High-resolution Imaging of Myeloperoxidase Activity Sensors in Human Cerebrovascular Disease.

Progress in clinical development of magnetic resonance imaging (MRI) substrate-sensors of enzymatic activity has been slow partly due to the lack of human efficacy data. We report here a strategy that may serve as a shortcut from bench to bedside. We tested ultra high-resolution 7T MRI (µMRI) of human surgical histology sections in a 3-year IRB approved, HIPAA compliant study of surgically clipped brain aneurysms. µMRI was used for assessing the efficacy of MRI substrate-sensors that detect myeloperoxidase activity in inflammation. The efficacy of Gd-5HT-DOTAGA, a novel myeloperoxidase (MPO) imaging agent synthesized by using a highly stable gadolinium (III) chelate was tested both in tissue-like phantoms and in human samples. After treating histology sections with paramagnetic MPO substrate-sensors we observed relaxation time shortening and MPO activity-dependent MR signal enhancement. An increase of normalized MR signal generated by ultra-short echo time MR sequences was corroborated by MPO activity visualization by using a fluorescent MPO substrate. The results of µMRI of MPO activity associated with aneurysmal pathology and immunohistochemistry demonstrated active involvement of neutrophils and neutrophil NETs as a result of pro-inflammatory signalling in the vascular wall and in the perivascular space of brain aneurysms.

Bow Hunter's Syndrome in a Patient with a Right Hypoplastic Vertebral Artery and a Dynamically Compressible Left Vertebral Artery.

This is a case report of a 48-year-old man with multiple transient ischemic attacks and a known hypoplastic right vertebral artery (VA) who presented after a syncopal event while turning his head to the left. The objective of this study is to demonstrate the necessity of proper diagnosis and management of cerebrovascular pathology including imaging and surgical intervention in patients with known anatomical anomalies. This study was conducted at Massachusetts, United States of America. Our patient's history was significant for a hypoplastic right VA and a stenotic segment of the right VA at the C3-C4 junction. There was also degeneration of the C3-C4 facet on the left, with osteophyte formation compressing the VA, and a fusion of the C2-C3 segment. Imaging demonstrated obliteration of the left VA flow with head rotation to the left and subsequent reconstitution of flow in the neutral position. After consultation, the patient decided to proceed with surgical management with an anterior cervical discectomy and fusion at the level of C3-C4. Symptoms of vertebrobasilar insufficiency including syncopal episodes resolved after treatment. VA anomalies, although uncommon, are important to understand. Our patient presented with an anomalous right VA, as well as severe degenerative changes to the C2/C3 vertebrae that contributed to the development of Bow Hunter's syndrome. It is essential that proper monitoring and follow-up has to be carried out in patients with abnormal cerebral vasculature to minimize the occurrence of Bow Hunter's syndrome.

Planning and Executing the Neurosurgery Boot Camp: The Bolivia Experience.

BACKGROUND: The neurosurgical boot camp has been fully incorporated into U.S. postgraduate education. This is the first implementation of the neurosurgical boot in a developing country. To advance neurosurgical education, we developed a similar boot camp program, in collaboration with Bolivian neurosurgeons, to determine its feasibility and effectiveness in an international setting. METHODS: In a collective effort, the Bolivian Society for Neurosurgery, Foundation for International Education in Neurological Surgery, Solidarity Bridge, and University of Massachusetts organized and executed the first South American neurosurgical boot camp in Bolivia in 2015. Both U.S. and Bolivian faculty led didactic lectures followed by a practicum day using mannequins and simulators. South American residents and faculty were surveyed after the course to determine levels of enthusiasm and their perceived improvement in fund of knowledge and course effectiveness. RESULTS: Twenty-four neurosurgery residents from 5 South American countries participated. Average survey scores ranged between 4.2 and 4.9 out of 5. Five Bolivian neurosurgeons completed the survey with average scores of 4.5-5. This event allowed for Bolivian leaders in the field to unify around education, resulting in the formation of an institute to continue similar initiatives. Total cost was estimated at $40 000 USD; however, significant faculty, industry, and donor support helped offset this amount. CONCLUSION: The first South American neurosurgical boot camp had significant value and was well received in Bolivia. This humanitarian model provides a sustainable solution to education needs and should be expanded to other regions as a means for standardizing the core competencies in neurosurgery.

Grading of Regional Apposition after Flow-Diverter Treatment (GRAFT): a comparative evaluation of VasoCT and intravascular OCT.

BACKGROUND: Poor vessel wall apposition of flow diverter (FD) stents poses risks for stroke-related complications when treating intracranial aneurysms, necessitating long-term surveillance imaging. To facilitate quantitative evaluation of deployed devices, a novel algorithm is presented that generates intuitive two-dimensional representations of wall apposition from either high-resolution contrast-enhanced cone-beam CT (VasoCT) or intravascular optical coherence tomography (OCT) images. METHODS: VasoCT and OCT images were obtained after FD implant (n=8 aneurysms) in an experimental sidewall aneurysm model in canines. Surface models of the vessel wall and FD device were extracted, and the distance between them was presented on a two-dimensional flattened map. Maps and cross-sections at potential locations of malapposition detected on VasoCT-based maps were compared. The performance of OCT-based apposition detection was evaluated on manually labeled cross-sections using logistic regression against a thresholded (≥0.25 mm) apposition measure. RESULTS: VasoCT and OCT acquisitions yielded similar Grading of Regional Apposition after Flow-Diverter Treatment (GRAFT) apposition maps. GRAFT maps from VasoCT highlighted 16 potential locations of malapposition, of which two were found to represent malapposed device struts. Logistic regression showed that OCT could detect malapposition with a sensitivity of 98% and a specificity of 81%. CONCLUSIONS: GRAFT delivered quantitative and visually convenient representations of potential FD malapposition and occasional acute thrombus formation. A powerful combination for future neuroendovascular applications is foreseen with the superior resolution delivered by intravascular OCT.

Dantrolene for cerebral vasospasm after subarachnoid haemorrhage: a randomised double blind placebo-controlled safety trial.

BACKGROUND: Dantrolene is neuroprotective in animal models and may attenuate cerebral vasospasm (cVSP) in human aneurysmal subarachnoid haemorrhage (aSAH). We evaluated safety, feasibility and tolerability of intravenous dantrolene (IV-D) in patients with aSAH. METHODS: In this single-centre, randomised, double blind, placebo-controlled trial, 31 patients with aSAH were randomised to IV-D 1.25 mg every 6 h for 7 days (n=16) or equiosmolar free water/5% mannitol (placebo; n=15). Primary safety end points were incidence of hyponatraemia (sNa≤132 mmol/L) and liver toxicity (proportion of patients alanine transaminase, aspartate aminotransferase and AlkPhos >5× upper-limit-of-normal). Secondary end points included tolerability, systemic hypotension and intracranial hypertension. Efficacy was explored for clinical/radiological cVSP, delayed cerebral ischaemia (DCI), and 3-month functional outcomes. Quantitative analyses of angiograms and daily transcranial Doppler (TCD) were performed. RESULTS: Between IV-D versus placebo, no differences were observed in the primary outcomes (hyponatremia 44% vs 67% (p=0.29); liver toxicity 6% vs 0% (p=1.0)). Three patients in the IV-D versus two in the placebo group had severe adverse events possibly attributable to infusion and reached stop criteria: one IV-D patient developed liver toxicity; two patients in each group developed brain oedema requiring osmotherapy. The majority of adverse events were not related to infusion (17 vs 5 (RR 2.2; 95% CI 0.7 to 6.7; p=0.16) in IV-D vs placebo). No differences in any categorical cVSP outcomes, DCI, 3-month outcomes or quantitative angiogram and TCD analyses were seen in this small safety trial not powered to detect efficacy. CONCLUSIONS: In this small trial, IV-D after aSAH was feasible, tolerable and safe. TRIAL REGISTRATION NUMBER: http://clinicaltrials.gov NCT01024972.

Myeloperoxidase in human intracranial aneurysms: preliminary evidence.

BACKGROUND AND PURPOSE: Noninvasive imaging identifying a predictive biomarker of the bleeding risk of unruptured intracranial aneurysms (UIAs) is needed. We investigated a potential biomarker of UIA instability, myeloperoxidase, in human aneurysm tissue. METHODS: Human brain aneurysms were harvested after clipping and were histologically and biochemically evaluated for the presence of myeloperoxidase. Of the tissue collected, 3 were from ruptured aneurysms and 20 were from UIAs. For each UIA, its 5-year aneurysm rupture risk was determined using the Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm and Site of Aneurysm (PHASES) model. RESULTS: All ruptured aneurysms were myeloperoxidase positive. Of the UIAs, half were myeloperoxidase positive. The median 5-year aneurysm rupture risk was higher for myeloperoxidase-positive UIA (2.28%) than myeloperoxidase-negative UIA (0.69%), and the distributions were statistically different (P<0.005, Wilcoxon-Mann-Whitney test). The likelihood for myeloperoxidase-positive UIA was significantly associated (P=0.031) with aneurysm rupture risk (odds ratio, 4.79; 95% confidence limits, 1.15-19.96). CONCLUSIONS: Myeloperoxidase is associated with PHASES estimated risk of aneurysm rupture and may potentially be used as an imaging biomarker of aneurysm instability.

Health impact and economic analysis of NGO-supported neurosurgery in Bolivia.

OBJECT: Bolivia, one of the poorest countries in the world, ranks 108th on the 2013 Human Development Index. With approximately 1 neurosurgeon per 200,000 people, access to neurosurgery in Bolivia is a growing health concern. Furthermore, neurosurgery in nonindustrialized countries has been considered both cost-prohibitive and lacking in outcomes evaluation. A non-governmental organization (NGO) supports spinal procedures in Bolivia (Solidarity Bridge), and the authors sought to determine its impact and cost-effectiveness. METHODS: In a retrospective review of prospectively collected data, 19 patients were identified prior to spinal instrumentation and followed over 12 months. For inclusion, patients required interviewing prior to surgery and during at least 2 follow-up visits. All causes of spinal pathology were included. Sixteen patients met inclusion criteria and were therefore part of the analysis. Outcomes measured included assessment of activities of daily living, pain, ambulation, return to work/school, and satisfaction. Cost-effectiveness was determined by cost-utility analysis. Utilities were derived using the Health Utilities Index. Complications were incorporated into an expected value decision tree. RESULTS: Median (± SD) preoperative satisfaction was 2.0 ± 0.3 (on a scale of 0-10), while 6-month postoperative satisfaction was 7 ± 1.4 (p < 0.0001). Ambulation, pain, and emotional disability data suggested marked improvement (56%, 69%, and 63%, respectively; p = 0.035, 0.003, and 0.006). Total discounted incremental quality-adjusted life year (QALY) gain was 0.771. The total discounted cost equaled $9036 (95% CI $8561-$10,740) at 2 years. Computing the incremental cost-effectiveness ratio resulted in a value of $11,720/QALY, ranging from $9220 to $15,473/QALY in a univariate sensitivity analysis. CONCLUSIONS: This NGO-supported spinal instrumentation program in Bolivia appears to be cost-effective, especially when compared with the conventional $50,000/QALY benchmark and the WHO endorsed country-specific threshold of $16,026/QALY. However, with a gross domestic product per capita in Bolivia equaling $4800 per year and 30.3% of the population living on less than $2 per day, this cost continues to appear unrealistic. Additionally, the study has several significant limitations, namely its limited sample size, follow-up period, the assumption that patients not receiving surgical intervention would not make any clinical improvement, the reliance on the NGO for patient selection and sustainable practices such as follow-up care and ancillary services, and the lack of a randomized prospective design. These limitations, as well as an unclear understanding of Bolivian willingness-to-pay data, affect the generalizability of the study findings and impede widespread economic policy reform. Because cost-effectiveness research may inevitably direct care decisions and prove that an effort such as this can be cost saving, a prospective, properly controlled investigation is now warranted.

Massachusetts health insurance mandate: effects on neurosurgical practice.

OBJECT: Massachusetts' health insurance mandate and subsidized insurance program, Commonwealth Care, have been active for 2 years. METHODS: The financial impact on the neurosurgery division and demographics of the relevant patient groups were assessed. The billing records of neurosurgical patients from January 2007 to September 2008 were collected and analyzed. RESULTS: Commonwealth Care comprised 2.2% of neurosurgical inpatients, and these patients did not have significantly different acuity or lengths of stay from the average. Length of stay of MassHealth patients was significantly greater, although acuity was significantly lower than the average. Increased free care reimbursement and increased MassHealth/Commonwealth Care enrollment resulted in a net gain in reimbursement of hospital charges. CONCLUSIONS: The increased insurance rates have resulted in increased reimbursement for the neurosurgical division.

Stent-assisted reconstructive endovascular repair of cranial fusiform atherosclerotic and dissecting aneurysms: long-term clinical and angiographic follow-up.

BACKGROUND AND PURPOSE: The purpose of this study was to investigate the periprocedural morbidity, mortality, and long-term clinical and angiographic follow-up using stent-assisted coiling and stenting alone for treatment of cranial fusiform dissecting and atherosclerotic aneurysms. METHODS: The Institutional Review Board approved the study. A retrospective analysis was performed of 30 fusiform dissecting and atherosclerotic aneurysms treated in 28 patients (20 females; mean age, 52.6 years). Eleven aneurysms (37%) were located in the posterior circulation. Twenty-one (70%) originated from arterial dissection and 4 aneurysms (13%) presented with subarachnoid bleeding. Twenty-four (80%) aneurysms were treated with stents and coils, whereas 6 (20%) were treated with stents alone. RESULTS: Immediate postprocedural angiograms in 24 aneurysms treated with stent-assisted coiling showed complete occlusion in 12 and subtotal occlusion in 11 aneurysms, whereas no occlusion was seen in one aneurysm and in all 6 aneurysms treated with stents alone. A clinical improvement or stable outcome was achieved in 25 patients (89%). The 2 cases of permanent morbidity included a patient with a finger dysesthesia associated with a perforator stroke and another patient with hemiparesis and aphasia due to a delayed in-stent thrombosis. One patient died after treatment of a giant vertebrobasilar junction aneurysm. Angiographic follow-up was available in 23 of the 27 surviving patients (85%) at a mean of 16.2 months (range, 1 to 108 months). Recanalization in 4 patients (17%) at 3, 5, 24, and 36 months required retreatment in 3. In-stent stenosis of

Multi-institutional reciprocal validation study of computed tomography predictors of suboptimal primary cytoreduction in patients with advanced ovarian cancer.

PURPOSE: Identify features on preoperative computed tomography (CT) scans to predict suboptimal primary cytoreduction in patients treated for advanced ovarian cancer in institution A. Reciprocally cross validate the predictors identified with those from two previously published cohorts from institutions B and C. PATIENTS AND METHODS: Preoperative CT scans from patients with stage III/IV epithelial ovarian cancer who underwent primary cytoreduction in institution A between 1999 and 2005 were retrospectively reviewed by radiologists blinded to surgical outcome. Fourteen criteria were assessed. Crossvalidation was performed by applying predictive model A to the patients from cohorts B and C, and reciprocally applying predictive models B and C to cohort A. RESULTS: Sixty-five patients from institution A were included. The rate of optimal cytoreduction ( 1 cm residual disease) was 78%. Diaphragm disease and large bowel mesentery implants were the only CT predictors of suboptimal cytoreduction on univariate (P < .02) and multivariate analysis (P < .02). In combination (model A), these predictors had a sensitivity of 79%, a specificity of 75%, and an accuracy of 77% for suboptimal cytoreduction. When model A was applied to cohorts B and C, accuracy rates dropped to 34% and 64%, respectively. Reciprocally, models B and C had accuracy rates of 93% and 79% in their original cohorts, which fell to 74% and 48% in cohort A. CONCLUSION: The high accuracy rates of CT predictors of suboptimal cytoreduction in the original cohorts could not be confirmed in the cross validation. Preoperative CT predictors should be used with caution when deciding between surgical cytoreduction and neoadjuvant chemotherapy.