obliteration rates were 100, 95 and 70%. Major clinical complications occurred in 10 patients (8 permanent, 2 transient) between 3 and 21 months after treatment; all were in the initial stage of the protocol (higher radiation doses). 10 patients bled from residual malformation between 4 and 34 months after treatment. Seizures were improved in 63% and headaches in 68% of patients. Excellent or good clinical outcome was achieved in 94% of patients. Compared to the natural history and risks of surgery for these difficult malformations, we consider these results encouraging. Heavy-charged-particle radiation is a valuable therapy for surgically inaccessible symptomatic cerebral arteriovenous malformations. The current procedure has two disadvantages: the prolonged latent period before complete obliteration and the small risk of serious neurological complications.

  View details for Web of Science ID A1991HG99200005

  View details for PubMedID 1808653

• CLINICAL DOSE-ESCALATION SAFETY STUDY OF THE NMDA ANTAGONIST, DEXTROMETHORPHAN IN NEUROSURGICAL PATIENTS STEINBERG, G. K., BELL, T. AMER HEART ASSOC. 1991: 141

  View details for Web of Science ID A1991ET89500084

• STEREOTAXIC HELIUM ION BRAGG PEAK RADIOSURGERY FOR ANGIOGRAPHICALLY OCCULT INTRACRANIAL VASCULAR MALFORMATIONS HARVARD RADIOSURGERY UPDATE COURSE ON RADIOSURGERY : ENHANCEMENT OF CLINICAL EXCELLENCE Steinberg, G. K., Levy, R. P., FABRIKANT, J. I., Frankel, K. A., Phillips, M. H., Marks, M. P. KARGER. 1991: 64–71

  Abstract

  Between July 1983 and July 1989, we treated 35 patients with surgically inaccessible, symptomatic angiographically occult vascular malformations (AOVMs) using stereotactic heavy-charged-particle radiosurgery. AOVMs were located in the brainstem (19), thalamus or internal capsule (9), basal ganglia (3), deep cerebral hemisphere and motor area (3), or cerebellopontine angle (1). All patients presented with clinical and radiological evidence of previous hemorrhage, usually with multiple episodes of hemorrhage. Treatment volumes ranged from 80 to 15,200 mm3 and treatment doses from 7.7 to 34.6 Gy. Mean follow-up was 40 months, with 31 patients followed for at least 2 years. Clinical outcome was excellent in 46%, good in 34% and poor in 14%; 6% died. Twenty-seven patients in excellent and good condition prior to treatment remained stable or improved neurologically. Two patients initially in poor condition, who had previously received conventional radiotherapy, died at 9 and 14 months after treatment, respectively. Six patients experienced recurrent hemorrhage 2-60 months following treatment. Three of these patients made a complete recovery. Although a larger number of treated patients must be followed over longer periods of time, stereotactic heavy-particle radiotherapy may be a valuable treatment modality for surgically inaccessible intracranial AOVMs.

  View details for Web of Science ID A1991HG99200007

  View details for PubMedID 1808656

• CEREBRAL SPARGANOSIS - CASE-REPORT AND REVIEW REVIEWS OF INFECTIOUS DISEASES Holodniy, M., ALMENOFF, J., Loutit, J., Steinberg, G. K. 1991; 13 (1): 155-159

  Abstract

  Sparganosis is a rare infection caused by a tapeworm larva from the genus Spirometra. A 21-year-old Indian man presented with an 18-month history of episodic confusion followed by a grand mal seizure. Computed tomography and magnetic resonance imaging of the brain confirmed the presence of a lesion of the left occipital lobe. Subsequent stereotactic biopsy revealed a plerocercoid larva or sparganum. Surgical resection resulted in cure. This case prompted a review of the literature on central nervous system sparganosis. Altogether, 17 other cases of primary cerebral sparganosis have been reported previously. Seizures, headache, and focal neurologic signs are common at presentation. Neuroradiologic imaging is sensitive but not specific for the identification of lesions. Enzyme-linked immunosorbent assay of cerebrospinal fluid or serum may be diagnostically helpful. However, the diagnosis is generally made after surgical resection, which is usually curative.

  View details for Web of Science ID A1991EU52000025

  View details for PubMedID 2017616

• ACUTE CEREBRAL-ISCHEMIA IN RABBITS - CORRELATION BETWEEN MR AND HISTOPATHOLOGY AMERICAN JOURNAL OF NEURORADIOLOGY DeLaPaz, R. L., Shibata, D., Steinberg, G. K., Zarnegar, R., George, C. 1991; 12 (1): 89-95

  Abstract

  The histologic description of cerebral ischemia is complex, and within most lesions there are regional variations in degrees of neuronal cell injury, edema, and neuropil disruption. These parameters of tissue injury were analyzed histopathologically in transient and permanent experimental cerebral ischemia in 15 rabbits and the results were spatially correlated with MR images of pre- and postmortem (formalin-fixed) brains. MR was performed at 1.5 T (eight animals) and at 0.38 T (seven animals). Areas of high signal on T2-weighted MR images were closely correlated with histologic signs of cytotoxic glial edema and with disruption of the neuropil (widening of the interstitial spaces in the background matrix of glial and neuronal cellular processes), but MR tended to underestimate the extent of ischemic neuronal injury, especially low-grade histologic changes (mild neuronal shrinkage and nuclear basophilia). Low-grade ischemic neuronal changes were often found in the penumbra zone of ischemic lesions in areas that appeared normal on T2-weighted MR. High-grade neuronal injury was also seen occasionally in areas of normal signal on MR, especially in the striatum. No significant differences were seen on T2-weighted MR between the experimental groups with respect to transient vs permanent occlusion, in vivo vs in vitro MR, and low vs high magnetic field. In the setting of suspected acute cerebral ischemia, an abnormal T2-weighted MR study often underestimates the extent of neuronal ischemic injury, especially potentially reversible injury; and a normal MR study does not completely exclude significant neuronal ischemic injury.

  View details for PubMedID 1704174

• CEREBRAL BLOOD-VESSELS - DISCUSSION STROKE Welch, K. M., SAPER, C. B., Koenig, H., DiRocco, R., Moskowitz, M., Dietrich, W. D., HALLENBECK, J. M., Lipton, P., Wieloch, T., Reis, D., Kraig, R. P., Caplan, L., Ackerman, R., Marcoux, F. W., Steinberg, G. K., Halsey, J. 1990; 21 (11): 177-178

  View details for Web of Science ID A1990EK51500049

• MODULATORS .2. - DISCUSSION STROKE Ginsberg, M., Simon, R., Krnjevic, K., Nowak, T. S., Bazan, N., Lipton, P., Auer, R. N., Steinberg, G. K., Wasterlain, C., DeLorenzo, R. J., Zivin, J., Grotta, J. C., Leon, A., Finklestein, S. 1990; 21 (11): 125-126

  View details for Web of Science ID A1990EK51500034

• OCCULT VASCULAR MALFORMATIONS OF THE OPTIC CHIASM - MAGNETIC-RESONANCE-IMAGING DIAGNOSIS AND SURGICAL LASER RESECTION NEUROSURGERY Steinberg, G. K., Marks, M. P., Shuer, L. M., SOGG, R. L., Enzmann, D. R., Silverberg, G. D. 1990; 27 (3): 466-470

  Abstract

  Angiographically occult vascular malformations of the optic nerve and chiasm are extremely rare. Before the advent of magnetic resonance imaging (MRI), it was difficult to diagnose these lesions preoperatively. We report MRI scan findings of optic chiasm cavernous angiomas in two patients with chiasmal syndrome. MRI was useful in localizing the vascular malformation and delineating its characteristics, especially chronic hemorrhage. One patient underwent biopsy of the lesion. The other patient underwent complete microsurgical resection of the malformation with the carbon dioxide laser with preservation of vision. Occult vascular malformations of the optic nerve and chiasm may be a more common cause of visual deterioration than previously recognized. The MRI scan is the imaging modality of choice for diagnosing and following these lesions. In certain patients, these vascular malformations may be amenable to complete surgical removal with stabilization or improvement of visual function.

  View details for Web of Science ID A1990DV49200023

  View details for PubMedID 2234344

• HEMORRHAGE IN INTRACEREBRAL ARTERIOVENOUS-MALFORMATIONS - ANGIOGRAPHIC DETERMINANTS RADIOLOGY Marks, M. P., Lane, B., Steinberg, G. K., Chang, P. J. 1990; 176 (3): 807-813

  Abstract

  The most serious and frequent complication of intracranial arteriovenous malformations (AVMs) is intracranial hemorrhage. Identification of patients at greatest risk for intracranial bleeding would be beneficial. Detailed analysis of vascular architecture was performed in 65 patients with intracranial AVMs to identify the vascular characteristics that correlated with hemorrhage. Fifteen characteristics were assessed. Hemorrhage was present in 45 patients (69%). The following characteristics correlated positively with hemorrhage (Fisher-Irwin exact test): central venous drainage (P less than .0001), periventricular or intraventricular location of the AVM (P = .0002), and intranidal aneurysm (P = .028). The following characteristics correlated negatively with hemorrhage: angiomatous change (P = .0005), peripheral venous drainage (P = .005), and mixed venous drainage (P = .021). Multivariate linear discriminant analysis demonstrated that central venous drainage, angiomatous change (negatively predictive), intranidal aneurysm, and periventricular or intraventricular location of the AVM were the most discriminating or predictive characteristics of hemorrhage. Detailed analysis of the vascular architecture of intracranial AVMs helped identify features that strongly correlate with clinical hemorrhage and have important prognostic implications for the treatment of patients with these lesions.

  View details for Web of Science ID A1990DV57900040

  View details for PubMedID 2389040

• STEREOTAXIC HEAVY-CHARGED-PARTICLE BRAGG-PEAK RADIATION FOR INTRACRANIAL ARTERIOVENOUS-MALFORMATIONS NEW ENGLAND JOURNAL OF MEDICINE Steinberg, G. K., FABRIKANT, J. I., Marks, M. P., Levy, R. P., Frankel, K. A., Phillips, M. H., Shuer, L. M., Silverberg, G. D. 1990; 323 (2): 96-101

  Abstract

  Heavy-charged-particle radiation has several advantages over protons and photons for the treatment of intracranial lesions; it has an improved physical distribution of the dose deep in tissue, a small angle of lateral scattering, and a sharp distal falloff of the dose.We present detailed clinical and radiologic follow-up in 86 patients with symptomatic but surgically inaccessible cerebral arteriovenous malformations that were treated with stereotactic helium-ion Bragg-peak radiation. The doses ranged from 8.8 to 34.6 Gy delivered to volumes of tissue of 0.3 to 70 cm3.Two years after radiation treatment, the rate of complete obliteration of the lesions, as detected angiographically, was 94 percent for lesions smaller than 4 cm3, 75 percent for those of 4 to 25 cm3, and 39 percent for those larger than 25 cm3. After three years, the rates of obliteration were 100, 95, and 70 percent, respectively. Major neurologic complications occurred in 10 patients (12 percent), of whom 8 had permanent deficits. All these complications occurred in the initial stage of the protocol, before the maximal dose of radiation was reduced to 19.2 Gy. In addition, hemorrhage occurred in 10 patients from residual malformations between 4 and 34 months after treatment. Seizures and headaches were less severe in 63 percent of the 35 and 68 percent of the 40 patients, respectively, who had them initially.Given the natural history of these inaccessible lesions and the high risks of surgery, we conclude that heavy-charged-particle radiation is an effective therapy for symptomatic, surgically inaccessible intracranial arteriovenous malformations. The current procedure has two disadvantages: a prolonged latency period before complete obliteration of the vascular lesion and a small risk of serious neurologic complications.

  View details for Web of Science ID A1990DM62600005

  View details for PubMedID 2359429

• EFFECT OF HYPERGLYCEMIA ON NEURONAL CHANGES IN A RABBIT MODEL OF FOCAL CEREBRAL-ISCHEMIA STROKE KRAFT, S. A., Larson, C. P., Shuer, L. M., Steinberg, G. K., BENSON, G. V., Pearl, R. G. 1990; 21 (3): 447-450

  Abstract

  In clinical medicine, cerebral ischemia is frequently due to a focal, rather than global, insult. The effect of hyperglycemia in focal cerebral ischemia is not well defined. We studied the effect of hyperglycemia on neuropathologic changes in a rabbit model of focal cerebral ischemia. Rabbits were randomized to receive saline (n = 12) or glucose (n = 12) infusions. The left anterior cerebral and left internal carotid arteries were clipped after the infusion began. After 6 hours of occlusion, the area of severe ischemic neuronal damage in the left neocortex and striatum on two standard sections of brain was calculated and expressed as a percentage of the total area of the left cortex or striatum. The mean +/- SEM cortical area of severe ischemic neuronal damage was 22.1 +/- 2.8% in the glucose-treated rabbits and 34.0 +/- 4.6% in the saline-treated rabbits (p less than 0.05). The cortical area of severe ischemic neuronal damage was inversely correlated with plasma glucose concentration at the time of arterial clipping (p less than 0.05). We conclude that hyperglycemia is associated with decreased histologic neuronal injury in this model of focal cerebral ischemia and may be protective when cerebral ischemia occurs from a focal insult.

  View details for Web of Science ID A1990CT20500015

  View details for PubMedID 2309269

• STEREOTACTIC HEAVY-CHARGED-PARTICLE BRAGG PEAK RADIOSURGERY FOR ANGIOGRAPHICALLY OCCULT INTRACRANIAL VASCULAR MALFORMATIONS STEINBERG, G. K., LEVY, R. P., FABRIKANT, J. I., FRANKEL, K. A., PHILLIPS, M. H., MARKS, M. P. AMER HEART ASSOC. 1990: 172

  View details for Web of Science ID A1990CJ77200087

• CEREBROVASCULAR AND METABOLIC PERTURBATIONS IN DELAYED HEAVY CHARGED-PARTICLE RADIATION-INJURY BRAIN RESEARCH LO, E. H., FRANKEL, K. A., DELAPAZ, R. L., POLJAK, A., WOODRUFF, K. H., BRENNAN, K. M., PHILLIPS, M. H., VALK, P. E., STEINBERG, G. K., FABRIKANT, J. I. 1989; 504 (1): 168–72

  Abstract

  Focal heavy charged particle irradiation of the rabbit brain created defined lesions which were observable by nuclear magnetic resonance (NMR) and positron emission tomography (PET) imaging techniques. The lesions appeared approximately 9-11 months after left partial hemibrain irradiation with 30 Gy (230 MeV/u helium ions), and were restricted to the white matter tracts and deep perithalamic and thalamic regions. 82Rubidium PET and Gadolinium DTPA enhanced NMR imaging were used to detect blood-brain barrier perturbations. 18Fluordeoxyglucose PET studies demonstrated widespread decreases in cerebral glucose uptake in the cortex and thalamus of the irradiated hemisphere. NMR and PET imaging results correlated well with histological findings. Rabbits irradiated with 15 Gy did not demonstrate any abnormalities in the brain with sequential NMR scans through 14 months post-irradiation.

  View details for DOI 10.1016/0006-8993(89)91619-3

  View details for Web of Science ID A1989CE73800030

  View details for PubMedID 2598014

• PRETREATMENT WITH THE NMDA ANTAGONIST DEXTROPHAN REDUCES CEREBRAL INJURY FOLLOWING TRANSIENT FOCAL ISCHEMIA IN RABBITS BRAIN RESEARCH Steinberg, G. K., Saleh, J., Delapaz, R., Kunis, D., Zarnegar, S. R. 1989; 497 (2): 382-386

  Abstract

  We studied the efficacy of systemic pre-treatment with dextrorphan (DX), a clinically tested N-methyl-D-aspartate (NMDA) antagonist, in a rabbit model of transient focal cerebral ischemia. Rabbits were treated with either a 24 mg/kg i.v. loading dose followed by 12 mg/kg/h i.v. infusion of 0.48% DX in normal saline (NS), or with an equivalent volume of NS alone. One and 1/2 h after starting the drug or NS, the rabbits underwent a 1 h occlusion of the left internal carotid and anterior cerebral arteries, followed by 4 h of reperfusion. The DX-treated rabbits had significantly less neocortical ischemic neuronal damage (7.4%) than the normal saline group (31.6%) and demonstrated a significant decrease in ischemic cortical edema. DX may prove useful in the treatment of clinical cerebrovascular disease.

  View details for Web of Science ID A1989AR53400022

  View details for PubMedID 2684345

• CARDIORESPIRATORY ARREST FOLLOWING INITIATION OF CRANIAL IRRADIATION FOR TREATMENT OF A BRAIN-STEM TUMOR ANESTHESIOLOGY Brose, W. G., SAMUELS, S. I., Steinberg, G. K. 1989; 71 (3): 450-451

  View details for Web of Science ID A1989AM76600024

  View details for PubMedID 2774274

• PROTECTIVE EFFECT OF N-METHYL-D-ASPARTATE ANTAGONISTS AFTER FOCAL CEREBRAL-ISCHEMIA IN RABBITS STROKE Steinberg, G. K., Saleh, J., Kunis, D., Delapaz, R., Zarnegar, S. R. 1989; 20 (9): 1247-1252

  Abstract

  We studied the efficacy of postischemic, systemic treatment with the N-methyl-D-aspartate (NMDA) receptor antagonists dextromethorphan and dextrorphan in a rabbit model of transient focal cerebral ischemia. Twenty-two rabbits underwent 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4.5 hours of reperfusion before sacrifice. One hour after the onset of ischemia, immediately after removing the arterial clips, the rabbits were blindly assigned to treatment with dextromethorphan (20 mg/kg i.v. loading dose followed by 10 mg/kg/hr maintenance infusion, n = 7), dextrorphan (15 mg/kg i.v. loading dose followed by 15 mg/kg/hr maintenance infusion, n = 7), or an equivalent volume of normal saline alone (n = 8). The maintenance infusion of drugs or saline was continued for the duration of the experiment. The formalin-fixed brains were analyzed with magnetic resonance imaging using coronal T2-weighted images, and ischemic neuronal damage was assessed on standard coronal hematoxylin-and- eosin-stained sections. The area of neocortical ischemic neuronal damage was significantly reduced in the groups treated with dextromethorphan (4.2%, p less than 0.01) and dextrorphan (6.1%, p less than 0.01) compared with the controls (36.2%). Magnetic resonance imaging demonstrated significantly smaller areas of cortical edema in the groups treated with dextromethorphan (14.6%, p less than 0.01) and dextrorphan (8.0%, p less than 0.01) compared with the controls (32.9%). These clinically tested antitussives with NMDA-antagonist properties may have therapeutic value in the treatment of human cerebrovascular disease.

  View details for Web of Science ID A1989AP80900019

  View details for PubMedID 2672427

• POSTERIOR-FOSSA STEREOTAXIC BIOPSY USING THE BROWN-ROBERTS-WELLS STEREOTAXIC SYSTEM - TECHNICAL NOTE JOURNAL OF NEUROSURGERY Guthrie, B. L., Steinberg, G. K., Adler, J. R. 1989; 70 (4): 649-652

  Abstract

  Stereotaxic biopsy has been shown to be a reliable means of diagnosing posterior fossa lesions. The authors describe a technique for infratentorial transcerebellar stereotaxic access to posterior fossa parenchymal lesions using the Brown-Roberts-Wells apparatus in its standard commercial configuration. The necessity for tissue diagnosis of these lesions is briefly discussed.

  View details for Web of Science ID A1989T886000025

  View details for PubMedID 2647921

• HYPERGLYCEMIA DECREASES ACUTE NEURONAL ISCHEMIC CHANGES AFTER MIDDLE CEREBRAL-ARTERY OCCLUSION IN CATS STROKE ZASSLOW, M. A., Pearl, R. G., Shuer, L. M., Steinberg, G. K., LIEBERSON, R. E., Larson, C. P. 1989; 20 (4): 519-523

  Abstract

  Hyperglycemia has been reported to worsen the tolerance of the brain to ischemia, and it has therefore been recommended that patients undergoing neurosurgical procedures not receive glucose-containing solutions. However, whereas most animal studies have used global ischemia models, most neurosurgical procedures are associated with risks of focal rather than global ischemia. We therefore studied the effects of glucose administration in an animal model of focal cerebral ischemia. We anesthetized 20 cats with halothane (0.85% end tidal in oxygen), and a focal cerebral ischemic lesion was produced by clip ligation of the left middle cerebral artery using a transorbital approach. Hyperglycemia (10 cats, mean +/- SEM plasma glucose concentration 561 +/- 36 mg/dl) was established before ligation by infusion of 50% glucose in 0.45% saline; the control group (10 cats, mean +/- SEM plasma glucose concentration 209 +/- 28 mg/dl) received 0.45% saline only. Total fluid administered, mean arterial blood pressure, body temperature, and arterial blood gas values did not differ between the two groups 0, 2, and 6 hours after ligation. The cats were killed 6 hours after ligation, and the area of severe ischemic neuronal damage was determined by microscopic examination of a coronal section at the level of the optic chiasm. The mean +/- SEM area of left cortical severe ischemic neuronal damage was 12 +/- 2% of the left cortex in the hyperglycemic group compared with 28 +/- 5% in the control group (p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

  View details for Web of Science ID A1989U149900014

  View details for PubMedID 2929029

• MAGNETIC-RESONANCE IMAGING OF VASCULAR COMPRESSION IN TRIGEMINAL NEURALGIA - CASE-REPORT JOURNAL OF NEUROSURGERY Wong, B. Y., Steinberg, G. K., Rosen, L. 1989; 70 (1): 132-134

  Abstract

  A case of trigeminal neuralgia is reported in which preoperative high-resolution magnetic resonance imaging demonstrated vascular compression of the trigeminal nerve. Surgery confirmed compression and indentation of the fifth nerve by a large branch of the superior cerebellar artery. Following microvascular decompression, the patient experienced no further pain. Magnetic resonance imaging may be useful in the evaluation of trigeminal neuralgia to identify a subgroup of patients who could benefit most from decompression.

  View details for Web of Science ID A1989R555400025

  View details for PubMedID 2909674

• DEXTROMETHORPHAN PROTECTS AGAINST CEREBRAL INJURY FOLLOWING TRANSIENT FOCAL ISCHEMIA IN RABBITS STROKE Steinberg, G. K., George, C. P., Delapaz, R., Shibata, D. K., Gross, T. 1988; 19 (9): 1112-1118

  Abstract

  We investigated dextromethorphan, both a dextrorotatory opioid derivative and a clinically tested N-methyl-D-aspartate (NMDA) receptor antagonist, in a rabbit model of transient focal cerebral ischemia. Fourteen rabbits were randomly assigned to treatment with a 20 mg/kg i.v. loading dose followed by a 10 mg/kg/hr infusion of 0.4% dextromethorphan in normal saline or with an equivalent volume of normal saline alone. One hour after treatment, the rabbits underwent a 1-hour occlusion of the left internal carotid and anterior cerebral arteries followed by 4 hours of reperfusion. The seven dextromethorphan-treated rabbits showed a significant decrease in the area of neocortical severe ischemic neuronal damage (10.5%) compared with the seven normal saline-treated controls (49.6%, p less than 0.001). The dextromethorphan-treated rabbits also demonstrated significantly smaller areas of cortical edema (10.2%) on magnetic resonance imaging than the controls (38.6%, p less than 0.01). Analysis of somatosensory evoked potentials revealed recovery of the ipsilateral amplitude to contralateral values within 5 minutes of reperfusion in the dextromethorphan-treated rabbits but not in the controls (p less than 0.01). In our rabbit model of transient focal cerebral ischemia, dextromethorphan appears to protect the brain against ischemic neuronal damage and edema, as well as to promote neurophysiologic recovery. This clinically available drug should be further investigated as having potential therapeutic value in the treatment of stroke.

  View details for PubMedID 3413809

• MR OF ACUTE CEREBRAL-ISCHEMIA - CORRELATION WITH HISTOPATHOLOGY IN THE RABBIT DELAPAZ, R., SHIBATA, D., ZARNEGAR, R., STEINBERG, G. AMER SOC NEURORADIOLOGY. 1988: 1037–38

  View details for Web of Science ID A1988P880400219

• THE EFFECTS OF A PROPHYLACTIC BOLUS OF LIDOCAINE IN FOCAL CEREBRAL-ISCHEMIA CANADIAN JOURNAL OF ANAESTHESIA-JOURNAL CANADIEN D ANESTHESIE Gelb, A. W., Steinberg, G. K., Lam, A. M., Manninen, P. H., Peerless, S. J., RASSINETO, A. 1988; 35 (5): 489-493

  Abstract

  In order to determine the cerebral protective effects of an intravenous bolus of 5 mg.kg-1 of lidocaine, the left middle cerebral artery (MCA) was transorbitally occluded in 19 cats. Ten animals received the lidocaine bolus and nine a similar volume of saline immediately before MCA occlusion. Somatosensory evoked potentials (SEP) were recorded before and after the lidocaine bolus as well as continually after MCA occlusion. After six hours of vessel occlusion and without reperfusion, the animals were sacrificed and the brains fixed for histology. Prior to MCA occlusion, lidocaine caused a statistically significant (p less than 0.01) reduction in the amplitude of the major cortical component of the SEP (10 +/- 1.2 microV vs 6.0 +/- 1.3 microV). Latency was unchanged. In the lidocaine group, SEP's persisted in 40 per cent immediately following occlusion whereas they disappeared in all of the control animals (p less than 0.05). Gradual recovery occurred in both groups and there were no differences at the end of the experiment although the amplitudes tended to be greater in the lidocaine group. There were no statistically significant differences in the histological size or severity of the infarcts between the groups. Although infarct size was not reduced, transient sparing of the SEP suggests that further studies of lidocaine by continuous infusion in models of temporary focal cerebral ischaemia may be warranted.

  View details for Web of Science ID A1988Q313100011

  View details for PubMedID 3168133

• DELAYED TREATMENT WITH DEXTROMETHORPHAN AND DEXTRORPHAN REDUCES CEREBRAL-DAMAGE AFTER TRANSIENT FOCAL ISCHEMIA NEUROSCIENCE LETTERS Steinberg, G. K., Saleh, J., Kunis, D. 1988; 89 (2): 193-197

  Abstract

  The N-methyl-D-aspartate (NMDA) antagonists dextromethorphan (DM) and dextrorphan (DX) were found to reduce significantly neocortical severe ischemic neuronal damage (SIND) when administered in a delayed fashion after the ischemic insult. Rabbits underwent occlusion of the left internal carotid artery and anterior cerebral artery for 1 h, followed by 4 h of reperfusion. Immediately after the completion of the 1 h arterial occlusion, animals were blindly treated intravenously with 20 mg/kg loading dose followed by 10 mg/kg/h of DM, 15 mg/kg loading dose followed by 15 mg/kg/h of DX, or an equivalent volume of normal saline (NS) alone. The area of neocortical SIND was 3.7% in the DM group, 4.4% in the DX group, and 41.3% in the normal saline controls. These drugs may have considerable therapeutic potential in clinical stroke.

  View details for Web of Science ID A1988N893000014

  View details for PubMedID 3292967

• DEXTROMETHORPHAN REDUCES NEOCORTICAL ISCHEMIC NEURONAL DAMAGE INVIVO BRAIN RESEARCH George, C. P., Goldberg, M. P., Choi, D. W., Steinberg, G. K. 1988; 440 (2): 375-379

  Abstract

  The dextrorotatory morphinan dextromethorphan (DM), a clinically tested antagonist of the N-methyl-D-aspartate (NMDA) receptor-channel complex, was tested in an in vivo model of acute transient focal cerebral ischemia. Rabbits were randomly assigned to pretreatment with a 20 mg/kg i.v. bolus followed by 10 mg/kg/h of 0.4% DM in normal saline (NS), or with an equivalent volume of NS alone. They then underwent 1 h occlusion of the left internal carotid artery an anterior cerebral artery followed by 4 h of reperfusion. DM-treated animals showed a significant decrease in the percentage of severe neocortical ischemic neuronal damage (10.5%), as compared to NS-treated animals (49.6%).

  View details for PubMedID 3359222

• REDUCTION CRANIOPLASTY AND SEVERE HYPOTENSION ANESTHESIOLOGY Parsons, D., SAMUELS, S. I., Steinberg, G., Shuer, L. 1988; 68 (1): 145-146

  View details for Web of Science ID A1988L597700028

  View details for PubMedID 3337371

• DEXTROMETHORPHAN PROTECTS AGAINST CEREBRAL INJURY FOLLOWING TRANSIENT FOCAL ISCHEMIA STEINBERG, G. K., GEORGE, C. P., DELAPAZ, R., SHIBATA, D. K. AMER HEART ASSOC. 1988: 146

  View details for Web of Science ID A1988L792300102

• PRELIMINARY-RESULTS OF HEAVY PARTICLE RADIATION FOR ARTERIOVENOUS-MALFORMATIONS OF THE BRAIN STEINBERG, G. K., SILVERBERG, G. D., FABRIKANT, J. I., SHUER, L. M., FRANKEL, K. A., PHILLIPS, M. H., LEVY, R. P., MARKS, M. P. AMER HEART ASSOC. 1988: 149

  View details for Web of Science ID A1988L792300112

• CORRELATION BETWEEN SOMATOSENSORY EVOKED-POTENTIALS AND NEURONAL ISCHEMIC CHANGES FOLLOWING MIDDLE CEREBRAL-ARTERY OCCLUSION STROKE Steinberg, G. K., Gelb, A. W., Lam, A. M., Manninen, P. H., Peerless, S. J., Neto, A. R., Floyd, P. 1986; 17 (6): 1193-1197

  Abstract

  In an attempt to determine the usefulness of evoked potentials as a measure of focal cerebral ischemia, we examined somatosensory evoked potentials (SEP's) and morphological neuronal changes in cats following unilateral middle cerebral artery (MCA) occlusion. Fifteen adult cats underwent transorbital occlusion of the MCA under halothane anesthesia. In seven cats the ipsilateral SEP's were abolished after middle cerebral artery occlusion, and did not show any recovery after 6 hours. The same seven cats showed the greatest area of moderate and severe ischemic neuronal changes, ranging from 21 to 64% (mean 39 +/- 14%) of the total ipsilateral cortical area. The remaining eight cats showed a complete flattening or decreased amplitude of the SEP after occlusion, but demonstrated a considerable recovery in the amplitude of the primary cortical potential during the six hours of the study. All these cats had ischemic areas of less than 15% (mean 9 +/- 3%) of the total ipsilateral cortex. These results demonstrate that the disappearance of the SEP and their failure to recover correlate with the extent and degree of histological cerebral ischemia.

  View details for Web of Science ID A1986F883300026

  View details for PubMedID 3810720

• AN UNUSUAL NEOPLASM OF THE CAUDA-EQUINA WITH GANGLIOMATOUS AND EPENDYMOMATOUS ELEMENTS SURGICAL NEUROLOGY Steinberg, G. K., ROWAN, L. M., WHITE, J. E., Kristt, D. A. 1984; 22 (2): 164-166

  Abstract

  A unique intradural neoplasm of the cauda equina is presented. The tumor was composed of two neoplastic populations: ependymal cells in a papillary pattern and ganglion cells occurring individually or in clusters. The patient remains asymptomatic 1 year after resection of the tumor.

  View details for Web of Science ID A1984TB17200009

  View details for PubMedID 6740480

• SYMPTOMATIC RATHKE CLEFT CYSTS - REPORT OF 2 CASES JOURNAL OF NEUROSURGERY STEINBERG, G. K., KOENIG, G. H., GOLDEN, J. B. 1982; 56 (2): 290–95

  Abstract

  Two unusual cases of symptomatic Rathke's cleft cysts are described. The first patient was a 47-year-old man who presented with recurrent aseptic meningitis in addition to visual symptoms, panhypopituitarism, and hydrocephalus. The second patient was a 41-year-old man presenting with increasing headache, and a large, nonenhancing sellar cyst showing suprasellar extension on computerized tomography. The similarities between Rathke's cleft cysts and craniopharyngiomas are discussed.

  View details for DOI 10.3171/jns.1982.56.2.0290

  View details for Web of Science ID A1982MZ04700020

  View details for PubMedID 7054442