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1.  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.
doi:10.3171/2014.12.FOCUS14758
PMCID: PMC4493051  PMID: 25727231
blood-brain barrier; focused ultrasound; convection-enhanced delivery; P-glycoprotein
2.  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.
Object
To evaluate the risk factors for complications, including new neurological deficits, in the largest cohort of adult spinal deformity patients to date.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3171/2014.2.FOCUS1419
PMCID: PMC4185213  PMID: 24785482
Three column osteotomy; pedicle subtraction; vertebral column resection; adult deformity; complications; Adult Spinal Deformity; Osteotomy
3.  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.
doi:10.3171/2013.10.FOCUS13404
PMCID: PMC4234034  PMID: 24380477
stroke; Glyburide; edema; glibenclamide; metalloproteinase; cytotoxic; SUR1; TRPM4
4.  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.
doi:10.3171/2011.10.FOCUS11252
PMCID: PMC4106119  PMID: 22208896
Brain tumors; blood brain barrier; focused ultrasound; chemotherapy
5.  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.
doi:10.3171/2012.2.FOCUS1224
PMCID: PMC4085989  PMID: 22537121
dural arteriovenous fistula; embolization; Onyx; recanalization; recurrence
6.  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.
doi:10.3171/2013.3.FOCUS1336
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
7.  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.
doi:10.3171/2013.1.FOCUS12426
PMCID: PMC3777219  PMID: 23544415
myelin; epilepsy; imaging; multicomponent relaxometry
8.  Imaging pre-ictal hemodynamic changes in neocortical epilepsy 
Neurosurgical focus  2013;34(4):E10.
Object
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.
Method
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.
Result
Recent optical mapping studies have demonstrated pre-ictal hemodynamic changes in both human and animal neocortex.
Conclusion
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.
doi:10.3171/2013.1.FOCUS12408
PMCID: PMC3961761  PMID: 23544406
epilepsy; seizure; optical imaging; neurosurgery
9.  Association of functional magnetic resonance imaging indices with postoperative language outcomes in patients with primary brain tumors 
Neurosurgical focus  2013;34(4):E6.
Object
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3171/2013.2.FOCUS12413
PMCID: PMC3954579  PMID: 23544412
functional magnetic resonance imaging; brain tumor; aphasia
10.  In vivo performance of a microelectrode neural probe with integrated drug delivery 
Neurosurgical focus  2009;27(1):E8.
Object
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3171/2009.4.FOCUS0983
PMCID: PMC3938951  PMID: 19569896
Drug delivery; neural engineering; microelectrode array
11.  Patient-assessed satisfaction and outcome after microsurgical resection of cavernomas causing epilepsy 
Neurosurgical focus  2010;29(3):E16.
Object
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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.3171/2010.6.FOCUS10127
PMCID: PMC3920597  PMID: 20809757
cavernoma; epilepsy; survey; patient outcome; postal questionnaire
12.  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.
Object
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.3171/2013.2.FOCUS12410
PMCID: PMC3817821  PMID: 23544413
Lesion-activation distance; morbidity; fMRI; tumor; SMA; preSMA
13.  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).
Results
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.
Conclusion
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.
doi:10.3171/2013.2.FOCUS12417
PMCID: PMC3807681  PMID: 23544414
14.  Volumetric analysis of syringomyelia following hindbrain decompression for Chiari malformation Type I: syringomyelia resolution follows exponential kinetics 
Neurosurgical focus  2011;31(3):E4.
Object
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.
Methods
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.
Results
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).
Conclusions
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.
doi:10.3171/2011.6.FOCUS11106
PMCID: PMC3731038  PMID: 21882909
Chiari malformation; syringomyelia; syrinx; MR imaging; volumetrics
15.  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.
doi:10.3171/FOC/2008/24/3-4/E17
PMCID: PMC3721356  PMID: 18341394
cell therapy; clinical trial; stem cells; traumatic brain injury
16.  Emerging clinical imaging techniques for cerebral cavernous malformations: a systematic review 
Neurosurgical focus  2010;29(3):E6.
Cerebral cavernous malformations (CCM) are divided into sporadic and familial forms. For clinical imaging, T2-weighted gradient-echo sequences have been shown to be more sensitive than conventional sequences. Recently more advanced imaging techniques such as high-field and susceptibility-weighted magnetic resonance imaging has been employed for the evaluation of CCMs. Furthermore, diffusion tensor imaging and functional magnetic resonance imaging have been applied to the preoperative and intraoperative management of these lesions. In this paper, the authors attempt to provide a concise review of the emerging imaging methods utilized in the clinical diagnosis and treatment of CCMs.
doi:10.3171/2010.5.FOCUS10120
PMCID: PMC3708641  PMID: 20809764
magnetic resonance imaging; cavernoma; cavernous malformations; susceptibility-weighted imaging; gradient echo; functional magnetic resonance imaging
17.  Levetiracetam versus phenytoin for seizure prophylaxis in severe traumatic brain injury 
Neurosurgical focus  2008;25(4):E3.
Object
Current standard of care for patients with severe traumatic brain injury (TBI) is prophylactic treatment with phenytoin for 7 days to decrease the risk of early posttraumatic seizures. Phenytoin alters drug metabolism, induces fever, and requires therapeutic-level monitoring. Alternatively, levetiracetam (Keppra) does not require serum monitoring or have significant pharmacokinetic interactions. In the current study, the authors compare the EEG findings in patients receiving phenytoin with those receiving levetiracetam monotherapy for seizure prophylaxis following severe TBI.
Methods
Data were prospectively collected in 32 cases in which patients received levetiracetam for the first 7 days after severe TBI and compared with data from a historical cohort of 41 cases in which patients received phenytoin monotherapy. Patients underwent 1-hour electroencephalographic (EEG) monitoring if they displayed persistent coma, decreased mental status, or clinical signs of seizures. The EEG results were grouped into normal and abnormal findings, with abnormal EEG findings further categorized as seizure activity or seizure tendency.
Results
Fifteen of 32 patients in the levetiracetam group warranted EEG monitoring. In 7 of these 15 cases the results were normal and in 8 abnormal; 1 patient had seizure activity, whereas 7 had seizure tendency. Twelve of 41 patients in the phenytoin group received EEG monitoring, with all results being normal. Patients treated with levetiracetam and phenytoin had equivalent incidence of seizure activity (p = 0.556). Patients receiving levetiracetam had a higher incidence of abnormal EEG findings (p = 0.003).
Conclusions
Levetiracetam is as effective as phenytoin in preventing early posttraumatic seizures but is associated with an increased seizure tendency on EEG analysis.
doi:10.3171/FOC.2008.25.10.E3
PMCID: PMC3705765  PMID: 18828701
antiepileptic drug; posttraumatic seizure; seizure prophylaxis; traumatic brain injury
18.  Decoding movement-related cortical potentials from electrocorticography 
Neurosurgical focus  2009;27(1):E11.
Object
Control signals for brain-machine interfaces may be obtained from a variety of sources, each with their own relative merits. Electrocorticography (ECoG) provides better spatial and spectral resolution than scalp electroencephalography and does not include the risks attendant upon penetration of the brain parenchyma associated with single and multiunit recordings. For these reasons, subdural electrode recordings have been proposed as useful primary or adjunctive control signals for brain-machine interfaces. The goal of the present study was to determine if 2D control signals could be decoded from ECoG.
Methods
Six patients undergoing invasive monitoring for medically intractable epilepsy using subdural grid electrodes were asked to perform a motor task involving moving a joystick in 1 of 4 cardinal directions (up, down, left, or right) and a fifth condition (“trigger”). Evoked activity was synchronized to joystick movement and analyzed in the theta, alpha, beta, gamma, and high-gamma frequency bands.
Results
Movement-related cortical potentials could be accurately differentiated from rest with very high accuracy (83–96%). Further distinguishing the movement direction (up, down, left, or right) could also be resolved with high accuracy (58–86%) using information only from the high-gamma range, whereas distinguishing the trigger condition from the remaining directions provided better accuracy.
Conclusions
Two-dimensional control signals can be derived from ECoG. Local field potentials as measured by ECoG from subdural grids will be useful as control signals for a brain-machine interface.
doi:10.3171/2009.4.FOCUS0990
PMCID: PMC3686514  PMID: 19569886
brain-machine interface; local field potentials; electrocorticography; motor control; epilepsy
19.  A Stepwise Illustration of the Translabyrinthine Approach to a Large Cystic Vestibular Schwannoma 
Neurosurgical focus  2012;33(3):E11.
Introduction
Of the presigmoid approaches, the translabyrinthine approach is often used when a large exposure is needed to the cerebello-pontine angle, but hearing preservation is not a concern. At our institution, this approach is performed in collboration with ENT/Otolaryngology for temporal bone drilling and exposure.
Methods
In this video and paper, we demonstrate the use of the translabyrinthine approach for resection of a large cystic vestibular schwannoma, delineating the steps of positioning, opening, temporal bone drilling, tumor resection and closure.
Results
Gross total resection was obtained in this patient. His postoperative facial function was House-Brackmann grade II on the side ipsilateral to the tumor, although this improved with time.
Conclusion
The translabyrinthine approach to the cerebello-pontine angle is an excellent approach for masses that extend toward the midline or anterior to the pons. Although hearing is sacrificed, facial nerve function is generally spared.
doi:10.3171/2012.7.FOCUS12208
PMCID: PMC3675780  PMID: 22937845
Translabyrinthine; Vestibular Schwannoma; Surgical Technique; Video
20.  Human cortical prostheses: lost in translation? 
Neurosurgical focus  2009;27(1):E5.
Direct brain control of a prosthetic system is the subject of much popular and scientific news. Neural technology and science have advanced to the point that proof-of-concept systems exist for cortically-controlled prostheses in rats, monkeys, and even humans. However, realizing the dream of making such technology available to everyone is still far off. Fortunately today there is great public and scientific interest in making this happen, but it will only occur when the functional benefits of such systems outweigh the risks. In this article, the authors briefly summarize the state of the art and then highlight many issues that will directly limit clinical translation, including system durability, system performance, and patient risk. Despite the challenges, scientists and clinicians are in the desirable position of having both public and fiscal support to begin addressing these issues directly. The ultimate challenge now is to determine definitively whether these prosthetic systems will become clinical reality or forever unrealized.
doi:10.3171/2009.4.FOCUS0987
PMCID: PMC3614414  PMID: 19569893
brain-machine interface; brain-computer interface; motor; communication; prostheses; performance; risk
21.  Symptomatic intracranial arterial disease: incidence, natural history, diagnosis, and management 
Neurosurgical focus  2011;30(6):E14.
Symptomatic intracranial arterial disease is associated with a high rate of recurrent ischemic events. The management of this condition is controversial, with some advocating medical therapy as a sole means of treatment and others recommending endovascular therapy in addition to best medical management. In rare cases, surgical intervention is considered. A thorough review of the available literature was performed, and treatment recommendations based on these data are provided.
doi:10.3171/2011.3.FOCUS1138
PMCID: PMC3593273  PMID: 21631215
intracranial stenosis; cerebral ischemia; balloon angioplasty; extracranial-intracranial bypass
22.  Quantitative and qualitative 5-aminolevulinic acid–induced protoporphyrin IX fluorescence in skull base meningiomas 
Neurosurgical focus  2011;30(5):E8.
Object
Complete resection of skull base meningiomas provides patients with the best chance for a cure; however, surgery is frequently difficult given the proximity of lesions to vital structures, such as cranial nerves, major vessels, and venous sinuses. Accurate discrimination between tumor and normal tissue is crucial for optimal tumor resection. Qualitative assessment of protoporphyrin IX (PpIX) fluorescence following the exogenous administration of 5-aminolevulinic acid (ALA) has demonstrated utility in malignant glioma resection but limited use in meningiomas. Here the authors demonstrate the use of ALA-induced PpIX fluorescence guidance in resecting a skull base meningioma and elaborate on the advantages and disadvantages provided by both quantitative and qualitative fluorescence methodologies in skull base meningioma resection.
Methods
A 52-year-old patient with a sphenoid wing WHO Grade I meningioma underwent tumor resection as part of an institutional review board–approved prospective study of fluorescence-guided resection. A surgical microscope modified for fluorescence imaging was used for the qualitative assessment of visible fluorescence, and an intraoperative probe for in situ fluorescence detection was utilized for quantitative measurements of PpIX. The authors assessed the detection capabilities of both the qualitative and quantitative fluorescence approaches.
Results
The patient harboring a sphenoid wing meningioma with intraorbital extension underwent radical resection of the tumor with both visibly and nonvisibly fluorescent regions. The patient underwent a complete resection without any complications. Some areas of the tumor demonstrated visible fluorescence. The quantitative probe detected neoplastic tissue better than the qualitative modified surgical microscope. The intraoperative probe was particularly useful in areas that did not reveal visible fluorescence, and tissue from these areas was confirmed as tumor following histopathological analysis.
Conclusions
Fluorescence-guided resection may be a useful adjunct in the resection of skull base meningiomas. The use of a quantitative intraoperative probe to detect PpIX concentration allows more accurate determination of neoplastic tissue in meningiomas than visible fluorescence and is readily applicable in areas, such as the skull base, where complete resection is critical but difficult because of the vital structures surrounding the pathology.
doi:10.3171/2011.2.FOCUS1112
PMCID: PMC3116440  PMID: 21529179
skull base meningioma; fluorescence-guided resection; protoporphyrin IX; 5-aminolevulinic acid; optical spectroscopy; biophotonics
23.  ELUCIDATING NOVEL MECHANISMS OF BRAIN INJURY FOLLOWING SUBARACHNOID HEMORRHAGE: AN EMERGING ROLE FOR NEUROPROTEOMICS 
Neurosurgical focus  2010;28(1):E10.
Subarachnoid hemorrhage (SAH) is a devastating neurological injury associated with significant patient morbidity and mortality. Since the first demonstration of cerebral vasospasm nearly 60 years ago, the preponderance of research focused on strategies to limit arterial narrowing and delayed cerebral ischemia following SAH. However, recent clinical and pre-clinical data indicates a functional dissociation between cerebral vasospasm and neurological outcome, signaling the need for a paradigm shift in the study of brain injury following SAH. Early brain injury (EBI) may contribute to the poor outcome and early mortality following SAH; however, elucidation of the complex cellular mechanisms underlying EBI remains a major challenge. The advent of modern neuroproteomics has rapidly advanced scientific discovery by allowing proteome-wide screening in an objective, non-biased manner, providing novel mechanisms of brain physiology and injury. In the context of neurosurgery, proteomic analysis of patient-derived cerebrospinal fluid will permit the identification of biomarkers and/or novel drug targets, which may not be intuitively linked with any particular disease. In the present report, we discuss the utility of neuroproteomics with a focus on the roles for this technology in understanding SAH. We also provide data from our laboratory, which identifies high-mobility group box protein-1 (HMGB1) as a potential biomarker of neurological outcome following SAH in humans.
doi:10.3171/2009.10.FOCUS09223
PMCID: PMC3151677  PMID: 20043714
Early Brain Injury; Hemorrhagic stroke; Cerebral aneurysm; Inflammation; Cerebrospinal Fluid; Biomarker
24.  Development of intraoperative electrochemical detection: wireless instantaneous neurochemical concentration sensor for deep brain stimulation feedback 
Neurosurgical focus  2010;29(2):E6.
Deep brain stimulation (DBS) is effective when there appears to be a distortion in the complex neurochemical circuitry of the brain. Currently, the mechanism of DBS is incompletely understood; however, it has been hypothesized that DBS evokes release of neurochemicals. Well-established chemical detection systems such as microdialysis and mass spectrometry are impractical if one is assessing changes that are happening on a second-to-second time scale or for chronically used implanted recordings, as would be required for DBS feedback. Electrochemical detection techniques such as fast-scan cyclic voltammetry (FSCV) and amperometry have until recently remained in the realm of basic science; however, it is enticing to apply these powerful recording technologies to clinical and translational applications. The Wireless Instantaneous Neurochemical Concentration Sensor (WINCS) currently is a research device designed for human use capable of in vivo FSCV and amperometry, sampling at subsecond time resolution. In this paper, the authors review recent advances in this electrochemical application to DBS technologies. The WINCS can detect dopamine, adenosine, and serotonin by FSCV. For example, FSCV is capable of detecting dopamine in the caudate evoked by stimulation of the subthalamic nucleus/substantia nigra in pig and rat models of DBS. It is further capable of detecting dopamine by amperometry and, when used with enzyme linked sensors, both glutamate and adenosine. In conclusion, WINCS is a highly versatile instrument that allows near real-time (millisecond) detection of neurochemicals important to DBS research. In the future, the neurochemical changes detected using WINCS may be important as surrogate markers for proper DBS placement as well as the sensor component for a “smart” DBS system with electrochemical feedback that allows automatic modulation of stimulation parameters. Current work is under way to establish WINCS use in humans.
doi:10.3171/2010.5.FOCUS10110
PMCID: PMC2939376  PMID: 20672923
deep brain stimulation; dopamine; adenosine; serotonin; fast-scan cyclic voltammetry; amperometry; electrochemistry
25.  Designing ideal conduits for peripheral nerve repair 
Neurosurgical focus  2009;26(2):E5.
Nerve tubes, guides, or conduits are a promising alternative for autologous nerve graft repair. The first biodegradable empty single lumen or hollow nerve tubes are currently available for clinical use and are being used mostly in the repair of small-diameter nerves with nerve defects of < 3 cm. These nerve tubes are made of different biomaterials using various fabrication techniques. As a result these tubes also differ in physical properties. In addition, several modifications to the common hollow nerve tube (for example, the addition of Schwann cells, growth factors, and internal frameworks) are being investigated that may increase the gap that can be bridged. This combination of chemical, physical, and biological factors has made the design of a nerve conduit into a complex process that demands close collaboration of bioengineers, neuroscientists, and peripheral nerve surgeons. In this article the authors discuss the different steps that are involved in the process of the design of an ideal nerve conduit for peripheral nerve repair.
doi:10.3171/FOC.2009.26.2.E5
PMCID: PMC2978041  PMID: 19435445
biomaterial; growth factor; nerve conduit; nerve guide; nerve tube; polymer; Schwann cell

Results 1-25 (38)