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issn:0148-396
1.  Selection of Optimal Programming Contacts Based on Local Field Potential Recordings From Subthalamic Nucleus in Patients With Parkinson’s Disease 
Neurosurgery  2010;67(2):390-397.
BACKGROUND
In the United States, the most commonly used surgical treatment for patients with Parkinson’s disease is the implantation of deep brain stimulation (DBS) electrodes within the subthalamic nucleus. However, DBS device programming remains difficult and is a possible source of decreased efficacy.
OBJECTIVE
We investigated the relationship between local field potential (LFP) activities in the subthalamic nucleus and the therapeutic response to programming.
METHODS
We recorded LFPs with macroelectrodes placed unilaterally for DBS in 4 PD patients, 3 weeks after implantation, before the start of log-term DBS. Power-frequency spectra were calculated for each of 7 possible electrode contacts or contact pairs, over multiple 5- to 10-minute quiet waking epochs and over 30-second epochs during hand movements. Subsequently, DBS devices were programmed, with testing to determine which electrode contacts or contact pairs demonstrated optimal therapeutic efficacy.
RESULTS
For each patient, the contact pair found to provide optimal efficacy was associated with the highest energy in the β (13–32 Hz) and γ (48–220 Hz) bands during postoperative LFP recordings at rest and during hand movements. Activities in other frequency bands did not show significant correlations between LFP power and optimal electrode contacts.
CONCLUSION
Postoperative subband analysis of LFP recordings in β and γ frequency ranges may be used to select optimal electrode contacts. These results indicate that LFP recordings from implanted DBS electrodes can provide important clues to guide the optimization of DBS therapy in individual patients.
doi:10.1227/01.NEU.0000372091.64824.63
PMCID: PMC4319368  PMID: 20644424
Deep brain stimulation; Local field potentials; Parkinson’s disease; Programming; Subthalamic nucleus
2.  Inhibition of c-Jun N-terminal kinase activity enhances vestibular schwannoma cell sensitivity to γ-irradiation 
Neurosurgery  2013;73(3):506-516.
Background
Radiosurgery is increasingly used to treat vestibular schwannomas (VSs). Increasing the sensitivity of VS cells to irradiation (IR) could allow for lower and/or more effective doses of IR, improving safety and efficacy. Persistent JNK activity in VS cells reduces cell death by suppressing accumulation of reactive oxygen species (ROS) raising the possibility that JNK activity protects against IR-induced VS cell death, which is mediated by ROS.
Objective
Determine the extent to which JNK signaling contributes to VS cell radiosensitivity.
Methods
Primary human VS cultures, derived from acutely resected tumors, received single doses (5–40 Gy) of γ-irradiation. Histone 2AX phosphorylation, a marker of IR-induced DNA damage, was assayed by western blot and immunostaining. ROS levels were quantified by measuring 2',7'-dichlorodihydrofluorescein diacetate (CM-H2DCFDA) fluorescence. Cell apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling.
Results
The JNK inhibitors, SP6000125 and I-JIP, reduced H2AX phosphorylation following IR. They also increased H2DCFDA fluorescence in non-irradiated cultures and significantly increased IR-induced (5–10 Gy) H2DCFDA fluorescence 72 hours, but not 2 hours, after IR. Finally, I-JIP (50 µM) significantly increased VS cell apoptosis in cultures treated with 20–40 Gy. I-JIP (20 µM), SP600125 (20 µM), and JNK1/2 siRNA knock-down each increased VS cell apoptosis in cultures treated with 30–40 Gy, but not lower doses, of IR.
Conclusions
Inhibition of JNK signaling decreases H2AX phosphorylation and increases ROS and apoptosis in VS cells following γ-irradiation. These results raise the possibility of using JNK inhibitors to increase the effectiveness of radiosurgery for treatment of VSs.
doi:10.1227/01.neu.0000431483.10031.89
PMCID: PMC4313352  PMID: 23728448
acoustic neuroma; cell death; histone H2AX; reactive oxygen species; radiosurgery; radiotherapy
3.  [No title available] 
PMCID: PMC3905970  PMID: 24149979
4.  [No title available] 
PMCID: PMC3916907  PMID: 24176954
5.  Phosphodiesterase 5 Inhibition Attenuates Cerebral Vasospasm and Improves Functional Recovery after Experimental Subarachnoid Hemorrhage 
Neurosurgery  2012;70(1):178-187.
Background
Cerebral vasospasm is an independent predictor of poor outcome after subarachnoid hemorrhage (SAH). The nitric oxide-cyclic GMP (NO-cGMP) vasodilatory pathway is strongly implicated in its pathophysiology. Preliminary studies suggest that phosphodiesterase 5 (PDE5) – an enzyme that degrades cGMP – may play a role, as the PDE5 inhibitor sildenafil was found to reduce vasospasm after SAH. However, several questions that are critical when considering translational studies remain unanswered.
Objective
To elucidate the mechanism of action of sildenafil against vasospasm, and to assess whether sildenafil attenuates SAH-induced neuronal cell death, improves functional outcome after SAH, or causes significant physiological side effects when administered at therapeutically relevant doses.
Methods
SAH was induced via endovascular perforation in male C57BL6 mice. Beginning two hours later, mice received sildenafil citrate (0.7, 2 or 5mg/kg P.O. BID) or vehicle. Neurological outcome was assessed daily. Vasospasm was determined on post-SAH Day 3. Brain PDE5 expression and activity, cGMP content, neuronal cell death, arterial blood pressure (BP), and intracranial pressure (ICP) were examined.
Results
We found that PDE5 activity (but not expression) is increased after SAH, leading to decreased cGMP levels. Sildenafil attenuates this increase in PDE5 activity and restores cGMP levels after SAH. Post-SAH initiation of sildenafil was found to reduce vasospasm, decrease neuronal cell death, and markedly improve neurological outcome, without causing significant physiological side effects.
Conclusion
Sildenafil–an FDA-approved drug with a proven track record of safety in humans –is a promising new therapy for vasospasm and neurological deficits following SAH.
doi:10.1227/NEU.0b013e31822ec2b0
PMCID: PMC4288819  PMID: 21796010
6.  Comparison of Endovascular and Intraventricular Gene Therapy With Adeno-Associated Virus–α-L-Iduronidase for Hurler Disease 
Neurosurgery  2014;74(1):99-111.
BACKGROUND
Hurler disease (mucopolysaccharidosis type I [MPS-I]) is an inherited metabolic disorder characterized by deficiency of the lysosomal enzyme α-L-iduronidase (IDUA). Currently, the only therapies for MPS-I, enzyme replacement and hematopoietic stem cell transplantation, are generally ineffective for central nervous system manifestations.
OBJECTIVE
To test whether brain-targeted gene therapy with recombinant adeno-associated virus (rAAV5)-IDUA vectors in an MPS-I transgenic mouse model would reverse the pathological hallmarks.
METHODS
Gene therapy approaches were compared using intraventricular or endovascular delivery with a marker (rAAV5-green fluorescent protein) or therapeutic (rAAV5-IDUA) vector. To improve the efficiency of brain delivery, we tested different applications of hyperosmolar mannitol to disrupt the blood-brain barrier or ependymal-brain interface.
RESULTS
Intraventricular delivery of 1 × 1011 viral particles of rAAV5-IDUA with systemic 5 g/kg mannitol co-administration resulted in IDUA expression throughout the brain, with global enzyme activity >200% of the baseline level in age-matched, wild-type mice. Endovascular delivery of 1 × 1012 viral particles of rAAV5-IDUA to the carotid artery with 29.1% mannitol blood-brain barrier disruption resulted in mainly ipsilateral brain IDUA expression and ipsilateral brain enzyme activity 42% of that in wild-type mice. Quantitative assays for glycosaminoglycans showed a significant decrease in both hemispheres after intraventricular delivery and in the ipsilateral hemisphere after endovascular delivery compared with untreated MPS-I mice. Immunohistochemistry for ganglioside GM3, another disease marker, showed reversal of neuronal inclusions in areas with IDUA co-expression in both delivery methods.
CONCLUSION
Physiologically relevant biochemical correction is possible with neurosurgical or endovascular gene therapy approaches for MPS-I. Intraventricular or endovascular delivery of rAAV5-IDUA was effective in reversing brain pathology, but in the latter method, effects were limited to the ipsilateral hemisphere.
doi:10.1227/NEU.0000000000000157
PMCID: PMC4116107  PMID: 24077583
AAV; Blood-brain barrier; Gene therapy; Hurler disease; Mannitol; Mucopolysaccharidosis
7.  Life Outcomes of Anterior Temporal Lobectomy: Serial Long-term Follow-up Evaluations 
Neurosurgery  2013;73(6):1018-1025.
Background
At three time points, this study examined long-term psychosocial life outcomes of individuals who underwent anterior temporal lobectomy (ATL) compared to individuals with temporal lobe epilepsy that were medically managed.
Objective
Participants were on average 17 years post-surgery. Seizure frequency, employment, driving, independent living, financial independence, mental health, and quality of life were examined at each follow-up assessment, and predictors of outcomes were examined.
Methods
All participants were diagnosed with medically intractable complex partial seizures of temporal lobe origin with or without secondary generalization. A structured clinical interview was utilized at all three time points. Information was obtained regarding seizure frequency, anti-epilepsy medications, employment, driving status, financial assistance, and independent living. Additionally, questions regarding quality of life, satisfaction with surgery, and presence of depression or anxiety were included.
Results
Surgery resulted in significantly improved and sustained seizure outcomes. At the first, second, and third follow-ups 67%, 72%, and 67% of participants in the surgery group remained seizure free in the year prior to follow-up interview. At each follow-up, 97%, 84%, and 84% reported that they would undergo surgery again. Seizure freedom predicted driving outcomes at all three time points, but was not a significant predictor for employment, independent living or financial independence. Psychosocial life outcomes in the surgical group were improved and maintained over time when compared to the medically managed group.
Conclusion
This systematic long-term investigation provides strong support for the positive impact of ATL on psychosocial life outcomes including driving, employment, independent living, and financial independence.
doi:10.1227/NEU.0000000000000145
PMCID: PMC4162125  PMID: 24056319
anterior temporal lobectomy; epilepsy; psychosocial outcomes; surgical outcomes
8.  5-Aminolevulinic Acid-Induced Protoporphyrin IX Fluorescence in Meningioma: Qualitative and Quantitative Measurements In Vivo 
Neurosurgery  2014;10(0 1):74-83.
BACKGROUND
The use of 5-aminolevulinic acid (ALA)-induced protoporphyrin IX (PpIX) fluorescence has shown promise as a surgical adjunct for maximizing the extent of surgical resection in gliomas. To date, the clinical utility of 5-ALA in meningiomas is not fully understood, with most descriptive studies using qualitative approaches to 5-ALA-PpIX.
OBJECTIVE
To assess the diagnostic performance of 5-ALA-PpIX fluorescence during surgical resection of meningioma.
METHODS
ALA was administered to 15 patients with meningioma undergoing PpIX fluorescence-guided surgery at our institution. At various points during the procedure, the surgeon performed qualitative, visual assessments of fluorescence by using the surgical microscope, followed by a quantitative fluorescence measurement by using an intra-operative probe. Specimens were collected at each point for subsequent neuropathological analysis. Clustered data analysis of variance was used to ascertain a difference between groups, and receiver operating characteristic analyses were performed to assess diagnostic capabilities.
RESULTS
Red-pink fluorescence was observed in 80% (12/15) of patients, with visible fluorescence generally demonstrating a strong, homogenous character. Quantitative fluorescence measured diagnostically significant PpIX concentrations (CPpIx) in both visibly and nonvisibly fluorescent tissues, with significantly higher CPpIx in both visibly fluorescent (P < .001) and tumor tissue (P = .002). Receiver operating characteristic analyses also showed diagnostic accuracies up to 90% for differentiating tumor from normal dura.
CONCLUSION
ALA-induced PpIX fluorescence guidance is a potential and promising adjunct in accurately detecting neoplastic tissue during meningioma resective surgery. These results suggest a broader reach for PpIX as a biomarker for meningiomas than was previously noted in the literature.
doi:10.1227/NEU.0000000000000117
PMCID: PMC4237006  PMID: 23887194
5-Aminolevulinic acid; Biophotonics; Brain tumor; Fluorescence-guided surgery; Meningioma Optical spectroscopy; Protoporphyrin IX
9.  Tumor Histology Predicts Patterns of Failure and Survival in Patients With Brain Metastases From Lung Cancer Treated With Gamma Knife Radiosurgery 
Neurosurgery  2013;73(4):10.1227/NEU.0000000000000072.
BACKGROUND
We review our experience with lung cancer patients with newly diagnosed brain metastases treated with Gamma Knife radiosurgery (GKRS).
OBJECTIVE
To determine whether tumor histology predicts patient outcomes.
METHODS
Between July 1, 2000, and December 31, 2010, 271 patients with brain metastases from primary lung cancer were treated with GKRS at our institution. Included in our study were 44 squamous cell carcinoma (SCC), 31 small cell carcinoma (SCLC), and 138 adenocarcinoma (ACA) patients; 47 patients with insufficient pathology to determine subtype were excluded. No non-small cell lung cancer (NSCLC) patients received whole-brain radiation therapy (WBRT) before their GKRS, and SCLC patients were allowed to have prophylactic cranial irradiation, but no previously known brain metastases. A median of 2 lesions were treated per patient with median marginal dose of 20 Gy.
RESULTS
Median survival was 10.2 months for ACA, 5.9 months for SCLC, and 5.3 months for SCC patients (P = .008). The 1-year local control rates were 86%, 86%, and 54% for ACA, SCC, and SCLC, respectively (P = .027). The 1-year distant failure rates were 35%, 63%, and 65% for ACA, SCC, and SCLC, respectively (P = .057). The likelihood of dying of neurological death was 29%, 36%, and 55% for ACA, SCC, and SCLC, respectively (P = .027). The median time to WBRT was 11 months for SCC and 24 months for ACA patients (P = .04). Multivariate analysis confirmed SCLC histology as a significant predictor of worsened local control (hazard ratio [HR]: 6.46, P = .025) and distant failure (HR: 3.32, P = .0027). For NSCLC histologies, SCC predicted for earlier time to salvage WBRT (HR: 2.552, P = .01) and worsened overall survival (HR: 1.77, P < .0121).
CONCLUSION
Histological subtype of lung cancer appears to predict outcomes. Future trials and prognostic indices should take these histology-specific patterns into account.
doi:10.1227/NEU.0000000000000072
PMCID: PMC3880778  PMID: 23842552
Cranial metastases; Lung cancer; Stereotactic radiosurgery
10.  Translating the Simulation of Procedural Drilling Techniques for Interactive Neurosurgical Training 
Neurosurgery  2013;73(0 1):74-80.
Background
Through previous and concurrent efforts, we have developed a fully virtual environment to provide procedural training of otologic surgical technique. The virtual environment is based on high-resolution volumetric data of the regional anatomy. This volumetric data helps drive an interactive multi-sensory, i.e., visual (stereo), aural (stereo), and tactile simulation environment. Subsequently, we have extended our efforts to support the training of neurosurgical procedural technique as part of the CNS simulation initiative.
Objective
The goal of this multi-level development is to deliberately study the integration of simulation technologies into the neurosurgical curriculum and to determine their efficacy in teaching minimally invasive cranial and skull base approaches.
Methods
We discuss issues of biofidelity as well as our methods to provide objective, quantitative automated assessment for the residents.
Results
We conclude with a discussion of our experiences by reporting on preliminary formative pilot studies and proposed approaches to take the simulation to the next level through additional validation studies.
Conclusion
We have presented our efforts to translate an otologic simulation environment for use in the neurosurgical curriculum. We have demonstrated the initial proof of principles and define the steps to integrate and validate the system as an adjuvant to the neurosurgical curriculum.
doi:10.1227/NEU.0000000000000092
PMCID: PMC4117341  PMID: 24051887
skull base; simulation; virtual reality; neurosurgery; training
11.  Dipyrone Inhibits Neuronal Cell Death and Diminishes Hypoxic/Ischemic Brain Injury 
Neurosurgery  2011;69(4):942-956.
Background and Objective
Dipyrone is an analgesic and antipyretic drug usually prescribed for patients with inflammatory conditions. We recently identified dipyrone as an anti-apoptotic agent by screening a library of 1040 compounds for their ability to inhibit cytochrome c release from isolated mitochondria. We investigated the potential neuroprotective properties of dipyrone in cerebral ischemia.
Methods
We evaluated the protective effects of dipyrone in experimental models of neuronal hypoxia/ischemia, including an oxygen/glucose deprivation model in primary cerebrocortical neurons and a focal cerebral ischemia model in mice.
Results
Dipyrone reduced hypoxia/ischemia injury in both cellular and animal models. Dipyrone inhibited the release of cytochrome c and other mitochondrial apoptogenic factors from mitochondria into the cytoplasm, and attenuated subsequent caspase-9 and caspase-3 activation both in vitro and in vivo. Moreover, dipyrone prevented ischemia-induced changes in Bcl-2 and tBid, and ameliorated OGD-mediated loss of mitochondrial membrane potential. Dipyrone also inhibited ischemia-induced reactive microgliosis. In the cellular models evaluated, dipyrone did not inhibit OGD-induced COX-2 activation.
Conclusion
This study demonstrates that dipyrone is remarkably neuroprotective in cerebral ischemia, and its COX-independent protective properties are, at least in part, due to the inhibition of mitochondrial cell death cascades.
doi:10.1227/NEU.0b013e318222afb2
PMCID: PMC4163057  PMID: 21552169
Cerebral ischemia; Cytochrome c release; Dipyrone; Drug screen; Mitochondria; Neuroprotection
12.  Deep Arteriovenous Malformations in the Basal Ganglia, Thalamus, and Insula: Microsurgical Management, Techniques, and Results 
Neurosurgery  2013;73(3):417-429.
Background
Arteriovenous malformations (AVMs) in the basal ganglia, thalamus, and insula are considered inoperable given their depth, eloquence, and limited surgical exposure. While many neurosurgeons opt for radiosurgery or observation, others have challenged the belief that deep AVMs are inoperable. Further discussion of patient selection, technique, and multimodality management is needed.
Objective
To describe and discuss the technical considerations of microsurgical resection for deep-seated AVMs.
Methods
Patients with deep AVMs who underwent surgery during a 14-year period were reviewed using a prospective AVM registry.
Results
Microsurgery was performed in 48 patients with AVMs in the basal ganglia (n=10), thalamus (n=13), or insula (n=25). The most common Spetzler-Martin grade was III- (68%). Surgical approaches included transsylvian (67%), transcallosal (19%), and transcortical (15%). Complete resection was achieved in 34 patients (71%), and patients with incomplete resection were treated with radiosurgery. Forty-five patients (94%) were improved or unchanged (mean follow-up 1.6 years).
Conclusion
This experience advances the notion that select deep AVMs may be operable lesions. Patients were highly selected for small size, hemorrhagic presentation, young age, and compactness – factors embodied in the Spetzler-Martin and Supplementary grading systems. Overall, 10 different approaches were used, exploiting direct, transcortical corridors created by hemorrhage or maximizing anatomical corridors through subarachnoid spaces and ventricles that minimize brain transgression. The same cautious attitude exercised in selecting patients for surgery was also exercised in deciding extent of resection, opting for incomplete resection and radiosurgery more than with other AVMs to prioritize neurological outcomes.
doi:10.1227/NEU.0000000000000004
PMCID: PMC4123817  PMID: 23728451
Arteriovenous malformation; Basal ganglia; Insula; Microsurgery; Thalamus
13.  National Variability in Intracranial Pressure Monitoring and Craniotomy for Children With Moderate to Severe Traumatic Brain Injury 
Neurosurgery  2013;73(5):746-752.
BACKGROUND
Traumatic brain injury (TBI) is a significant cause of mortality and disability in children. Intracranial pressure monitoring (ICPM) and craniotomy/craniectomy (CRANI) may affect outcomes. Sources of variability in the use of these interventions remain incompletely understood.
OBJECTIVE
To analyze sources of variability in the use of ICPM and CRANI.
METHODS
Retrospective cross-sectional study of patients with moderate/severe pediatric TBI with the use of data submitted to the American College of Surgeons National Trauma Databank.
RESULTS
We analyzed data from 7140 children at 156 US hospitals during 7 continuous years. Of the children, 27.4% had ICPM, whereas 11.7% had a CRANI. Infants had lower rates of ICPM and CRANI than older children. A lower rate of ICPM was observed among children hospitalized at combined pediatric/adult trauma centers than among children treated at adult-only trauma centers (relative risk = 0.80; 95% confidence interval 0.66-0.97). For ICPM and CRANI, 18.5% and 11.6%, respectively, of residual model variance was explained by between-hospital variation in care delivery, but almost no correlation was observed between within-hospital tendency toward performing these procedures.
CONCLUSION
Infants received less ICPM than older children, and children hospitalized at pediatric trauma centers received less ICPM than children at adult-only trauma centers. In addition, significant between-hospital variability existed in the delivery of ICPM and CRANI to children with moderate-severe TBI.
doi:10.1227/NEU.0000000000000097
PMCID: PMC4127400  PMID: 23863766
Decompressive craniectomy; Intracranial pressure monitoring
14.  Biopsy of the Superficial Cortex: Predictors of Effectiveness and Outcomes 
Neurosurgery  2013;73(2):224-232.
BACKGROUND
Brain biopsies of superficial cortex are performed for diagnosis of neurological diseases, but preoperative predictors of successful diagnosis and risks are lacking.
OBJECTIVE
We evaluated effectiveness and outcomes of superficial cortical biopsies and determined preoperative predictors of diagnosis, outcomes, morbidities, and mortality.
METHODS
A single-institution retrospective analysis of 170 patients who underwent open brain biopsies of superficial cortex was performed. Clinical predictors of effectiveness and outcomes were determined using univariate/multivariate analyses and a system for risk-benefit stratification was created and tested.
RESULTS
Brain biopsies led to successful diagnosis in 122 of 170 (71.8%) and affected management in 97 of 170 (57.1%) cases. Factors increasing the odds of diagnostic pathology included age older than 45 years (odds ratio [OR]: 2.67, 95% confidence interval [CI]: 1.34-5.27, P < .01), previous cancer diagnosis (OR: 3.64, 95% CI: 1.69-7.85, P < .001), focal (OR: 3.90, 95% CI: 1.91-8.00, P < .001) and enhancing (OR: 5.03, 95% CI: 2.41-10.52, P < .001) lesions on magnetic resonance imaging, biopsy of specific lesions on magnetic resonance imaging (OR: 9.34, 95% CI: 4.29-20.33, P < .001), and use of intraoperative navigation (OR: 6.59, 95% CI: 3.04-14.28, P < .001). Brain biopsies led to symptomatic intracranial hemorrhage, seizures, other significant morbidities, and perioperative mortality in 12.4%, 16.2%, 37.1%, and 8% of cases, respectively. Risk of postoperative intracranial hemorrhage was increased by a history of aspirin use (OR: 2.51, 95% CI: 1.23-5.28, P < .05) and age older than 60 years (OR: 2.66, 95% CI: 1.36-5.18, P < .01).
CONCLUSION
Effectiveness and risk of morbidity/mortality can be estimated preoperatively for patients undergoing open brain biopsies of the superficial cortex. Older age and specific imaging characteristics increase the odds of diagnostic biopsy. Conversely, older age and aspirin use increases the risk of postoperative complications.
doi:10.1227/01.neu.0000430310.63702.3e
PMCID: PMC3934358  PMID: 23632761
Brain tumor; Dementia; Efficacy; Hemorrhage; Open brain biopsy; Outcomes; Pathology
15.  Magnetic Resonance Guided Focused Ultrasound Surgery: Part 2 – A Review of Current and Future Applications 
Neurosurgery  2012;71(4):755-763.
Magnetic Resonance guided Focused Ultrasound Surgery (MRgFUS) represents a novel combination of technologies that is actively being realized as a non-invasive therapeutic tool for a myriad of conditions. These applications are reviewed with a focus on neurological utilization. A combined search of Pubmed and Medline was performed to identify the key events and current status of MRgFUS, with a focus on neurological applications.
MRgFUS signifies a potentially ideal device for the treatment of neurological diseases. As it is nearly real-time, it allows monitored provision of treatment location and energy deposition, is noninvasive, thereby limiting or eliminating disruption of normal tissue, provides focal delivery of therapeutic agents, enhances radiation delivery, and permits modulation of neural function. Multiple clinical applications are currently in clinical use and many more are under active preclinical investigation.
The therapeutic potential of MRgFUS is expanding rapidly. Although clinically in its infancy, preclinical and early phase I clinical trials in neurosurgery suggest a promising future for MRgFUS. Further investigation is necessary to define its true potential and impact.
doi:10.1227/NEU.0b013e3182672ac9
PMCID: PMC4104674  PMID: 22791029
Focused Ultrasound; Ultrasound; MRI; Therapy; Neurosurgery
16.  High intensity focused ultrasound surgery (HIFU) of the brain: A historical perspective, with modern applications 
Neurosurgery  2009;64(2):201-211.
The field of MRI-guided high intensity focused ultrasound surgery (MRgFUS) is a rapidly evolving one with many potential applications in neurosurgery. This is the first of three articles on MRgFUS, this paper focuses on the historical development of the technology and it's potential applications to modern neurosurgery.
The evolution of MRgFUS has occurred in parallel with modern neurological surgery and the two seemingly distinct disciplines share many of the same pioneering figures. Early studies on focused ultrasound treatment in the 1940's and 1950's demonstrated the ability to perform precise lesioning in the human brain, with a favorable risk-benefit profile. However, the need for a craniotomy, as well as lack of sophisticated imaging technology resulted in limited growth of HIFU for neurosurgery. More recently, technological advances, have permitted the combination of HIFU along with MRI guidance to provide an opportunity to effectively treat a variety of CNS disorders.
Although challenges remain, HIFU-mediated neurosurgery may offer the ability to target and treat CNS conditions that were previously extremely difficult to perform. The remaining two articles in this series will focus on the physical principles of modern MRgFUS as well as current and future avenues for investigation.
doi:10.1227/01.NEU.0000336766.18197.8E
PMCID: PMC4068031  PMID: 19190451
HIFU; Focused Ultrasound; Neurosurgery; MRI; Surgery; Ultrasound
17.  Comparative Effectiveness of 3-Dimensional vs 2-Dimensional and High-Definition vs Standard-Definition Neuroendoscopy: A Preclinical Randomized Crossover Study 
Neurosurgery  2013;74(4):375-381.
BACKGROUND:
Although the potential benefits of 3-dimensional (3-D) vs 2-dimensional (2-D) and high-definition (HD) vs standard-definition (SD) endoscopic visualization have long been recognized in other surgical fields, such endoscopes are generally considered too large and bulky for use within the brain. The recent development of 3-D and HD neuroendoscopes may therefore herald improved depth perception, better appreciation of anatomic details, and improved overall surgical performance.
OBJECTIVE:
To compare simultaneously the effectiveness of 3-D vs 2-D and HD vs SD neuroendoscopy.
METHODS:
Ten novice neuroendoscopic surgeons were recruited from a university hospital. A preclinical randomized crossover study design was adopted to compare 3-D vs 2-D and HD vs SD neuroendoscopy. The primary outcomes were time to task completion and accuracy. The secondary outcomes were perceived task workload using the NASA (National Aeronautics and Space Administration) Task Load Index and subjective impressions of the endoscopes using a 5-point Likert scale.
RESULTS:
Time to task completion was significantly shorter when using the 3-D vs the 2-D neuroendoscopy (P = .001), and accuracy of probe placement was significantly greater when using the HD vs the SD neuroendoscopy (P = .009). We found that 3-D endoscopy significantly improved perceived depth perception (P < .001), HD endoscopy significantly improved perceived image quality (P < .001), and both improved participants’ overall impression (P < .001).
CONCLUSION:
Three-dimensional neuroendoscopy and HD neuroendoscopy have differing but complementary effects on surgical performance, suggesting that neither alone can completely compensate for the lack of the other. There is therefore strong preclinical evidence to justify 3-D HD neuroendoscopy.
ABBREVIATIONS:
HD, high definition
SD, standard definition
doi:10.1227/NEU.0000000000000249
PMCID: PMC4053590  PMID: 24220007
Endoscopy; HD; High definition; Minimally invasive neurosurgery; 3D; 3-dimensional
18.  Internal Maxillary Artery-Middle Cerebral Artery Bypass: Infratemporal Approach for Subcranial-Intracranial (SC-IC) Bypass 
Neurosurgery  2014;75(1):87-95.
BACKGROUND:
Internal maxillary artery (IMax)–middle cerebral artery (MCA) bypass has been recently described as an alternative to cervical extracranial-intracranial bypass. This technique uses a “keyhole” craniectomy in the temporal fossa that requires a technically challenging end-to-side anastomosis.
OBJECTIVE:
To describe a lateral subtemporal craniectomy of the middle cranial fossa floor to facilitate wide exposure of the IMax to facilitate bypass.
METHODS:
Orbitozygomatic osteotomy is used followed by frontotemporal craniotomy and subsequently laterotemporal fossa craniectomy, reaching its medial border at a virtual line connecting the foramen rotundum and foramen ovale. The IMax was identified by using established anatomic landmarks, neuronavigation, and micro Doppler probe (Mizuho Inc. Tokyo, Japan). Additionally, we studied the approach in a cadaveric specimen in preparation for microsurgical bypass.
RESULTS:
There were 4 cases in which the technique was used. One bypass was performed for flow augmentation in a hypoperfused hemisphere. The other 3 were performed as part of treatment paradigms for giant middle cerebral artery aneurysms. Vein grafts were used in all patients. The proximal anastomosis was performed in an end-to-side fashion in 1 patient and end-to-end in 3 patients. Intraoperative graft flow measured with the Transonic flow probe ranged from 20 to 60 mL/min. Postoperative angiography demonstrated good filling of the graft with robust distal flow in all cases. All patients tolerated the procedure well.
CONCLUSION:
IMax to middle cerebral artery subcranial-intracranial bypass is safe and efficacious. The laterotemporal fossa craniectomy technique resulted in reliable identification and wide exposure of the IMax, facilitating the proximal anastomosis.
ABBREVIATIONS:
EC-IC, extracranial-intracranial
IMax, internal maxillary artery
MCA, middle cerebral artery
SC-IC, subcranial-intracranial
STA, superficial temporal artery
doi:10.1227/NEU.0000000000000340
PMCID: PMC4053591  PMID: 24618804
Brachiocephalic vein; EC-IC bypass; Infratemporal approach; Internal maxillary artery
19.  Transsphenoidal Surgery for Cushing Disease: Experience With 136 Patients 
Neurosurgery  2012;70(1):70-81.
BACKGROUND
This is a retrospective study of 136 patients with Cushing disease treated with transsphenoidal microsurgery.
OBJECTIVE
To evaluate factors influencing immediate postoperative results and long-term outcomes.
METHODS
Data regarding clinical presentation, endocrine evaluation, imaging studies, surgical technique, immediate postoperative biochemical remission (IPBR), and long-term results were entered into a database and analyzed statistically. IPBR was based on biochemical evidence of adrenal cortical insufficiency and clinical evidence of such insufficiency.
RESULTS
IPBR for the entire series was 83.4%. In microadenomas, IPBR was 89.8% with a mean immediate postoperative plasma cortisol (IPPC) of 2.1 μg/dL (range, <0.5–5.3). Positive magnetic resonance imaging (MRI) was associated with 18 times greater odds of finding microadenoma at surgery (P < .001) and with 4.1 times greater odds of IPBR (P = .07). In patients with a negative MRI, a positive inferior petrosal sinus sampling (IPSS) test was associated with 93% of IPBR (P = .004). IPBR in macroadenomas was 30.7%. Of patients followed for 12 months or longer, 34.8% required glucocorticoid replacement for the duration of follow-up. The mean follow-up in microadenomas was 68.4 months with a 9.67% incidence of recurrences. The estimated actuarial incidence of recurrences increased with the passage of time and IPPC of greater than 2 μg/dL was associated with higher incidence of recurrences, although without statistical significance (P = .08).
CONCLUSION
In microadenomas, a positive MRI and positive IPSS test were associated with a higher incidence of IPBR. Recurrences increased with the passage of time, and an IPPC of greater than 2 μg/dL may be associated with higher incidence of recurrences.
doi:10.1227/NEU.0b013e31822dda2c
PMCID: PMC4051420  PMID: 21772221
Cushing disease; Immediate postoperative remission; Long-term results; Statistical analysis; Transsphenoidal surgery
20.  Arterial Blood Pressure Management during Carotid Endarterectomy and Early Cognitive Dysfunction 
Neurosurgery  2014;74(3):245-253.
Background
A common practice during cross-clamp of carotid endarterectomy (CEA) is to manage mean arterial pressure (MAP) above baseline to optimize collateral cerebral blood flow and reduce risk of ischemic stroke.
Objective
To determine whether MAP management ≥20% above baseline during cross-clamp is associated with lower risk of early cognitive dysfunction, a subtler form of neurologic injury than stroke.
Methods
One hundred eighty-three patients undergoing CEA were enrolled in this ad hoc study. All patients had radial arterial catheters placed prior to induction of general anesthesia. MAP was managed at the discretion of the anesthesiologist. All patients were evaluated with a battery of neuropsychometric tests pre-operatively and 24hrs post-operatively.
Results
Overall, 28.4% of CEA patients exhibited early cognitive dysfunction (eCD). Significantly fewer patients with MAP ≥20% above baseline during cross-clamp exhibited eCD than those managed <20% above (11.6% vs. 38.6%, P<0.001). In a multivariate logistic regression model, MAP ≥20% above baseline during the cross-clamp period was associated with significantly lower risk of eCD (OR: 0.18 [0.07–0.40], P<0.001), while diabetes mellitus (OR: 2.73 [1.14–6.61], P=0.03) and each additional year of education (OR: 1.19 [1.06–1.34], P=0.003) were associated with significantly higher risk of eCD.
Conclusion
The observations of this study suggest MAP management ≥20% above baseline during cross-clamp of the carotid artery may be associated with lower risk of eCD after CEA. More prospective work is necessary to determine whether MAP ≥20% above baseline during cross-clamp can improve the safety of this commonly performed procedure.
doi:10.1227/NEU.0000000000000256
PMCID: PMC4038378  PMID: 24335822
carotid endarterectomy; pressure management; cognitive dysfunction
21.  Intraarterial Mitoxantrone Delivery in Rabbits: An Optical Pharmacokinetic Study 
Neurosurgery  2011;69(3):706-712.
Background
Several human studies have demonstrated the feasibility of intraarterial delivery of mitoxantrone in systemic malignancies. Computational models predict that intraarterial bolus injection of mitoxatrone during transient cerebral hypoperfusion will enhance brain tissue drug deposition compared to injections during normal blood flow.
Objective
To assess whether transient reduction in cerebral blood flow would enhance the delivery of mitoxantrone. This is accomplished by obtaining real-time measurements of mitoxantrone concentrations in brain tissues using a novel optical pharmacokinetics technique, based on reflectance spectroscopy.
Methods
The blood-brain-barrier of anesthetized rabbits was disrupted by intracarotid injection of mannitol (8 ml, 25% over 40 seconds). Thereafter, animals received 3 mg of mitoxantrone injection during normal perfusion (n=5) or cerebral hypoperfusion (CHP) that was induced by contralateral arterial occlusion and systemic hypotension (n=8).
Results
CHP significantly decreased the cerebral blood flow, allowing a longer exposure time of the drug. It was determined that therapeutic concentrations of mitoxantrone were achieved in both groups, however, hypoperfusion did not increase the tissue concentrations of mitoxantrone after 20 minutes.
Conclusion
These results demonstrate the effective delivery of mitoxantrone by the intraarterial route, after blood-brain-barrier disruption, but the predicted benefits of flow reduction for improving intraarterial deposition of mitoxantrone was not evident.
doi:10.1227/NEU.0b013e3182181b67
PMCID: PMC4028021  PMID: 21430588
intracarotid; mitoxantrone; optical; pharmacokinetics
22.  SPORT: Do outcomes vary across centers for surgery for lumbar disc herniation? 
Neurosurgery  2012;71(4):833-842.
Background
Lumbar discectomy is the most common procedure performed in spine surgery. Different centers performing this procedure may have different outcomes.
Objective
To determine whether the choice of academic spine center in which surgery is performed affects outcome after lumbar discectomy.
Methods
Spine Patient Outcomes Research Trial (SPORT) cohort participants with a confirmed diagnosis of intervertebral disc herniation (IDH) undergoing standard first-time open discectomy were followed from baseline at 6 weeks, and 3, 6, 12 months and yearly thereafter, at 13 spine clinics in 11 US states. Patient data were retrospectively reviewed. As of August 2009, the mean (SD) follow-up among all analyzed IDH patients was 41.3 (14.6) months. The median (range) follow-up time among all analyzed IDH patients was 47.4 (1.3, 95.3) months. Enrollment began in March 2000 and ended in November 2004.
Results
792 patients underwent first-time lumbar discectomy. Significant differences were found amongst centers with regard to patient age and race, and in baseline levels of disability and treatment preferences. There were no significant differences among the study centers in other patient characteristics (e.g., sex, body mass index, the prevalence of smoking, diabetes or hypertension), or disease characteristics (herniation level or type). Some short-term outcomes varied significantly among centers, including operative duration and blood loss, the incidence of durotomy and the length of hospital stay. Unadjusted reoperation rates also varied across centers. There were no differences among the various centers in incidence of nerve root injury, post-operative mortality, SF-36 scores of body pain or physical function, or Oswestry Disability Index at 4 years.
Conclusions
Although mean operative blood loss, risk of durotomy and length of hospital stay vary across academic centers performing lumbar discectomy, there appears to be no difference in long-term functional outcomes. The role of different reoperation rates in producing similar outcomes remains unclear.
doi:10.1227/NEU.0b013e31826772cb
PMCID: PMC4011394  PMID: 22791040
Clinical outcomes; Lumbar spine; Surgical complications
23.  The Relationship Between Delayed Infarcts and Angiographic Vasospasm After Aneurysmal Subarachnoid Hemorrhage 
Neurosurgery  2013;72(5):702-708.
Background
Delayed cerebral ischemia is common after aneurysmal subarachnoid hemorrhage (aSAH) and is a major contributor to poor outcome. Yet, while generally attributed to arterial vasospasm, neurologic deterioration may also occur in the absence of vasospasm.
Objective
To determine the relationship between delayed infarction and angiographic vasospasm and compare the characteristics of infarcts related vs. those unrelated to vasospasm.
Methods
A retrospective review of patients with aSAH admitted from July 2007 through June 2011. Patients were included if they were admitted within 48 hours of SAH, had a CT scan both 24–48 hours following aneurysm treatment and ≥ 7 days after SAH, and had a catheter angiogram to evaluate for vasospasm. Delayed infarcts seen on late CT but not post-procedurally were attributed to vasospasm if there was moderate or severe vasospasm in the corresponding vascular territory on angiography. Infarct volume was measured by perimeter tracing.
Results
Of 276 aSAH survivors, 134 had all imaging requisite for inclusion. 54 (34%) had moderate or severe vasospasm, of which 17 (31%) had delayed infarcts, compared to only 3 (4%) of 80 patients without vasospasm (p<0.001). There were a total of 29 delayed infarcts in these 20 patients; 21 were in a territory with angiographic vasospasm while 8 (28%) were not. Infarct volume did not differ between vasospasm-related (18±25cc) and vasospasm-unrelated (11±12cc) infarcts (p=0.54), but infarcts in the absence of vasospasm were more likely watershed (50% vs. 10%, p=0.03).
Conclusion
Delayed infarcts following aSAH can occur in territories without angiographic vasospasm and are more likely watershed in distribution.
doi:10.1227/NEU.0b013e318285c3db
PMCID: PMC3787688  PMID: 23313984
Cerebral vasospasm; Delayed cerebral ischemia; Stroke; Subarachnoid hemorrhage
24.  Mechanisms of Stroke after Intracranial Angioplasty and Stenting in the SAMMPRIS Trial 
Neurosurgery  2013;72(5):777-795.
Background
Enrollment in the Stenting and Aggressive Medical Management for the Prevention of stroke in Intracranial Stenosis (SAMMPRIS) trial was halted owing to higher than expected 30-day stroke rates in the stenting arm. Improvement in peri-procedural stroke rates from angioplasty and stenting for intracranial atherosclerotic disease (ICAD) requires an understanding of the mechanisms of these events.
Objective
To identify the types and mechanisms of peri-procedural stroke after angioplasty and stenting for ICAD.
Methods
Patients that suffered a hemorrhagic or ischemic stroke or a cerebral infarct with temporary signs (CITS) within 30 days of attempted angioplasty and stenting in SAMMPRIS were identified. Study records, including case report forms, procedure notes, and imaging were reviewed. Strokes were categorized as ischemic or hemorrhagic. Ischemic strokes were categorized as perforator territory, distal embolic, or delayed stent thrombosis. Hemorrhagic strokes were categorized as subarachnoid or intraparenchymal. Causes of hemorrhage (wire perforation, vessel rupture) were recorded.
Results
Three patients suffered an ischemic stroke after diagnostic angiography. Two were unrelated to the procedure. Twenty-one patients suffered an ischemic stroke (n= 19) or CITS (n=2) within 30 days of angioplasty and stenting. Most (n=15) were perforator territory and many of these occurred after angiographically successful angioplasty and stenting of the basilar artery (n = 8). Six patients suffered subarachnoid hemorrhage (three from wire perforation) and seven a delayed intraparenchymal hemorrhage.
Conclusion
Efforts at reducing complications from angioplasty and stenting for ICAD must focus on reducing the risks of regional perforator infarction, delayed intraparenchymal hemorrhage, and wire perforation.
doi:10.1227/NEU.0b013e318286fdc8
PMCID: PMC3696348  PMID: 23328689
Angioplasty and Stenting; Stroke; Hemorrhage
25.  Neural Engineering to Produce in Vitro Nerve Constructs and Neurointerence 
Neurosurgery  2007;60(1):137-142.
Objective
Recently, our laboratory recapitulated a natural form of axon growth that occurs between late embryogenesis and early adulthood. In this article, we describe how this novel neural engineering approach may be used to produce a nervous tissue interface to integrate disconnected motor and sensory functions for external control.
Methods
For nervous system repair, we recently developed a unique method to engineer nervous tissue constructs in vitro consisting of bundles of axons spanning two populations of neuronal somata. To integrate electronics and nervous tissue to transform electrophysiological signals into electronic signals, we have designed a nervous tissue interface.
Results
Our nervous tissue interface consists of stretch-grown nervous tissue with one end interfaced with a multiple electrode array, enabling us to detect and record real-time efferent signals conducted down the nerve and stimulate afferent sensory signaling.
Conclusion
Our ultimate goal is to develop a neurally controlled prosthesis and a nervous system interface that could be linked to the patient's thoughts, providing two-way signaling for motor control and feedback from multiple external stimuli.
doi:10.1227/01.NEU.0000249197.61280.1D
PMCID: PMC3979335  PMID: 17228262
Nervous system repair; Neurally controlled prosthesis; Peripheral nerve injury; Signaling

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