Nicholas Boulis

Emory University, Atlanta, Georgia, United States

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Publications (41)160.13 Total impact

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    ABSTRACT: We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material. EudraCT:2009-014484-39 .
    Journal of Translational Medicine 12/2015; 13(1):371. DOI:10.1186/s12967-014-0371-2 · 3.99 Impact Factor
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    ABSTRACT: A 12-month double-blind sham-surgery-controlled trial assessing adeno-associated virus type 2 (AAV2)-neurturin injected into the putamen bilaterally failed to meet its primary endpoint, but showed positive results for the primary endpoint in the subgroup of subjects followed for 18 months and for several secondary endpoints. Analysis of postmortem tissue suggested impaired axonal transport of neurturin from putamen to substantia nigra. In the present study, we tested the safety and efficacy of AAV2-neurturin delivered to putamen and substantia nigra. We performed a 15- to 24-month, multicenter, double-blind trial in patients with advanced Parkinson disease (PD) who were randomly assigned to receive bilateral AAV2-neurturin injected bilaterally into the substantia nigra (2.0 × 10(11) vector genomes) and putamen (1.0 × 10(12) vector genomes) or sham surgery. The primary endpoint was change from baseline to final visit performed at the time the last enrolled subject completed the 15-month evaluation in the motor subscore of the Unified Parkinson's Disease Rating Scale in the practically defined off state. Fifty-one patients were enrolled in the trial. There was no significant difference between groups in the primary endpoint (change from baseline: AAV2-neurturin, -7.0 ± 9.92; sham, -5.2 ± 10.01; p = 0.515) or in most secondary endpoints. Two subjects had cerebral hemorrhages with transient symptoms. No clinically meaningful adverse events were attributed to AAV2-neurturin. AAV2-neurturin delivery to the putamen and substantia nigra bilaterally in PD was not superior to sham surgery. The procedure was well tolerated, and there were no clinically significant adverse events related to AAV2-neurturin. Ann Neurol 2015. © 2015 American Neurological Association.
    Annals of Neurology 06/2015; DOI:10.1002/ana.24436 · 11.91 Impact Factor
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    ABSTRACT: Background We report the initial results from a phase I clinical trial for ALS. We transplanted GMP-grade, fetal human neural stem cells from natural in utero death (hNSCs) into the anterior horns of the spinal cord to test for the safety of both cells and neurosurgical procedures in these patients. The trial was approved by the Istituto Superiore di Sanità and the competent Ethics Committees and was monitored by an external Safety Board. Methods Six non-ambulatory patients were treated. Three of them received 3 unilateral hNSCs microinjections into the lumbar cord tract, while the remaining ones received bilateral (n = 3 + 3) microinjections. None manifested severe adverse events related to the treatment, even though nearly 5 times more cells were injected in the patients receiving bilateral implants and a much milder immune-suppression regimen was used as compared to previous trials. Results No increase of disease progression due to the treatment was observed for up to18 months after surgery. Rather, two patients showed a transitory improvement of the subscore ambulation on the ALS-FRS-R scale (from 1 to 2). A third patient showed improvement of the MRC score for tibialis anterior, which persisted for as long as 7 months. The latter and two additional patients refused PEG and invasive ventilation and died 8 months after surgery due to the progression of respiratory failure. The autopsies confirmed that this was related to the evolution of the disease. Conclusions We describe a safe cell therapy approach that will allow for the treatment of larger pools of patients for later-phase ALS clinical trials, while warranting good reproducibility. These can now be carried out under more standardized conditions, based on a more homogenous repertoire of clinical grade hNSCs. The use of brain tissue from natural miscarriages eliminates the ethical concerns that may arise from the use of fetal material. Trial registration EudraCT:2009-014484-39 webcite.
    Journal of Translational Medicine 01/2015; 13(3). DOI:10.1186/s12967-014-0371-2. · 3.99 Impact Factor
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    ABSTRACT: After injection into muscle and peripheral nerves, a variety of viral vectors undergo retrograde transport to lower motor neurons. However, because of its attractive safety profile and durable gene expression, adeno-associated virus (AAV) remains the only vector to have been applied to the human nervous system for the treatment of neurodegenerative disease. Nonetheless, only a very small fraction of intramuscularly injected AAV vector arrives at the spinal cord. To engineer a novel AAV vector by inserting a neuronal targeting peptide (Tet1), with binding properties similar to those of tetanus toxin, into the AAV1 capsid. Integral to this approach was the use of structure-based design to increase the effectiveness of functional capsid engineering. This approach allowed the optimization of scaffolding regions for effective display of the foreign epitope while minimizing disruption of the native capsid structure. We also validated an approach by which low-titer tropism-modified AAV vectors can be rescued by particle mosaicism with unmodified capsid proteins. Importantly, our rationally engineered AAV1-based vectors exhibited markedly enhanced transduction of cultured motor neurons, diminished transduction of nontarget cells, and markedly superior retrograde delivery compared with unmodified AAV1 vector. This approach promises a significant advancement in the rational engineering of AAV vectors for diseases of the nervous system and other organs. AAV, adeno-associated virusALS, amyotrophic lateral sclerosisDMEM, Dulbecco-modified Eagle mediumDRG, dorsal root gangliaDRP, DNase-resistant particleMOI, multiplicity of infectionPBS, phosphate-buffered salinePCR, polymerase chain reactionrAAV, recombinant adeno-associated virus.
    Neurosurgery 12/2014; 76(2). DOI:10.1227/NEU.0000000000000589 · 3.03 Impact Factor
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    ABSTRACT: Several case reports and small series have indicated that tardive dystonia is responsive to globus pallidus deep brain stimulation. Whether different subtypes or distributions of tardive dystonia are associated with different outcomes remains unknown.Methods We assessed the outcomes and temporal profile of improvement of eight tardive dystonia patients who underwent globus pallidus deep brain stimulation over the past six years through record review. Due to the retrospective nature of this study, it was not blinded or placebo controlled.ResultsConsistent with previous studies, deep brain stimulation improved the overall the Burke-Fahn-Marsden motor scores by 85.1±13.5%. The distributions with best responses in descending order were upper face, lower face, larynx/pharynx, limbs, trunk, and neck. Patients with prominent cervical dystonia demonstrated improvement in the Toronto Western Spasmodic Torticollis Rating Scale but improvements took several months. In four patients the effects of deep brain stimulation on improvement in Burke Fahn Marsden score was rapid, while in four cases there was partial rapid response of neck and trunk dystonia followed by was gradual resolution of residual symptoms over 48 months.Conclusion Our retrospective analysis shows excellent resolution of tardive dystonia after globus pallidus deep brain stimulation. We found instantaneous response, except with neck and trunk dystonia where partial recovery was followed by further resolution at slower rate. Such outcome is encouraging for using deep brain stimulation in treatment of tardive dystonia.
    Parkinsonism & Related Disorders 11/2014; 21(2). DOI:10.1016/j.parkreldis.2014.11.013 · 4.13 Impact Factor
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    ABSTRACT: Objective The first US Food and Drug Administration–approved clinical trial to treat amyotrophic lateral sclerosis (ALS) with neural stem cell–based therapy is in progress. The goal of the current study was to identify and assess the survival of human spinal cord–derived neural stem cells (HSSCs) transplanted into the spinal cord in patients with ALS.Methods Spinal cords transplanted with HSSCs were examined from six autopsy cases. Homogenized tissues were interrogated for the presence of donor versus recipient DNA using real-time PCR methods (qPCR). Fluorescence in situ hybridization (FISH) was performed using DNA probes for XY chromosomes to identify male donor HSSCs in one female case, and immunohistochemistry (IHC) was used to characterize the identified donor cells.ResultsGenomic DNA from donor HSSCs was identified in all cases, comprising 0.67–5.4% of total tissue DNA in patients surviving 196 to 921 days after transplantation. In the one female patient a “nest” of cells identified on H&E staining were XY-positive by FISH, confirming donor origin. A subset of XY-positive cells labeled for the neuronal marker NeuN and stem cell marker SOX2.InterpretationThis is the first study to identify human neural stem cells transplanted into a human spinal cord. Transplanted HSSCs survived up to 2.5 years posttransplant. Some cells differentiated into neurons, while others maintained their stem cell phenotype. This work is a proof of concept of the survival and differentiation of human stems cell transplanted into the spinal cord of ALS patients.
    11/2014; 1(11). DOI:10.1002/acn3.134
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    ABSTRACT: Diseases of the nervous system have devastating effects and are widely distributed among the population, being especially prevalent in the elderly. These diseases are often caused by inherited genetic mutations that result in abnormal nervous system development, neurodegeneration, or impaired neuronal function. Other causes of neurological diseases include genetic and epigenetic changes induced by environmental insults, injury, disease-related events or inflammatory processes. Standard medical and surgical practice has not proved effective in curing or treating these diseases, and appropriate pharmaceuticals do not exist or are insufficient to slow disease progression. Gene therapy is emerging as a powerful approach with potential to treat and even cure some of the most common diseases of the nervous system. Gene therapy for neurological diseases has been made possible through progress in understanding the underlying disease mechanisms, particularly those involving sensory neurons, and also by improvement of gene vector design, therapeutic gene selection, and methods of delivery. Progress in the field has renewed our optimism for gene therapy as a treatment modality that can be used by neurologists, ophthalmologists and neurosurgeons. In this Review, we describe the promising gene therapy strategies that have the potential to treat patients with neurological diseases and discuss prospects for future development of gene therapy.
    Nature Reviews Neurology 04/2013; DOI:10.1038/nrneurol.2013.56 · 14.10 Impact Factor
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    ABSTRACT: OBJECTIVE: In an effort to account for deficiencies in axonal transport that limit the effectiveness of neurotrophic factors, this study tested the safety and feasibility, in moderately advanced Parkinson disease (PD), of bilaterally administering the gene therapy vector AAV2-neurturin (CERE-120) to the putamen plus substantia nigra (SN, a relatively small structure deep within the midbrain, in proximity to critical neuronal and vascular structures). METHODS: After planning and minimizing risks of stereotactically targeting the SN, an open-label, dose-escalation safety trial was initiated in 6 subjects with PD who received bilateral stereotactic injections of CERE-120 into the SN and putamen. RESULTS: Two-year safety data for all subjects suggest the procedures were well-tolerated, with no serious adverse events. All adverse events and complications were expected for patients with PD undergoing stereotactic brain surgery. CONCLUSIONS: Bilateral stereotactic administration of CERE-120 to the SN plus putamen in PD is feasible and this evaluation provides initial empirical support that it is safe and well-tolerated. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that bilateral neurturin gene delivery (CERE-120) to the SN plus putamen in patients with moderately advanced PD is feasible and safe.
    Neurology 04/2013; 80:1698-1701. DOI:10.1212/WNL.0b013e3182904faa · 8.30 Impact Factor
  • Jonathan Riley, Carl V Hurtig, Nicholas Boulis
    Personalized Medicine 08/2012; 9(6):645-655. DOI:10.2217/pme.12.74 · 1.13 Impact Factor
  • Jonathan Riley, Jason Lamanna, Nicholas Boulis
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    ABSTRACT: An abstract is unavailable. This article is available as HTML full text and PDF.
    03/2012; 34(6):1–5. DOI:10.1097/01.CNE.0000412968.16798.d1
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    ABSTRACT: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease, which is the leading genetic cause of mortality in children. To date no effective treatment exists for SMA. The genetic basis for SMA has been well documented as a mutation in the gene for survival of motor neuron (SMN). Because there is an understanding of which gene needs to be replaced (SMN) and where it needs to be replaced (spinal motor systems), SMA is an ideal target for gene replacement via gene therapy. While a variety of animal models for SMA exist, they are either too fulminant to realistically test most gene delivery strategies, or too mild to provide a robust read out of the therapeutic effect. The field, therefore, requires a robust model with a slower symptomatic progression. A conditional knockout of SMN in neuronal cell types, giving a phenotype of functional motor defects, weight loss and reduced life expectancy partially satisfies this need (Frugier, Tiziano et al. 2000). This Cre/LoxP mediated neuron specific model presents an attractive alternative. In the present manuscript, we characterize the functional motor deficits of the model. We observed a decline in locomotor ability, as assessed by open field testing. The finer functions of motor skills such as righting reflex and grip strength were also observed to degenerate in the SMA mice. The decline in motor function that we observed here correlates with the anatomical decline in motor neurons and motor axons presented in the literature (Ferri, Melki et al. 2004). This work adds to our understanding and knowledge base of this Cre/LoxP model and provides a basis from which functional recovery, following interventions can be assessed.
    Neurobiology of Disease 12/2011; 45(3):992-8. DOI:10.1016/j.nbd.2011.12.018 · 5.20 Impact Factor
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    ABSTRACT: Adeno-associated viral vector 9 (AAV9) has recently been shown to penetrate the blood-brain barrier via intravascular administration, making it a good candidate for diffuse gene delivery. However, the potential side effects of systemic delivery are unknown. Intrathecal viral vector administration may be more invasive than intravenous injections, but it requires far less vector and it can be performed on an outpatient basis, making it an ideal route of delivery for clinical translation. A total of 12 domestic farm pigs (<20 kg) underwent a single-level lumbar laminectomy with intrathecal catheter placement for AAV9 delivery. Animals were perfused and the tissue was harvested 30 days after treatment. Gene expression was assessed by anti-green fluorescent protein immunohistochemistry. Although a single lumbar injection resulted in gene expression limited to the lumbar segment of the spinal cord, three consecutive boluses via a temporary catheter resulted in diffuse transduction of motor neurons (MNs) throughout the cervical, thoracic and lumbar spinal cords. We now present the first successful robust transduction of MNs in the spinal cord of a large animal via intrathecal gene delivery using a self-complementary AAV9. These promising results can be translated to many MN diseases requiring diffuse gene delivery.
    Gene therapy 09/2011; 19(8):852-9. DOI:10.1038/gt.2011.130 · 4.20 Impact Factor
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    Chalonda R Handy, Christina Krudy, Nicholas Boulis
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    ABSTRACT: Chronic pain is experienced by as many as 90% of cancer patients at some point during the disease. This pain can be directly cancer related or arise from a sensory neuropathy related to chemotherapy. Major pharmacological agents used to treat cancer pain often lack anatomical specificity and can have off-target effects that create new sources of suffering. These concerns establish a need for improved cancer pain management. Gene therapy is emerging as an exciting prospect. This paper discusses the potential for viral vector-based treatment of cancer pain. It describes studies involving vector delivery of transgenes to laboratory pain models to modulate the nociceptive cascade. It also discusses clinical investigations aimed at regulating pain in cancer patients. Considering the prevalence of pain among cancer patients and the growing potential of gene therapy, these studies could set the stage for a new class of medicines that selectively disrupt nociceptive signaling with limited off-target effects.
    06/2011; 2011(2090-1542):987597. DOI:10.1155/2011/987597
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    ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive loss of motor neurons, muscle wasting, and respiratory dysfunction. With disease progression, secondary symptoms arise creating new problematic conditions for ALS patients. Amongst these is pain. Although not a primary consequence of disease, pain occurs in a substantial number of individuals. Yet, studies investigating its pathomechanistic properties in the ALS patient are lacking. Therefore, more exploratory efforts into its scope, severity, impact, and treatment should be initiated. Several studies investigating the use of Clostridial neurotoxins for the reduction of pain in ALS patients suggest the potential for a neural specific approach involving focal drug delivery. Gene therapy represents a way to accomplish this. Therefore, the use of viral vectors to express transgenes that modulate the nociceptive cascade could prove to be an effective way to achieve meaningful benefit in conditions of pain in ALS.
    05/2011; 2011(2090-1852):403808. DOI:10.1155/2011/403808
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    ABSTRACT: The authors use an instructive case to review the challenges of diagnosis in subarachnoid hemorrhage (SAH) and to reinforce the nuances of clinical management. The presented case highlights critical issues in patient selection and challenges in the diagnosis of SAH and the management of both aneurysmal and arteriovenous fistula-related SAH. The critical points in decision making and diagnosis are discussed, and the case is accompanied by a brief review of the literature on the issues being faced. The present case is a patient presenting with SAH who was found to have an anterior communicating artery aneurysm. However, clues in the presentation and workup point to another etiology. A strong history of sudden neck pain before headache and abundance of SAH along the brainstem mandates a need to thoroughly evaluate the source of hemorrhage from cervical vessels through an angiogram.
    Neurosurgery 03/2011; 68(3):E866-73. DOI:10.1227/NEU.0b013e3182080474 · 3.03 Impact Factor
  • Nicholas Boulis, Thais Federici
    Neurosurgery 02/2011; 68(2):E599-600. DOI:10.1227/NEU.0b013e3182095e2e · 3.03 Impact Factor
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    ABSTRACT: In an open-label phase 1 trial, gene delivery of the trophic factor neurturin via an adeno-associated type-2 vector (AAV2) was well tolerated and seemed to improve motor function in patients with advanced Parkinson's disease. We aimed to assess the safety and efficacy of AAV2-neurturin in a double-blind, phase 2 randomised trial. We did a multicentre, double-blind, sham-surgery controlled trial in patients with advanced Parkinson's disease. Patients were randomly assigned (2:1) by a central, computer generated, randomisation code to receive either AAV2-neurturin (5·4 × 10¹¹ vector genomes) injected bilaterally into the putamen or sham surgery. All patients and study personnel with the exception of the neurosurgical team were masked to treatment assignment. The primary endpoint was change from baseline to 12 months in the motor subscore of the unified Parkinson's disease rating scale in the practically-defined off state. All randomly assigned patients who had at least one assessment after baseline were included in the primary analyses. This trial is registered at ClinicalTrials.gov, NCT00400634. Between December, 2006, and November, 2008, 58 patients from nine sites in the USA participated in the trial. There was no significant difference in the primary endpoint in patients treated with AAV2-neurturin compared with control individuals (difference -0·31 [SE 2·63], 95% CI -5·58 to 4·97; p=0·91). Serious adverse events occurred in 13 of 38 patients treated with AAV2-neurturin and four of 20 control individuals. Three patients in the AAV2-neurturin group and two in the sham surgery group developed tumours. Intraputaminal AAV2-neurturin is not superior to sham surgery when assessed using the UPDRS motor score at 12 months. However, the possibility of a benefit with additional targeting of the substantia nigra and longer term follow-up should be investigated in further studies. Ceregene and Michael J Fox Foundation for Parkinson's Research.
    The Lancet Neurology 10/2010; 9(12):1164-72. DOI:10.1016/S1474-4422(10)70254-4 · 21.82 Impact Factor
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    ABSTRACT: The purpose of Clinical Problem Solving articles is to present management challenges to give practicing neurosurgeons insight into how field leaders address these dilemmas. This illustration is accompanied by a brief review of the literature on the topic. The case of a 16-year-old boy presenting with headaches is presented. The patient is found to have a typical colloid cyst at the foramen of Monro. Bilateral ventriculoperitoneal shunt placement had been performed as an initial treatment of the patient before presentation. Surgeons experienced in open and endoscopic surgery discuss their individual approaches to colloid cysts, in the context of previous shunting, providing a varied perspective on the clinical challenges posed by these lesions. Both open and endoscopic options remain viable for excision of a colloid cyst. Each has associated potential complications, as illustrated by the current case.
    Neurosurgery 07/2010; 67(1):197-203; discussion 203-4. DOI:10.1227/01.NEU.0000370602.15820.E4 · 3.03 Impact Factor
  • Parkinsonism & Related Disorders 12/2009; 15. DOI:10.1016/S1353-8020(09)70464-X · 4.13 Impact Factor
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    ABSTRACT: Patients with intracranial aneurysms, both ruptured and unruptured, are frequently eligible for both open surgery ("clipping") and endovascular repair ("coiling"). Although results of randomized trials have informed this decision, the actual choice of clipping or coiling for individual patients remains complex. At the 2007 Congress of Neurological Surgeons (CNS) Annual Meeting, a novel active learning process called Integrated Medical Learning (IML) was applied to education about this critical treatment choice. CNS members received an electronically distributed premeeting survey and educational materials about the clipping versus coiling decision and related topics. At the Annual Meeting, participants used handheld devices to choose clipping or coiling for treatment of individual aneurysms, both before and after expert opinion presentations. After the meeting, members who had answered premeeting surveys received a follow-up questionnaire. In the premeeting poll, respondents with self-described specialties of "vascular," Cerebrovascular Section members, surgeons with active cerebrovascular practices, and surgeons in practice for less than 20 years had higher levels of baseline knowledge of cerebrovascular literature (P < .03). Surgeons' clinical volumes of clipping and coiling strongly influenced their vote for clipping or coiling for a hypothetical patient (P < .01). At the meeting, in 6 of 8 cases of ruptured aneurysms the audience was split 75%:25% or closer to "clinical equipoise" (50:50 split). Surgeons with vascular specialty, academic surgeons, and residents were more likely to recommend clipping for individual cases (P < .05). After experts' presentations, in 6 of 8 cases the audience opinion changed significantly. Vascular specialists and younger surgeons were less likely to change their opinion (P < .03). The 2 cases with no shift in opinion were the most-clippable and most-coilable cases. Postmeeting surveys showed evidence of retained knowledge from the meeting, and respondents thought IML had been helpful. Using IML, we were able to study baseline knowledge and practice patterns for an important cerebrovascular treatment decision. Evidence suggested that expert presentations were effective in changing audience opinion, at least in cases where preexisting opinion was close to clinical equipoise.
    Neurosurgery 11/2009; 66(1):19-34; discussion 34. DOI:10.1227/01.NEU.0000362005.93515.5B · 3.03 Impact Factor

Publication Stats

748 Citations
160.13 Total Impact Points

Institutions

  • 2008–2015
    • Emory University
      • • Department of Neurosurgery
      • • Department of Pathology and Laboratory Medicine
      Atlanta, Georgia, United States
  • 2005
    • The Ohio State University
      Columbus, Ohio, United States
  • 2004
    • Cleveland Clinic
      • Department of Neurosurgery
      Cleveland, Ohio, United States
  • 1999–2003
    • University of Michigan
      • • Department of Neurology
      • • Department of Surgery
      Ann Arbor, Michigan, United States