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1.  Versatile utilization of real-time intraoperative contrast-enhanced ultrasound in cranial neurosurgery: technical note and retrospective case series 
Neurosurgical focus  2016;40(3):E6.
Intraoperative contrast-enhanced ultrasound (iCEUS) offers dynamic imaging and provides functional data in real time. However, no standardized protocols or validated quantitative data exist to guide its routine use in neurosurgery. The authors aimed to provide further clinical data on the versatile application of iCEUS through a technical note and illustrative case series.
Five patients undergoing craniotomies for suspected tumors were included. iCEUS was performed using a contrast agent composed of lipid shell microspheres enclosing perflutren (octafluoropropane) gas. Perfusion data were acquired through a time-intensity curve analysis protocol obtained using iCEUS prior to biopsy and/or resection of all lesions.
Three primary tumors (gemistocytic astrocytoma, glioblastoma multiforme, and meningioma), 1 metastatic lesion (melanoma), and 1 tumefactive demyelinating lesion (multiple sclerosis) were assessed using real-time iCEUS. No intraoperative complications occurred following multiple administrations of contrast agent in all cases. In all neoplastic cases, iCEUS replicated enhancement patterns observed on preoperative Gd-enhanced MRI, facilitated safe tumor de-bulking by differentiating neoplastic tissue from normal brain parenchyma, and helped identify arterial feeders and draining veins in and around the surgical cavity. Intraoperative CEUS was also useful in guiding a successful intraoperative needle biopsy of a cerebellar tumefactive demyelinating lesion obtained during real-time perfusion analysis.
Intraoperative CEUS has potential for safe, real-time, dynamic contrast-based imaging for routine use in neurooncological surgery and image-guided biopsy. Intraoperative CEUS eliminates the effect of anatomical distortions associated with standard neuronavigation and provides quantitative perfusion data in real time, which may hold major implications for intraoperative diagnosis, tissue differentiation, and quantification of extent of resection. Further prospective studies will help standardize the role of iCEUS in neurosurgery.
PMCID: PMC5101076  PMID: 26926064
ultrasound; sonography; perfusion; microbubbles; contrast; dynamic imaging
2.  Molecularly targeted therapies for recurrent glioblastoma: current and future targets 
Neurosurgical focus  2014;37(6):E15.
Glioblastoma is the most aggressive and diffusely infiltrative primary brain tumor. Recurrence is expected and is extremely difficult to treat. Over the past decade, the accumulation of knowledge regarding the molecular and genetic profile of glioblastoma has led to numerous molecularly targeted therapies. This article aims to review the literature and highlight the mechanisms and efficacies of molecularly targeted therapies for recurrent glioblastoma.
A systematic search was performed with the phrase “(name of particular agent) and glioblastoma” as a search term in PubMed to identify all articles published up until 2014 that included this phrase in the title and/or abstract. The references of systematic reviews were also reviewed for additional sources. The review included clinical studies that comprised at least 20 patients and reported results for the treatment of recurrent glioblastoma with molecular targeted therapies.
A total of 42 articles were included in this review. In the treatment of recurrent glioblastoma, various targeted therapies have been tested over the past 10–15 years. The targets of interest include epidermal growth factor receptor, vascular endothelial growth factor receptor, platelet-derived growth factor receptor, Ras pathway, protein kinase C, mammalian target of rapamycin, histone acetylation, and integrins. Unfortunately, the clinical responses to most available targeted therapies are modest at best. Radiographic responses generally range in the realm of 5%–20%. Progression-free survival at 6 months and overall survival were also modest with the majority of studies reporting a 10%–20% 6-month progression-free survival and 5- to 8-month overall survival. There have been several clinical trials evaluating the use of combination therapy for molecularly targeted treatments. In general, the outcomes for combination therapy tend to be superior to single-agent therapy, regardless of the specific agent studied.
Recurrent glioblastoma remains very difficult to treat, even with molecular targeted therapies and anticancer agents. The currently available targeted therapy regimens have poor to modest activity against recurrent glioblastoma. As newer agents are actively being developed, combination regimens have provided the most promising results for improving outcomes. Targeted therapies matched to molecular profiles of individual tumors are predicted to be a critical component necessary for improving efficacy in future trials.
PMCID: PMC5058366  PMID: 25434384
combination treatment; glioblastoma; molecular therapy; overall survival; progression-free survival; recurrent
3.  4.7-T diffusion tensor imaging of acute traumatic peripheral nerve injury 
Neurosurgical focus  2015;39(3):E9.
Diagnosis and management of peripheral nerve injury is complicated by the inability to assess microstructural features of injured nerve fibers via clinical examination and electrophysiology. Diffusion tensor imaging (DTI) has been shown to accurately detect nerve injury and regeneration in crush models of peripheral nerve injury, but no prior studies have been conducted on nerve transection, a surgical emergency that can lead to permanent weakness or paralysis. Acute sciatic nerve injuries were performed microsurgically to produce multiple grades of nerve transection in rats that were harvested 1 hour after surgery. High-resolution diffusion tensor images from ex vivo sciatic nerves were obtained using diffusion-weighted spin-echo acquisitions at 4.7 T. Fractional anisotropy was significantly reduced at the injury sites of transected rats compared with sham rats. Additionally, minor eigenvalues and radial diffusivity were profoundly elevated at all injury sites and were negatively correlated to the degree of injury. Diffusion tensor tractography showed discontinuities at all injury sites and significantly reduced continuous tract counts. These findings demonstrate that high-resolution DTI is a promising tool for acute diagnosis and grading of traumatic peripheral nerve injuries.
PMCID: PMC4786003  PMID: 26323827
diffusion tensor imaging; diffusion tensor tractography; MRI; neurography; peripheral nerve injury; nerve transection; neurotmesis
4.  The utility of high-resolution intraoperative MRI in endoscopic transsphenoidal surgery for pituitary macroadenomas: early experience in the Advanced Multimodality Image Guided Operating suite 
Neurosurgical focus  2016;40(3):E18.
Endoscopic skull base surgery has become increasingly popular among the skull base surgery community, with improved illumination and angled visualization potentially improving tumor resection rates. Intraoperative MRI (iMRI) is used to detect residual disease during the course of the resection. This study is an investigation of the utility of 3-T iMRI in combination with transnasal endoscopy with regard to gross-total resection (GTR) of pituitary macroadenomas.
The authors retrospectively reviewed all endoscopic transsphenoidal operations performed in the Advanced Multimodality Image Guided Operating (AMIGO) suite from November 2011 to December 2014. Inclusion criteria were patients harboring presumed pituitary macroadenomas with optic nerve or chiasmal compression and visual loss, operated on by a single surgeon.
Of the 27 patients who underwent transsphenoidal resection in the AMIGO suite, 20 patients met the inclusion criteria. The endoscope alone, without the use of iMRI, would have correctly predicted 13 (65%) of 20 cases. Gross-total resection was achieved in 12 patients (60%) prior to MRI. Intraoperative MRI helped convert 1 STR and 4 NTRs to GTRs, increasing the number of GTRs from 12 (60%) to 16 (80%).
Despite advances in visualization provided by the endoscope, the incidence of residual disease can potentially place the patient at risk for additional surgery. The authors found that iMRI can be useful in detecting unexpected residual tumor. The cost-effectiveness of this tool is yet to be determined.
PMCID: PMC4992957  PMID: 26926058
intraoperative MRI; endoscope; pituitary adenomas; resection; AMIGO
5.  Improving the accuracy of brain tumor surgery via Raman-based technology 
Neurosurgical focus  2016;40(3):E9.
Despite advances in the surgical management of brain tumors, achieving optimal surgical results and identification of tumor remains a challenge. Raman spectroscopy, a laser-based technique that can be used to nondestructively differentiate molecules based on the inelastic scattering of light, is being applied toward improving the accuracy of brain tumor surgery. Here, the authors systematically review the application of Raman spectroscopy for guidance during brain tumor surgery. Raman spectroscopy can differentiate normal brain from necrotic and vital glioma tissue in human specimens based on chemical differences, and has recently been shown to differentiate tumor-infiltrated tissues from noninfiltrated tissues during surgery. Raman spectroscopy also forms the basis for coherent Raman scattering (CRS) microscopy, a technique that amplifies spontaneous Raman signals by 10,000-fold, enabling real-time histological imaging without the need for tissue processing, sectioning, or staining. The authors review the relevant basic and translational studies on CRS microscopy as a means of providing real-time intraoperative guidance. Recent studies have demonstrated how CRS can be used to differentiate tumor-infiltrated tissues from noninfiltrated tissues and that it has excellent agreement with traditional histology. Under simulated operative conditions, CRS has been shown to identify tumor margins that would be undetectable using standard bright-field microscopy. In addition, CRS microscopy has been shown to detect tumor in human surgical specimens with near-perfect agreement to standard H & E microscopy. The authors suggest that as the intraoperative application and instrumentation for Raman spectroscopy and imaging matures, it will become an essential component in the neurosurgical armamentarium for identifying residual tumor and improving the surgical management of brain tumors.
PMCID: PMC4992579  PMID: 26926067
brain metastasis; brain/tumor margin; coherent Raman scattering microscopy; glioma; primary brain tumors; Raman spectroscopy
6.  Neurorestoration after stroke 
Neurosurgical focus  2016;40(5):E2.
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 scientifc and clinical implications of neurorestorative therapies for stroke.
PMCID: PMC4916840  PMID: 27132523
optogenetics; exogenous stem cells; brain-computer interface; neuroplasticity
7.  Bevacizumab for glioblastoma: current indications, surgical implications, and future directions 
Neurosurgical focus  2014;37(6):E9.
Initial enthusiasm after promising Phase II trials for treating recurrent glioblastomas with the antiangiogenic drug bevacizumab—a neutralizing antibody targeting vascular endothelial growth factor—was tempered by recent Phase III trials showing no efficacy for treating newly diagnosed glioblastomas. As a result, there is uncertainty about the appropriate indications for the use of bevacizumab in glioblastoma treatment. There are also concerns about the effects of bevacizumab on wound healing that neurosurgeons must be aware of. In addition, biochemical evidence suggests a percentage of tumors treated with bevacizumab for an extended period of time will undergo transformation into a more biologically aggressive and invasive phenotype with a particularly poor prognosis. Despite these concerns, there remain numerous examples of radiological and clinical improvement after bevacizumab treatment, particularly in patients with recurrent glioblastoma with limited therapeutic options. In this paper, the authors review clinical results with bevacizumab for glioblastoma treatment to date, ongoing trials designed to address unanswered questions, current clinical indications based on existing data, neurosurgical implications of bevacizumab use in patients with glioblastoma, the current scientific understanding of the tumor response to short- and long-term bevacizumab treatment, and future studies that will need to be undertaken to enable this treatment to fulfill its therapeutic promise for glioblastoma.
PMCID: PMC4839778  PMID: 25581938
bevacizumab; Avastin; anti-angiogenic; glioblastoma
8.  Survival and low grade glioma: the emergence of genetic information 
Neurosurgical focus  2015;38(1):E6.
Significant gaps exist in our understanding of the causes and clinical management of glioma. One of the biggest gaps is how best to manage low grade (World Health Organization (WHO) grade II) glioma patients. Low grade glioma is a uniformly fatal disease of young adults (mean age 41 years) with survival averaging approximately 7 years. Although low grade glioma patients have better survival than patients with high grade (WHO grade III/IV) glioma, all low grade gliomas eventually progress to high grade glioma and death. Data from the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute suggest that for the majority of low grade glioma patients, overall survival has not significantly improved over the past three decades, highlighting the need for intensified study of this tumor. Newly published research suggests that historically utilized clinical variables are not sufficient (and are likely inferior) prognostic and predictive indicators relative to information provided by recently discovered tumor markers (e.g..1p/19q deletion and IDH1/2 mutation status), tumor expression profiles (e.g. the Proneural Profile) and/or constitutive genotype (e.g. rs55705857 on 8q24.21). Discovery of such tumor and constitutive variation may identify variables needed to improve randomization in clinical trials as well as patients more sensitive to current treatments and targets for improved treatment in the future. This manuscript reports on survival trends for patients diagnosed with low grade glioma within the United States from 1973–2011 and reviews the emerging role of tumor and constitutive genetics in refining risk stratification, defining targeted therapy, and improving survival for this group of relatively young patients.
PMCID: PMC4361022  PMID: 25552286
glioma; low grade; survival; SEER; epidemiology; genes; GWAS; treatment
9.  Treatment and outcomes of ARUBA-eligible patients with unruptured brain arteriovenous malformations at a single institution 
Neurosurgical focus  2014;37(3):E8.
Management of unruptured arteriovenous malformations is controversial. In the first randomized trial of unruptured AVMs (ARUBA), medically managed had a significantly lower risk of death or stroke and better outcomes. The University of California, San Francisco (UCSF) was one of the participating ARUBA sites. While 473 patients were screened for eligibility, only 4 patients were enrolled in ARUBA. The purpose of this study is to report the treatment and outcomes of all ARUBA eligible patients at UCSF.
We compared the treatment and outcomes of ARUBA eligible patients using prospectively collected data from the UCSF brain AVM (BAVM) registry. Similar to ARUBA, we compared the rate of stroke or death in observed and treated patients and used the modified Rankin scale to grade outcomes
61 of 74 patients received an intervention and 13 patients were observed. Most treated patients had a surgical resection with or without preoperative embolization (43/61; 70.5%). One observed patient died from AVM hemorrhage (1/13). Nine treated patients had a stroke or died (9/61). There was no significant difference in the rate of stroke or death (HR 1.34 95% C.I. 0.12–14.53 p=0.807) or clinical impairment (Fisher’s exact p=0.68) between observed and treated patients.
The risk of stroke or death and degree of clinical impairment among treated patients was lower than reported in ARUBA. We found no significant difference in outcomes between observed and treated ARUBA eligible patients at the University of California, San Francisco. Results in ARUBA-eligible patients managed outside that trial lead to an entirely different conclusion about AVM intervention, due to the primary role of surgery, judicious surgical selection with established outcome predictors, and technical expertise developed at high-volume AVM centers.
PMCID: PMC4420142  PMID: 25175446
arteriovenous malformation; ARUBA trial; observation; microsurgical resection
10.  The natural history of AVM hemorrhage in the posterior fossa: comparison of hematoma volumes and neurological outcomes in patients with ruptured infra- and supratentorial AVMs 
Neurosurgical focus  2014;37(3):E6.
Patients with posterior fossa arteriovenous malformations (AVMs) are more likely to present with hemorrhage than those with supratentorial AVMs. Observed patients subject to the AVM natural history should be informed of the individualized effects of AVM characteristics on the clinical course following a new, first-time hemorrhage. The authors hypothesize that the debilitating effects of first-time bleeding from an AVM in a previously intact patient with an unruptured AVM are more pronounced when AVMs are located in the posterior fossa.
The University of California, San Francisco prospective registry of brain AVMs was searched for patients with a ruptured AVM who had a pre-hemorrhage modified Rankin Scale (mRS) score of 0 and a post-hemorrhage mRS score obtained within 2 days of the hemorrhagic event. A total of 154 patients met the inclusion criteria for this study. Immediate post-hemorrhage presentation mRS scores were dichotomized into nonsevere outcome (mRS > 3) and severe outcome (mRS > 3). There were 77 patients in each group. Univariate and multivariate logistic regression analyses using severe outcome as the binary response were run. The authors also performed a logistic regression analysis to measure the effects of hematoma volume and AVM location on severe outcome.
Posterior fossa location was a significant predictor of severe outcome (OR 2.60, 95% CI 1.20–5.67, p = 0.016) and the results were strengthened in a multivariate model (OR 4.96, 95% CI 1.73–14.17, p = 0.003). Eloquent location (OR 3.47, 95% CI 1.37–8.80, p = 0.009) and associated arterial aneurysms (OR 2.58, 95% CI 1.09, 6.10; p = 0.031) were also significant predictors of poor outcome. Hematoma volume for patients with a posterior fossa AVM was 10.1 ± 10.1 cm3 compared with 25.6 ± 28.0 cm3 in supratentorial locations (p = 0.003). A logistic analysis (based on imputed hemorrhage volume values) found that posterior fossa location was a significant predictor of severe outcome (OR 8.03, 95% CI 1.20–53.77, p = 0.033) and logarithmic hematoma volume showed a positive, but not statistically significant, association in the model (p = 0.079).
Patients with posterior fossa AVMs are more likely to have severe outcomes than those with supratentorial AVMs based on this natural history study. Age, sex, and ethnicity were not associated with an increased risk of severe outcome after AVM rupture, but posterior fossa location, associated aneurysms, and eloquent location were associated with poor post-hemorrhage mRS scores. Posterior fossa hematomas are poorly tolerated, with severe outcomes observed even with smaller hematoma volumes. These findings support an aggressive surgical posture with respect to posterior fossa AVMs, both before and after rupture.
PMCID: PMC4425310  PMID: 25175444
arteriovenous malformation; infratentorial; posterior fossa; supplementary grade; Spetzler-Martin grade; microsurgical resection
11.  Therapeutic strategies to improve drug delivery across the blood-brain barrier 
Neurosurgical focus  2015;38(3):E9.
Resection of brain tumors is followed by chemotherapy and radiation to ablate remaining malignant cell populations. Targeting these populations stands to reduce tumor recurrence and offer the promise of more complete therapy. Thus, improving access to the tumor, while leaving normal brain tissue unscathed, is a critical pursuit. A central challenge in this endeavor lies in the limited delivery of therapeutics to the tumor itself. The blood-brain barrier (BBB) is responsible for much of this difficulty but also provides an essential separation from systemic circulation. Due to the BBB’s physical and chemical constraints, many current therapies, from cytotoxic drugs to antibody-based proteins, cannot gain access to the tumor. This review describes the characteristics of the BBB and associated changes wrought by the presence of a tumor. Current strategies for enhancing the delivery of therapies across the BBB to the tumor will be discussed, with a distinction made between strategies that seek to disrupt the BBB and those that aim to circumvent it.
PMCID: PMC4493051  PMID: 25727231
blood-brain barrier; focused ultrasound; convection-enhanced delivery; P-glycoprotein
12.  Evaluation of Complications and Neurological Deficits with Three Column Spine Reconstructions for Complex Spinal Deformity: A Retrospective Scoli-Risk 1 Study 
Neurosurgical focus  2014;36(5):E17.
To evaluate the risk factors for complications, including new neurological deficits, in the largest cohort of adult spinal deformity patients to date.
Scoli-RISK-1 inclusion criteria were used to identify eligible patients from five centers, treated from June 1, 2009 to June 1, 2011. Records were reviewed for patient demographics, surgical data, and reports of perioperative complications. Neurological deficits were recorded as pre-existing or as new neurological deficits. Patients undergoing a three column osteotomies (3CO) were compared to those not (PSF). Between group comparisons were performed using independent samples t-tests and Chi-square analyses.
Two hundred and seven patients were identified, with 75 PSF and 132. 3CO patients were older (58.9 vs 49.4, p<0.0001), had higher BMI (29.0 vs 25.8, p=0.034), had smaller preoperative coronal Cobb measurements (33.8 vs 56.3, p<0.001), had more preoperative sagittal malalignment (116.6 vs 54.5mm, p<0.001), and had similar sagittal Cobb measurements (45.8 vs 57.7, p=0.113). Operative times were similar (393 vs 423 min, p=0.112), though 3CO sustained higher EBL (2120 vs 1700mL, p=0.013). Rates of new neurologic deficits were similar (PSF:6.7% vs 3CO:9.8%, p=0.435) and rates of any perioperative medical complication were similar (PSF:45.3% vs 3CO:34.8%, p=0.136). VCR patients were more likely to sustain medical complications than PSO (73.7% vs 46.9%, p=0.031), though new neurologic deficits were similar (15.8% vs 8.8%, p=0.348). Regression analysis did not reveal significant predictors of neurologic injury nor complication from collected data.
Despite higher EBL, rates of all complications (49.3%) and new neurologic deficits (8.7%) did not vary for complex reconstruction patients, whether a 3-CO is performed or not. VCR patients sustained more medical complications without an increase in new neurologic deficits. Prospective study of patient factors, provider factors, and refined surgical data are needed to define and optimize risk factors for complication and neurologic deficits.
PMCID: PMC4185213  PMID: 24785482
Three column osteotomy; pedicle subtraction; vertebral column resection; adult deformity; complications; Adult Spinal Deformity; Osteotomy
13.  Effect of glibenclamide on the prevention of secondary brain injury following ischemic stroke in humans 
Neurosurgical focus  2014;36(1):E11.
Cerebral edema and hemorrhagic conversion are common, potentially devastating complications of ischemic stroke and are associated with high rates of mortality and poor functional outcomes. Recent work exploring the molecular pathophysiology of the neurogliovascular unit in ischemic stroke suggests that deranged cellular ion homeostasis due to altered function and regulation of ion pumps, channels, and secondary active transporters plays an integral role in the development of cytotoxic and vasogenic edema and hemorrhagic conversion. Among these proteins involved in ion homeostasis, the ischemia-induced, nonselective cation conductance formed by the SUR1-TRPM4 protein complex appears to play a prominent role and is potently inhibited by glibenclamide, an FDA-approved drug commonly used in patients with Type 2 diabetes. Several robust preclinical studies have demonstrated the efficacy of glibenclamide blockade of SUR1-TRPM4 activity in reducing edema and hemorrhagic conversion in rodent models of ischemic stroke, prompting the study of the potential protective effects of glibenclamide in humans in an ongoing prospective phase II clinical trial. Preliminary data suggest glibenclamide significantly reduces cerebral edema and lowers the rate of hemorrhagic conversion following ischemic stroke, suggesting the potential use of glibenclamide to improve outcomes in humans.
PMCID: PMC4234034  PMID: 24380477
stroke; Glyburide; edema; glibenclamide; metalloproteinase; cytotoxic; SUR1; TRPM4
14.  Focused ultrasound disruption of the blood brain barrier: a new frontier for therapeutic delivery in molecular neuro-oncology 
Neurosurgical focus  2012;32(1):E3.
Recent advances in molecular neuro-oncology provide unique opportunities for targeted molecular-based therapies. However, the blood brain barrier (BBB) remains a major limitation to the delivery of tumor-specific therapies directed against aberrant signaling pathways in brain tumors. Given the dismal prognosis of patients with malignant brain tumors, novel strategies that overcome the intrinsic limitations of the BBB are therefore highly desirable. Focused ultrasound (FUS) BBB disruption is emerging as a novel strategy for enhanced delivery of therapeutics into the brain via focal, reversible and safe BBB disruption. This review examines the potential role and implications of FUS in molecular neuro-oncology.
PMCID: PMC4106119  PMID: 22208896
Brain tumors; blood brain barrier; focused ultrasound; chemotherapy
15.  Recurrence of “cured” dural arteriovenous fistulas after Onyx embolization 
Neurosurgical focus  2012;32(5):E12.
Endovascular embolization with Onyx has been increasingly used to treat intracranial and spinal dural arteriovenous fistulas (DAVFs). Several case series have been published in recent years reporting high DAVF cure rates with this technique. Although it is seldom reported, DAVF recurrence may occur despite initial “cure.” The authors present 3 separate cases of a recurrent DAVF after successful transarterial Onyx embolization. Despite adequate Onyx penetration into the fistula and draining vein, these cases demonstrate that DAVF recanalization may reappear with filling from previous or newly recruited arterial feeders. Other published reports of DAVF recurrence are examined, and potential contributory factors are discussed. These cases highlight the need for awareness of this possible phenomenon and suggest that follow-up angiography should be considered in patients treated with catheter embolization.
PMCID: PMC4085989  PMID: 22537121
dural arteriovenous fistula; embolization; Onyx; recanalization; recurrence
16.  Successful surgical treatment of an inflammatory lesion associated with new-onset refractory status epilepticus 
Neurosurgical focus  2013;34(6):10.3171/2013.3.FOCUS1336.
New-onset refractory status epilepticus (NORSE) has high morbidity and mortality. The authors describe the successful surgical treatment of a 56-year-old man presenting with NORSE. Magnetic resonance imaging showed a left temporal lobe lesion suspicious for a low-grade tumor, while PET imaging with the alpha[11C]methyl-L-tryptophan (AMT) radiotracer showed increased cortical uptake extending beyond this lesion and partly overlapping with epileptogenic cortex mapped by chronic intracranial electroencephalographic monitoring. Resection of the epileptic focus resulted in long-term seizure freedom, and the nonresected portion of the PET-documented abnormality normalized. Histopathology showed reactive gliosis and inflammatory markers in the AMT-PET–positive cortex. Molecular imaging of neuroinflammation can be instrumental in the management of NORSE by guiding placement of intracranial electrodes or assessing the extent and severity of inflammation for antiinflammatory interventions.
PMCID: PMC3880136  PMID: 23724839
refractory status epilepticus; epilepsy surgery; new-onset refractory status epilepticus; inflammation; interleukin-1β; indoleamine 2, 3-dioxygenase; alpha[11C]methyl-L-tryptophan; positron emission tomography; molecular imaging
17.  Advances in myelin imaging with potential clinical application to pediatric imaging 
Neurosurgical focus  2013;34(4):E9.
White matter development and myelination are critical processes in neurodevelopment. Myelinated white matter facilitates the rapid and coordinated brain messaging required for higher-order cognitive and behavioral processing. Whereas several neurological disorders such as multiple sclerosis are associated with gross white matter damage and demyelination, other disorders such as epilepsy may involve altered myelination in the efferent or afferent white matter pathways adjoining epileptic foci. Current MRI techniques including T1 weighting, T2 weighting, FLAIR, diffusion tensor imaging, and MR spectroscopy permit visualization of gross white matter abnormalities and evaluation of underlying white matter fiber architecture and integrity, but they provide only qualitative information regarding myelin content. Quantification of these myelin changes could provide new insight into disease severity and prognosis, reveal information regarding spatial location of foci or lesions and the associated affected neural systems, and create a metric to evaluate treatment efficacy. Multicomponent analysis of T1 and T2 relaxation data, or multicomponent relaxometry (MCR), is a quantitative imaging technique that is sensitive and specific to myelin content alteration. In the past, MCR has been associated with lengthy imaging times, but a new, faster MCR technique (mcDESPOT) has made quantitative analysis of myelin content more accessible for clinical research applications. The authors briefly summarize traditional white matter imaging techniques, describe MCR and mcDESPOT, and discuss current and future clinical applications of MCR, with a particular focus on pediatric epilepsy.
PMCID: PMC3777219  PMID: 23544415
myelin; epilepsy; imaging; multicomponent relaxometry
18.  Imaging pre-ictal hemodynamic changes in neocortical epilepsy 
Neurosurgical focus  2013;34(4):E10.
The ability to predict seizure occurrence is extremely important to trigger abortive therapies and to warn patients and their caregivers. Optical imaging of hemodynamic parameters such as blood flow, blood volume and tissue and hemoglobin oxygenation has already been shown to successfully localize epileptic events with high spatial and temporal resolution. The ability to actually predict seizure occurrence using hemodynamic parameters is less well explored.
In this paper, we will critically review the literature on data from neocortical epilepsy using optical imaging and discus these pre-ictal hemodynamic changes findings and its application in neurosurgery.
Recent optical mapping studies have demonstrated pre-ictal hemodynamic changes in both human and animal neocortex.
Optical measurements of blood flow and oxygenation may become increasingly important for predicting as well as localizing epileptic events. The ability to successfully predict ictal onsets may be useful to trigger closed-loop abortive therapies.
PMCID: PMC3961761  PMID: 23544406
epilepsy; seizure; optical imaging; neurosurgery
19.  Association of functional magnetic resonance imaging indices with postoperative language outcomes in patients with primary brain tumors 
Neurosurgical focus  2013;34(4):E6.
Functional MRI (fMRI) has the potential to be a useful presurgical planning tool to treat patients with primary brain tumor. In this study the authors retrospectively explored relationships between language-related postoperative outcomes in such patients and multiple factors, including measures estimated from task fMRI maps (proximity of lesion to functional activation area, or lesion-to-activation distance [LAD], and activation-based language lateralization, or lateralization index [LI]) used in the clinical setting for presurgical planning, as well as other factors such as patient age, patient sex, tumor grade, and tumor volume.
Patient information was drawn from a database of patients with brain tumors who had undergone preoperative fMRI-based language mapping of the Broca and Wernicke areas. Patients had performed a battery of tasks, including word-generation tasks and a text-versus-symbols reading task, as part of a clinical fMRI protocol. Individually thresholded task fMRI activation maps had been provided for use in the clinical setting. These clinical imaging maps were used to retrospectively estimate LAD and LI for the Broca and Wernicke areas.
There was a relationship between postoperative language deficits and the proximity between tumor and Broca area activation (the LAD estimate), where shorter LADs were related to the presence of postoperative aphasia. Stratification by tumor location further showed that for posterior tumors within the temporal and parietal lobes, more bilaterally oriented Broca area activation (LI estimate close to 0) and a shorter Wernicke area LAD were associated with increased postoperative aphasia. Furthermore, decreasing LAD was related to decreasing LI for both Broca and Wernicke areas. Preoperative deficits were related to increasing patient age and a shorter Wernicke area LAD.
Overall, LAD and LI, as determined using fMRI in the context of these paradigms, may be useful indicators of postsurgical outcomes. Whereas tumor location may influence postoperative deficits, the results indicated that tumor proximity to an activation area might also interact with how the language network is affected as a whole by the lesion. Although the derivation of LI must be further validated in individual patients by using spatially specific statistical methods, the current results indicated that fMRI is a useful tool for predicting postoperative outcomes in patients with a single brain tumor.
PMCID: PMC3954579  PMID: 23544412
functional magnetic resonance imaging; brain tumor; aphasia
20.  In vivo performance of a microelectrode neural probe with integrated drug delivery 
Neurosurgical focus  2009;27(1):E8.
The availability of sophisticated neural probes is a key prerequisite in the development of future brain machine interfaces (BMI). In this study, we developed and validated a neural probe design capable of simultaneous drug delivery and electrophysiology recordings in vivo. Focal drug delivery has promise to dramatically extend the recording lives of neural probes, a limiting factor to clinical adoption of BMI technology.
To form the multifunctional neural probe, we affixed a 16-channel microfabricated silicon electrode array to a fused silica catheter. Three experiments were conducted to characterize the performance of the device. Experiment 1 examines cellular damage from probe insertion and the drug distribution in tissue. Experiment 2 measures the effects of saline infusions delivered through the probe on concurrent electrophysiology. Experiment 3 demonstrates that a physiologically relevant amount of drug can be delivered in a controlled fashion. For these experiments, Hoechst and propidium iodide were used to assess insertion trauma and the tissue distribution of the infusate. Artificial cerebral spinal fluid and tetrodotoxin were injected to determine the efficacy of drug delivery.
The newly developed multifunctional neural probes were successfully inserted into rat cortex and were able to deliver fluids and drugs that resulted in the expected electrophysiological and histological responses. The damage from insertion of the device into brain tissue was substantially less than the volume of drug dispersion in tissue. Electrophysiological activity, including both individual spikes as well as local field potentials, was successfully recorded with this device during real-time drug delivery. No significant changes were seen in response to delivery of artificial cerebral spinal fluid as a control experiment, whereas delivery of tetrodotoxin produced the expected result of suppressing all spiking activity in the vicinity of the catheter outlet.
Multifunctional neural probes such as the ones developed and validated within this study have great potential to help further understand the design space and criteria for the next generation of neural probe technology. By incorporating integrated drug delivery functionality into the probes, new treatment options for neurological disorders and regenerative neural interfaces utilizing localized and feedback controlled delivery of drugs can be realized in the near future.
PMCID: PMC3938951  PMID: 19569896
Drug delivery; neural engineering; microelectrode array
21.  Patient-assessed satisfaction and outcome after microsurgical resection of cavernomas causing epilepsy 
Neurosurgical focus  2010;29(3):E16.
Microsurgical resection of supratentorial cavernomas associated with intractable epilepsy is performed frequently. Despite its common occurrence, little is known about patient perceptions of microsurgical resection for cavernomas. This survey study was performed to investigate patient perceived outcome after surgery for cavernomas associated with intractable epilepsy.
The authors’ surgical database was searched for cavernoma resection performed between 1971 and July of 2006. Of the initial 173 patients identified, 102 met criteria for medically intractable seizures. These 102 patients were then mailed a survey to determine follow-up and patient satisfaction. Thirty-nine surveys were returned as undeliverable, and 30 (48%) of the remaining 63 patients responded.
The average age at surgery for patients responding to this survey was 40 ± 16 years compared with 35 ± 15 years for all 102 patients. At prolonged follow-up, 87% of patients reported being seizure-free. Of those with seizures, 2 (7%) reported being nearly seizure-free (rare disabling seizures), 2 (7%) believed they had a worthwhile improvement in seizure frequency, and no patient (0%) in this series believed they did not have a worthwhile improvement in seizure frequency. Ninety percent of responders stated they definitely, and 10% probably, would have surgery again. No patient responded that they probably or definitely would not have epilepsy surgery. Mean clinical follow-up was 36 ± 8 months and survey follow-up was 97 ± 13 months for these 30 patients. Use of the mail-in survey increased follow-up length 2.7 times longer compared with clinical follow-up.
It is clear from this select group of survey responders that patients undergoing surgery for cavernomas associated with medically intractable epilepsy are happy they underwent surgery (100%) and had excellent surgical outcomes (87% seizure-free) at prolonged follow-up of 97 ± 13 months. These survey results support that microsurgical resection for cavernomas is highly effective and significantly improves these patients’ quality of life.
PMCID: PMC3920597  PMID: 20809757
cavernoma; epilepsy; survey; patient outcome; postal questionnaire
22.  The role of secondary motor and language cortices in morbidity and mortality: A retrospective fMRI study of surgical planning for patients with intracranial tumors 
Neurosurgical focus  2013;34(4):10.3171/2013.2.FOCUS12410.
Functional magnetic resonance imaging (fMRI) is commonly utilized by neurosurgeons to pre-operatively identify brain regions associated with essential behaviors, such as language and motor abilities. This study investigated the relationship between the distance from tumor border area to functional activations in secondary motor and language cortices to patient morbidity and mortality.
Patients with primary or metastatic brain tumors who underwent pre-operative fMRI motor and language mapping were selected from a large database of tumor patients. The lesion-to-activation distance (LAD) was measured in each subject relative to the supplementary motor area for motor tasks and pre-supplementary motor area for language tasks. The association between LAD and the incidence of deficits was investigated using Fisher’s exact tests of significance. The impact of other variables, including age, handedness, gender, and tumor grade were also investigated. In a subset of subjects, logistic regression was performed to identify the likelihood of deficits based on LAD to primary and secondary regions. Finally, Mantel-Cox log-rank tests were performed to determine whether survival time significantly related to LAD to secondary motor and language areas.
A significant association was observed between LAD to the SMA and the incidence of motor deficits, with the percentage of patients with deficits dropping for those in the LAD > 2 cm group. The relationship between LAD to the pSMA and the incidence of language deficits was not significant. Logistic regression demonstrated that the LAD to primary sensorimotor cortex does affect the incidence of motor deficits, but LAD to SMA does not. Finally, we observed no relationship between LAD to secondary regions and patient mortality.
These results demonstrate that LAD to SMA structures does affect morbidity, although not to the extent of LAD to primary structures. In addition, motor deficits are significantly associated with LAD to secondary structures, but language deficits are not. This should be considered by neurosurgeons for patient consultation and pre-operative planning.
PMCID: PMC3817821  PMID: 23544413
Lesion-activation distance; morbidity; fMRI; tumor; SMA; preSMA
23.  Characterizing the relationship between fMRI derived measures and clinical outcomes in vascular lesion patients 
Neurosurgical focus  2013;34(4):10.3171/2013.2.FOCUS12417.
Background and Purpose
Functional magnetic resonance imaging (fMRI) has proven to be an effective component of pretreatment planning in patients harboring a variety of different brain lesions. Our group has recently reported significant relationships concerning distances between brain tumor border and area of functional activation (Lesion-to-Activation-Distance; LAD) with regard to patient morbidity and mortality. This study further examines the relationship between LAD, focusing on a host of vascular lesions, and pre- and posttreatment morbidity.
Materials and Methods
This study included a sample population (n=106) of patients with vascular lesions, primarily arteriovenous malformations (AVM) and cavernomas. These patients underwent pretreatment fMRI-based motor mapping (n=72) or language mapping (n=84). The impact of LAD and other variables derived from the patient medical record were analyzed with respect to functional deficits in terms of morbidity (weakness and/or aphasia).
In patients with no pretreatment deficits, there was trend for a significant relationship between Wernicke's area LAD and posttreatment language deficits. In patients with or without pretreatment deficits, a trend toward significance was observed between sensorimotor LAD and posttreatment motor deficits. Additionally, lesion type (AVMs or cavernomas) impacted posttreatment deficits with more patients with cavernomas showing posttreatment language deficits than patients with AVMs. This difference was however not observed for posttreatment motor deficits.
These findings suggest that the proximity of a vascular lesion to sensorimotor and language areas is a relevant parameter in estimating patient prognosis in the peri-operative period. Additionally, vascular lesion type and existence of pretreatment deficits play a significant role in outcomes.
PMCID: PMC3807681  PMID: 23544414
24.  Volumetric analysis of syringomyelia following hindbrain decompression for Chiari malformation Type I: syringomyelia resolution follows exponential kinetics 
Neurosurgical focus  2011;31(3):E4.
Resolution of syringomyelia is common following hindbrain decompression for Chiari malformation, yet little is known about the kinetics governing this process. The authors sought to establish the volumetric rate of syringomyelia resolution.
A retrospective cohort of patients undergoing hindbrain decompression for a Chiari malformation Type I with preoperative cervical or thoracic syringomyelia was identified. Patients were included in the study if they had at least 3 neuroimaging studies that detailed the entirety of their preoperative syringomyelia over a minimum of 6 months postoperatively. The authors reconstructed the MR images in 3 dimensions and calculated the volume of the syringomyelia. They plotted the syringomyelia volume over time and constructed regression models using the method of least squares. The Akaike information criterion and Bayesian information criterion were used to calculate the relative goodness of fit. The coefficients of determination R2 (unadjusted and adjusted) were calculated to describe the proportion of variability in each individual data set accounted for by the statistical model.
Two patients were identified as meeting inclusion criteria. Plots of the least-squares best fit were identified as 4.01459e−0.0180804x and 13.2556e−0.00615859x. Decay of the syringomyelia followed an exponential model in both patients (R2 = 0.989582 and 0.948864).
Three-dimensional analysis of syringomyelia resolution over time enables the kinetics to be estimated. This technique is yet to be validated in a large cohort. Because syringomyelia is the final common pathway for a number of different pathological processes, it is possible that this exponential only applies to syringomyelia related to treatment of Chiari malformation Type I.
PMCID: PMC3731038  PMID: 21882909
Chiari malformation; syringomyelia; syrinx; MR imaging; volumetrics
25.  Cell therapies for traumatic brain injury 
Neurosurgical focus  2008;24(0):E18.
Preliminary discoveries of the efficacy of cell therapy are currently being translated to clinical trials. Whereas a significant amount of work has been focused on cell therapy applications for a wide array of diseases, including cardiac disease, bone disease, hepatic disease, and cancer, there continues to be extraordinary anticipation that stem cells will advance the current therapeutic regimen for acute neurological disease. Traumatic brain injury is a devastating event for which current therapies are limited. In this report the authors discuss the current status of using adult stem cells to treat traumatic brain injury, including the basic cell types and potential mechanisms of action, preclinical data, and the initiation of clinical trials.
PMCID: PMC3721356  PMID: 18341394
cell therapy; clinical trial; stem cells; traumatic brain injury

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