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

Dr. Steinberg has practiced neurosurgery at Stanford for more than 29 years. He has pioneered microsurgical techniques to repair intracranial vascular malformations and certain aneurysms that were previously considered untreatable. He has also refined revascularization techniques for patients with cerebrovascular arterial occlusions, as well as moyamoya disease. He is leading novel clinical trials of stem cell therapy for stroke and spinal cord injury.

Clinical Focus

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

Academic Appointments

Administrative Appointments

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

Professional Education

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

Research & Scholarship

Current Research and Scholarly Interests

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

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

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

Clinical Trials

  • Familial Intracranial Aneurysm Study II Not Recruiting

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

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

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  • A Study of Modified Stem Cells in Traumatic Brain Injury (TBI) Recruiting

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

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

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

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

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

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

    Stanford is currently not accepting patients for this trial.

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

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

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

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

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2017-18 Courses

Stanford Advisees

Graduate and Fellowship Programs


All Publications

  • 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


    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: 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


    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


    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

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


    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


    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


    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

    View details for PubMedCentralID PMC4704723

  • 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
  • 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


    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 Web of Science ID 000339062500006

    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


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

    View details for DOI 10.1227/NEU.0000000000000119

    View details for PubMedID 23921707

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


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

    View details for DOI 10.1227/NEU.0b013e318283c9c2

    View details for PubMedID 23262564

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


    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 Web of Science ID 000304294000022

    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


    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 Web of Science ID 000294342800031

    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


    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 Web of Science ID 000293586200005

    View details for PubMedID 21430584

  • 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


    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

  • 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


    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

  • 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


    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 Web of Science ID 000288123100038

    View details for PubMedID 21221025

  • Transplanted Stem Cell-Secreted VEGF Effects Post-Stroke Recovery, Inflammation, and Vascular Repair. Stem cells (Dayton, Ohio) 2011


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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)


    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 Web of Science ID 000396307600001

    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
  • 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
  • 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


    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

  • 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
  • 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


    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


    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-?


    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

  • 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


    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

  • 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


    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 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)


    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)


    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
  • 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


    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
  • 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

    View details for DOI 10.3174/ajnr.A4535

    View details for Web of Science ID 000369111200013

  • 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


    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 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 Web of Science ID 000373564300006

    View details for PubMedID 26687838

    View details for PubMedCentralID PMC4707064

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


    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: .

    View details for DOI 10.3171/2016.1.FocusVid.15420

    View details for PubMedID 26722680

  • 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-?


    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

  • 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


    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

  • 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)

    View details for DOI 10.1016/j.wneu.2015.08.032

    View details for Web of Science ID 000366286300113

    View details for PubMedID 26341435

  • 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
  • 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


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

    View details for DOI 10.1136/neurintsurg-2013-011089

    View details for PubMedID 24739599

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


    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


    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


    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


    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


    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

    View details for DOI 10.1002/acn3.142

    View details for Web of Science ID 000209815800003

  • 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


    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

  • 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
  • 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

  • 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


    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 Web of Science ID 000341283900014

    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-?


    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


    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
  • 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-?


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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

  • 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


    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


    : 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

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


    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)

    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)


    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

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

    View details for Web of Science ID 000318759100001

    View details for PubMedID 23518061

  • 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

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


    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

  • Combined endovascular and microsurgical management of complex cerebral aneurysms FRONTIERS IN NEUROLOGY Choudhri, O., Mukerji, N., Steinberg, G. K. 2013; 4
  • Aberrant expression of lymphatic-associated proteins in human brain arteriovenous malformations Shoemaker, L., Fuentes, L., Santiago, S., Steinberg, G., Chang, S. SPRINGER. 2013: 269–70
  • Imaging Neural Stem Cell Graft-Induced Structural Repair in Stroke CELL TRANSPLANTATION Daadi, M. M., Hu, S., Klausner, J., Li, Z., Sofilos, M., Sun, G., Wu, J. C., Steinberg, G. K. 2013; 22 (5): 881-892
  • 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


    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

  • 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


    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)


    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 Web of Science ID 000308738800005

    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


    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


    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 Web of Science ID 000308328300032

    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


    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)


    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

  • 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


    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

  • 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


    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


    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



    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

  • 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


    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 Web of Science ID 000303249100065

    View details for PubMedID 22451913

    View details for PubMedCentralID PMC3340046

  • 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


    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


    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

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


    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


    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 2012

    View details for DOI 10.1016/j.wneu.2012.11.018

    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


    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


    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

  • 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


    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


    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


    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 Web of Science ID 000295217100052

    View details for PubMedID 21836091

    View details for PubMedCentralID PMC3371396

  • 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


    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


    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

  • 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


    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

  • Stem cells and stroke: opportunities, challenges and strategies EXPERT OPINION ON BIOLOGICAL THERAPY Burns, T. C., Steinberg, G. K. 2011; 11 (4): 447-461


    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

  • 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


    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

  • 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


    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

  • Glycyrrhizin Protects Against Focal Ischemia and Attenuates Peripheral Immunosuppression in Rats International Stroke Conference Xiong, X., Gu, L., Li, L., Lee, J., Li, M., Xu, L., Giffard, R., Krams, S. M., Steinberg, G. K., Zhao, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: E67–E68
  • Moderate Hypothermia Attenuates Peripheral Immunodepression Caused by Stroke in Rats International Stroke Conference Gu, L., Xiong, X., Ito, T., Lee, J., Krams, S., Steinberg, G. K., Zhao, H. LIPPINCOTT WILLIAMS & WILKINS. 2011: E302–E303
  • 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
  • Angiographic Staging Of 215 Moyamoya Patients: Defining A New Modified Staging And Correlating Results To Patient Demographics And Clinical Findings International Stroke Conference Khan, N., Marks, M. P., Petralia, J., Tunovic, E., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2011: E201–E201
  • Transplanted Stem Cell-Secreted Vascular Endothelial Growth Factor Effects Poststroke Recovery, Inflammation, and Vascular Repair STEM CELLS Horie, N., Pereira, M. P., Niizuma, K., Sun, G., Keren-Gill, H., Encarnacion, A., Shamloo, M., Hamilton, S. A., Jiang, K., Huhn, S., Palmer, T. D., Bliss, T. M., Steinberg, G. K. 2011; 29 (2): 274-285


    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


    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 Web of Science ID 000291815300006

    View details for PubMedID 21135550

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


    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

  • 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


    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 Web of Science ID 000284565100009

    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


    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

  • 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


    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-?


    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/

    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)
  • 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


    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

  • 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
  • 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


    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


    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

  • 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


    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

  • 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


    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 Web of Science ID 000271375500012

    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)


    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 Web of Science ID 000271373800014

    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
  • 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


    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

  • 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


    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

  • 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


    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

  • 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)


    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)


    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)


    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)


    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)


    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

  • 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
  • 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
  • Therapeutic Homing of Neurosphere-Derived Multipotent Precursors After Intracarotid Delivery in Stroke is Dependent on the MCP-1/CCR2 Interaction. American-Association-International-Stroke Conference 2009 Andres, R. H., Choi, R., Gaeta, X., Wang, N., Cote, J., Lee, S. W., Palmer, T. D., Guzman, R., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2009: E171–E171
  • Quantitative hemodynamic studies in moyamoya disease NEUROSURGICAL FOCUS Lee, M., Zaharchuk, G., Guzman, R., Achrol, A., Bell-Stephens, T., Steinberg, G. K. 2009; 26 (4)


    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


    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


    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


    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


    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 Web of Science ID 000263304400025

    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


    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 Web of Science ID 000262059400045

    View details for PubMedID 18948613

  • 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
  • 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
  • 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


    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

  • 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–
  • 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


    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


    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


    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


    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 Web of Science ID 000258174400025

    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


    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

  • 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


    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 Web of Science ID 000256245300024

    View details for PubMedID 18518720

  • 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


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

    View details for DOI 10.1002/jnr.21604

    View details for Web of Science ID 000256646400001

    View details for PubMedID 18189318

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


    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

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

    View details for DOI 10.2217/17460751.3.3.249

    View details for Web of Science ID 000257995200001

    View details for PubMedID 18462048

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


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

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

    View details for Web of Science ID 000257218500011

    View details for PubMedID 18580802

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


    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


    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

  • 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


    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)


    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

  • 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)


    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

  • 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)


    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

  • 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


    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

  • 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


    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

  • 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
  • Analysis of intraoperative flow measurements in moyamoya patients during revascularization surgery 33rd International Stroke Conference Lee, M., Guzman, R., Bell-Stephens, T., Steinberg, G. LIPPINCOTT WILLIAMS & WILKINS. 2008: 720–20
  • Limb remote-preconditioning protects against focal ischemia in rats and contradicts the dogma of therapeutic time windows for preconditioning. 33rd International Stroke Conference Ren, C., Gao, X., Steinberg, G. K., Zhao, H. LIPPINCOTT WILLIAMS & WILKINS. 2008: 664–64
  • 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
  • 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


    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)


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

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

    View details for Web of Science ID 000256268400018

    View details for PubMedID 18275292

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


    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


    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

  • 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


    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


    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 Web of Science ID 000248266700005

    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


    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 Web of Science ID 000246034100017

    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


    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 Web of Science ID 000246047800008

    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


    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


    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

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


    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/

    View details for Web of Science ID 000244122600036

    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


    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/

    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


    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

  • 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


    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


    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


    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


    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


    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 Web of Science ID 000240623900013

    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


    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


    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


    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


    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

  • Surgical management of posterior fossa arteriovenous malformations NEUROSURGERY Sinclair, J., Kelly, M. E., Steinberg, G. K. 2006; 58 (4): 189-201
  • 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
  • Elevated serum levels of VEGF, bFGF, MMP-2, and MMP-9 in patients with Moyamoya disease 31st International Stroke Conference Lim, M., Wang, Y., Bower, R., Cheshier, S., Sims, L., Choi, S., Harsh, G., Steinberg, G., Guccione, S. LIPPINCOTT WILLIAMS & WILKINS. 2006: 701–
  • Hypothermia protects against cerebral ischemia by suppressing delta Pkc activation in rats 31st International Stroke Conference Shimohata, T., Zhao, H., Steinberg, G. K. LIPPINCOTT WILLIAMS & WILKINS. 2006: 677–77
  • 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-?


    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
  • 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-?


    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


    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 Web of Science ID 000243591900005

    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


    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/

    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


    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


    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 Web of Science ID 000236681500018

    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
  • 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-?


    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


    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


    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

  • 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


    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 Web of Science ID 000227628500016

    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


    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 Web of Science ID 000227387600005

    View details for PubMedID 16148983

  • 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
  • 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
  • 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


    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


    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


    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 Web of Science ID 000230678700005

    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


    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

  • 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


    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 Web of Science ID 000223102500004

    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


    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 Web of Science ID 000223191500008

    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


    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 Web of Science ID 000222726500020

    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


    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


    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


    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


    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


    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
  • 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


    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


    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


    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 Web of Science ID 000185400100007

    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


    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


    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 Web of Science ID 000183988600001

    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


    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


    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


    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


    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


    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 Web of Science ID 000181922400006

    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


    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 Web of Science ID 000182422900008

    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


    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
  • 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
  • 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


    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
  • 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


    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

  • 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


    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


    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

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


    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


    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


    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

  • 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
  • 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
  • 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
  • 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


    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


    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


    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


    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 Web of Science ID 000171119500028

    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


    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


    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-?


    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


    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


    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

  • 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


    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


    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


    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


    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


    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


    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
  • 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


    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 Web of Science ID 000086360100034

    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


    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


    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


    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 Web of Science ID 000084540200123

    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


    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


    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


    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 Web of Science ID 000084092000055

    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


    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


    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


    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 Web of Science ID 000081201500030

    View details for PubMedID 10414566

  • 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


    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 Web of Science ID 000080091700026

    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


    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 Web of Science ID 000079903800030

    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


    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 Web of Science ID 000079903800096

    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


    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 Web of Science ID 000078716500020

    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


    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

  • 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 1180–81


    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

  • 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


    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

  • 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
  • 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


    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


    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


    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


    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 Web of Science ID 000078035900037

    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


    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


    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 Web of Science ID 000074979500006

    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


    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-?


    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


    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


    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


    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 Web of Science ID 000072610300011

    View details for PubMedID 9545184

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


    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

  • 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


    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


    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


    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


    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


    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


    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


    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

  • 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


    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


    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


    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 Web of Science ID A1996UM58700003

    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


    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 Web of Science ID A1996UG54000028

    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


    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


    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


    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

  • 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


    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

  • 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


    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

  • 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


    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

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


    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



    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



    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



    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



    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) 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



    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



    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 Web of Science ID A1995QB20600006

    View details for PubMedID 7900585



    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


    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 Web of Science ID A1994NN21500004

    View details for PubMedID 8177246



    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 Web of Science ID A1994NL03200004

    View details for PubMedID 8059648



    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 Web of Science ID A1994NG95500026

    View details for PubMedID 8153318



    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 Web of Science ID A1994NH38600010

    View details for PubMedID 8052377



    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

  • 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


    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


    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



    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



    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 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



    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



    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 Web of Science ID A1993LM07000009

    View details for PubMedID 8352152



    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



    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 Web of Science ID A1993KR57000004

    View details for PubMedID 8456702



    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


    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



    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



    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



    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


    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



    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


    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



    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



    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



    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


    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



    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



    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



    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



    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



    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



    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



    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



    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 Web of Science ID A1991EN93800020

    View details for PubMedID 1704174

  • 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
  • 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


    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



    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



    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



    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



    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


    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


    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



    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 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



    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



    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 Web of Science ID A1988Q135200008

    View details for PubMedID 3413809



    In order to determine the cerebral protective effects of an intravenous bolus of 5 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



    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



    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 Web of Science ID A1988M354900024

    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



    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



    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