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BACKGROUND Experimental studies to assess aneurysm occlusion or perfusion typically rely on macroscopic examination or histological analysis but cannot assess dynamic perfusion. OBJECTIVE To describe an easy-to-implement and inexpensive fluorescence angiographic technique for the in vivo assessment and imaging of the dynamic perfusion status of aneurysms and their underlying blood vessels in a rat model. METHODS In a rat sidewall aneurysm model, the angiographic setup included 2 bandpass filters, a video camera, and a bicycle spotlight. After 48 rats underwent fluorescein angiography, dissections were performed to confirm the perfusion status by macroscopic and histologic examination of the aneurysm. RESULTS Direct injection of 0.2 mL fluorescein 10% Faure achieved strong, clear visibility in all 48 aneurysms. Macro-/microscopic examination identified residual perfusion in 25 and complete healing in 23 aneurysms. Fluorescein imaging identified 21 of these 25 aneurysms (84%) with residual perfusion and 22 of 23 aneurysms (96%) with no residual perfusion. CONCLUSION Our fluorescein imaging technique proved efficient for the evaluation of aneurysm patency and parent artery integrity in this experimental setting. Fluorescein is nontoxic, can be re-administered if needed, and, in this technique, can expand the armamentarium for the preclinical evaluation of dynamic perfusion status.

Background and Purpose: Endovascular aneurysm treatment relies on a biological process, including cell migration for thrombus organization and growth of a neointima. To better understand aneurysm healing, our study explores the origin of neointima-forming and thrombus-organizing cells in a rat saccular sidewall aneurysm model. Methods: Saccular aneurysms were transplanted onto the abdominal aorta of male Lewis rats and endovascularly treated with coils (n=28) or stents (n=26). In 34 cases, GFP+ (green fluorescent protein)-expressing vital aneurysms were sutured on wild-type rats, and in 23 cases, decellularized wild-type aneurysms were sutured on GFP+ rats. Follow-up at 3, 7, 14, 21, and 28 days evaluated aneurysms by fluorescence angiography, macroscopic inspection, and microscopy for healing and inflammation status. Furthermore, the origin of cells was tracked with fluorescence histology. Results: In animals with successful functional healing, histological studies showed a gradually advancing thrombus organization over time characterized by progressively growing neointima from the periphery of the aneurysm toward the center. Cell counts revealed similar distributions of GFP+ cells for coil or stent treatment in the aneurysm wall (54.4% versus 48.7%) and inside the thrombus (20.5% versus 20.2%) but significantly more GFP+ cells in the neointima of coiled (27.2 %) than stented aneurysms (10.4%; P =0.008). Conclusions: Neointima formation and thrombus organization are concurrent processes during aneurysm healing. Thrombus-organizing cells originate predominantly in the parent artery. Neointima formation relies more on cell migration from the aneurysm wall in coiled aneurysms but receives greater contributions from cells originating in the parent artery in stent-treated aneurysms. Cell migration, which allows for a continuous endothelial lining along the parent artery’s lumen, may be a prerequisite for complete aneurysm healing after endovascular therapy. In terms of translation into clinical practice, these findings may explain the variability in achieving complete aneurysm healing after coil treatment and the improved healing rate in stent-assisted coiling.

Background: Biological processes that lead to aneurysm formation, growth and rupture are insufficiently understood. Vessel wall inflammation and degeneration are suggested to be the driving factors. In this study, we aimed to investigate the natural course of vital (non-decellularized) and decellularized aneurysms in a rabbit sidewall and bifurcation model. Methods: Arterial pouches were sutured end-to-side on the carotid artery of New Zealand White rabbits (vital [n = 6] or decellularized [n = 6]), and into an end-to-side common carotid artery bifurcation (vital [n = 6] and decellularized [n = 6]). Patency was confirmed by fluorescence angiography. After 28 days, all animals underwent magnetic resonance and fluorescence angiography followed by aneurysm harvesting for macroscopic and histological evaluation. Results: None of the aneurysms ruptured during follow-up. All sidewall aneurysms thrombosed with histological inferior thrombus organization observed in decellularized compared to vital aneurysms. In the bifurcation model, half of all decellularized aneurysms thrombosed whereas the non-decellularized aneurysms remained patent with relevant increase in size compared to baseline. Conclusions: Poor thrombus organization in decellularized sidewall aneurysms confirmed the important role of mural cells in aneurysm healing after thrombus formation. Several factors such as restriction by neck tissue, small dimensions and hemodynamics may have prevented aneurysm growth despite pronounced inflammation in decellularized aneurysms. In the bifurcation model, rarefication of mural cells did not increase the risk of aneurysm growth but tendency to spontaneous thrombosis.

Background and purposeDespite significant technical advances, recanalization rates after endovascular therapy of ruptured intracranial aneurysms (IAs) remain a clinical challenge. A histopathological hallmark of ruptured human IA walls is mural cell loss. Mural smooth muscle cells (SMCs) are known to promote intraluminal healing in thrombosed experimental aneurysms. In this rat model we assess the natural history and healing process after coil embolization in SMC-rich and decellularized aneurysms.MethodsSaccular aneurysms were created by end-to-side anastomosis of an arterial graft from the descending thoracic aorta of a syngeneic donor rat to the infrarenal abdominal aorta of recipient male Wistar rats. Untreated arterial grafts were immediately transplanted, whereas aneurysms with loss of mural cells were chemically decellularized before implantation. Aneurysms underwent coil implantation during aneurysm anastomosis. Animals were randomly assigned either to the non-decellularized or decellularized group and underwent macroscopic and histological analyses on days 3, 7, 21, or 90 post-coil implantation.ResultsA total of 55 rats underwent macroscopic and histologic analysis. After coil embolization, aneurysms with SMC-rich walls showed a linear course of thrombosis and neointima formation whereas decellularized aneurysms showed marked inflammatory wall degeneration with increased recanalization rates 21 days (p=0.002) and 90 days (p=0.037) later. The SMCs showed the ability to actively migrate into the intra-aneurysmal thrombus and participate in thrombus organization.ConclusionsCoil embolization of aneurysms with highly degenerated walls is prone to further wall degeneration, increased inflammation, and recanalization compared with aneurysms with vital SMC-rich walls.

BackgroundAdvances in stent-assisted coiling have incrementally expanded endovascular treatment options for complex cerebral aneurysms. After successful coil consolidation and aneurysm occlusion, endovascular scaffolds are no longer needed. Thus, bioresorbable stents that disappear after aneurysm healing could avoid future risks of in-stent thrombosis and the need for lifelong antiplatelet therapy.ObjectiveTo assess the applicability and compatibility of a bioresorbable magnesium- alloy stent (brMAS) for assisted coiling.MethodsSaccular sidewall aneurysms were created in 84 male Wistar rats and treated with brMAS alone, brMAS + aspirin, or brMAS + coils + aspirin. Control groups included no treatment (natural course), solely aspirin treatment, or conventional cobalt–chromium stent + coils + aspirin treatment. After 1 and 4 weeks, aneurysm specimens were harvested and macroscopically, histologically, and molecularly examined for healing, parent artery perfusion status, and inflammatory reactions. Stent degradation was monitored for up to 6 months with micro-computed and optical coherence tomography.ResultsAneurysms treated with brMAS showed advanced healing, neointima formation, and subsequent stent degradation. Additional administration of aspirin sustained aneurysm healing while reducing stent-induced intraluminal and periadventitial inflammatory responses. No negative interaction was detected between platinum coils and brMAS. Progressive brMAS degradation was confirmed.ConclusionsbrMAS induced appropriate healing in this sidewall aneurysm model. The concept of using bioresorbable materials to promote complete aneurysm healing and subsequent stent degradation seems promising. These results should encourage further device refinements and clinical evaluation of this treatment strategy for cerebrovascular aneurysms.

Objective Catheter malpositioning is one of the most frequent causes of ventriculoperitoneal shunt dysfunction and revision surgery. Most intraoperative tools used to improve the accuracy of catheter insertion are time consuming and expensive or do not display the final position. We evaluate the usefulness of intraoperative fluoroscopy to decrease catheter malpositioning, and define radiological landmarks to identify the correct localization. Methods A total of 104 patients undergoing ventriculoperitoneal shunt placement were analyzed for shunt position, revision surgery and outcome. The results for patients operated on using intraoperative biplanar fluoroscopic assessment of catheter location (X-ray group, n = 57) were compared with a control group operated without intraoperative radiography (control, n = 47). In order to generate a surgical reference map for intraoperative validation of shunt location, different ventricular system landmarks were defined on three-dimensional computed tomography reconstructions of hydrocephalic patients (n = 60) and exported to a two-dimensional layer of the skull. Results The use of intraoperative X-ray imaging correlated with a significant increase of optimal catheter positions (X-ray group, n = 45, 79%; control group, n = 23, 49%; P = 0.0018). The sensitivity and positive predictive value for estimating an optimal shunt catheter position on biplanar imaging was 96% (95% confidence interval, 87%–99%). The specificity and negative predictive value were both 92% (95% confidence interval, 78%–98%). Conclusions Intraoperative fluoroscopy is easy to perform and is a reliable method to assess correct catheter positioning. Based on its predictive value, corrections of malpositioned ventricular catheters can be performed during the same procedure. The use of intraoperative fluoroscopy decreases early surgical revisions in ventriculoperitoneal shunt treatment.

Objective Catheter malposition represents one of the major causes of ventriculoperitoneal (VP) shunt dysfunction. The usefulness of intraoperative fluoroscopy using skull landmarks has already been proved to decrease catheter malposition and surgical revision rates. After introducing intraoperative computed tomography (iCT) in our department, our objective was to evaluate the accuracy of this imaging modality to decrease cranial catheter misplacement compared with intraoperative fluoroscopy. Methods In our retrospective analysis of 152 patients, catheter placement was evaluated by iCT (n = 48) and biplane fluoroscopy (n = 57). A control group (n = 47) had no intraoperative imaging. Outcome measures included accuracy of ventricular catheter position, revision surgeries, and clinical outcomes. Results Ventricular catheter placement was accurate in 24/48 patients with iCT and 45/57 patients with fluoroscopy (P = 0.002) versus 23/47 patients in the control group. Sensitivity and positive predictive value for estimating optimal catheter position with iCT were 100% and 54%. The specificity and negative predictive value were 50% and 100%. After intraoperative revision, 4 catheters remained malpositioned in the iCT group, whereas the fluoroscopy group had none (P = 0.03); 2 of these 4 catheters were revised postoperatively. Conclusions Fluoroscopy may be the method of choice to intraoperatively assess ventricular catheter positioning. In our experience, iCT shows a tendency to be more time consuming and, in the beginning, was not associated with a steeper learning curve. Another consideration was the significant higher radiation exposure per patient. iCT did not improve the accuracy of catheter placement and did not decrease early revisions for VP placement patients.

Background and Purpose— To identify predictors of in-hospital mortality in patients with aneurysmal subarachnoid hemorrhage and to estimate their impact. Methods— Retrospective analysis of prospective data from a nationwide multicenter registry on all aneurysmal subarachnoid hemorrhage cases admitted to a tertiary neurosurgical department in Switzerland (Swiss SOS [Swiss Study on Aneurysmal Subarachnoid Hemorrhage]; 2009–2015). Both clinical and radiological independent predictors of in-hospital mortality were identified, and their effect size was determined by calculating adjusted odds ratios (aORs) using multivariate logistic regression. Survival was displayed using Kaplan–Meier curves. Results— Data of n=1866 aneurysmal subarachnoid hemorrhage patients in the Swiss SOS database were available. In-hospital mortality was 20% (n=373). In n=197 patients (10.6%), active treatment was discontinued after hospital admission (no aneurysm occlusion attempted), and this cohort was excluded from analysis of the main statistical model. In the remaining n=1669 patients, the rate of in-hospital mortality was 13.9% (n=232). Strong independent predictors of in-hospital mortality were rebleeding (aOR, 7.69; 95% confidence interval, 3.00–19.71; P P P =0.003), and new infarction post-treatment (aOR, 2.57; 95% confidence interval, 1.43–4.62; P =0.002). Conclusions— Several—and among them modifiable—factors seem to be associated with in-hospital mortality after aneurysmal subarachnoid hemorrhage. Our data suggest that strategies aiming to reduce the risk of rebleeding are most promising in patients where active treatment is initially pursued. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT03245866.

Resection of left hemisphere (LH) tumors is often complicated by the risks of causing language dysfunction. Although neurosurgeons' concerns when operating on the presumed dominant hemisphere are well known, literature evaluating laterality as a predictive surgical parameter in glioblastoma (GB) patients is sparse. We evaluated whether tumor laterality correlated with surgical performance, functional outcome, and survival.All patients with GB treated at our institution between 2006 and 2016 were reviewed. Analysis comprised clinical characteristics, extent of resection (EOR), neurologic outcome, and survival in relation to tumor lateralization.Two hundred thirty-five patients were included. Right hemisphere (RH) tumors were larger and more frequently extended into the frontal lobe. Preoperatively, limb paresis was more frequent in RH, whereas language deficits were more frequent in LH tumors (P = 0.0009 and P0.0001, respectively). At 6 months after resection, LH patients presented lower Karnofsky Performance Status (KPS) score (P = 0.036). More patients with LH tumors experienced dysphasia (P0.0001), and no difference was seen for paresis. Average EOR was comparable, but complete resection was achieved less often in LH tumors (37.7 vs. 64.8%; P = 0.0028). Although overall survival did not differ between groups, progression-free survival was shorter in LH tumors (7.4 vs. 10.1 months; P = 0.0225).Patients with LH tumors had a pronounced KPS score decline and shorter progression-free survival without effects on overall survival. This observation might partially be attributed to a more conservative surgical resection. Further investigation is needed to assess whether systematic use of awake surgery and intraoperative mapping results in increased EOR and improved quality survival of patients with GB.

Magnetic Resonance Image-guided Focused Ultrasound (MRgFUS) has been used to achieve transient blood brain barrier (BBB) opening without tissue injury. Delivery of a targeted ultrasonic wave causes an interaction between administered microbubbles and the capillary bed resulting in enhanced vessel permeability. The use of MRgFUS in the brainstem has not previously been shown but could provide value in the treatment of tumours such as Diffuse Intrinsic Pontine Glioma (DIPG) where the intact BBB has contributed to the limited success of chemotherapy. Our primary objective was to determine whether the use of MRgFUS in this eloquent brain region could be performed without histological injury and functional deficits. Our secondary objective was to select an effective chemotherapeutic against patient derived DIPG cell lines and demonstrate enhanced brainstem delivery when combined with MRgFUS in vivo. \ud \ud \ud \ud Female Sprague Dawley rats were randomised to one of four groups: 1) Microbubble administration but no MRgFUS treatment; 2) MRgFUS only; 3) MRgFUS + microbubbles; and 4) MRgFUS + microbubbles + cisplatin. Physiological assessment was performed by monitoring of heart and respiratory rates. Motor function and co-ordination were evaluated by Rotarod and grip strength testing. Histological analysis for haemorrhage (H & E), neuronal nuclei (NeuN) and apoptosis (cleaved Caspase-3) was also performed. A drug screen of eight chemotherapy agents was conducted in three patient-derived DIPG cell lines (SU-DIPG IV, SU-DIPG XIII and SU-DIPG XVII). Doxorubicin was identified as an effective agent. NOD/SCID/GAMMA (NSG) mice were subsequently administered with 5 mg/kg of intravenous doxorubicin at the time of one of the following: 1) Microbubbles but no MRgFUS; 2) MRgFUS only; 3) MRgFUS + microbubbles and 4) no intervention. Brain specimens were extracted at 2 h and doxorubicin quantification was conducted using liquid chromatography mass spectrometry (LC/MS). \ud \ud \ud \ud BBB opening was confirmed by contrast enhancement on T1-weighted MR imaging and positive Evans blue staining of the brainstem. Normal cardiorespiratory parameters were preserved. Grip strength and Rotarod testing demonstrating no decline in performance across all groups. Histological analysis showed no evidence of haemorrhage, neuronal loss or increased apoptosis. \ud \ud \ud \ud Doxorubicin demonstrated cytotoxicity against all three cell lines and is known to have poor BBB permeability. Quantities measured in the brainstem of NSG mice were highest in the group receiving MRgFUS and microbubbles (431.5 ng/g). This was significantly higher than in mice who received no intervention (7.6 ng/g). \ud \ud \ud \ud Our data demonstrates both the preservation of histological and functional integrity of the brainstem following MRgFUS for BBB opening and the ability to significantly enhance drug delivery to the region, giving promise to the treatment of brainstem-specific conditions.

The steady progess in the armamentarium of techniques available for endovascular treatment of intracranial aneurysms requires affordable and reproducable experimental animal models to test novel embolization materials such as stents and flow diverters. The aim of the present project was to design a safe, fast, and standardized surgical technique for stent assisted embolization of saccular aneurysms in a rat animal model. Saccular aneurysms were created from an arterial graft from the descending aorta.The aneurysms were microsurgically transplanted through end-to-side anastomosis to the infrarenal abdominal aorta of a syngenic male Wistar rat weighing >500 g. Following aneurysm anastomosis, aneurysm embolization was performed using balloon expandable magnesium stents (2.5 mm x 6 mm). The stent system was retrograde introduced from the lower abdominal aorta using a modified Seldinger technique. Following a pilot series of 6 animals, a total of 67 rats were operated according to established standard operating procedures. Mean surgery time, mean anastomosis time, and mean suturing time of the artery puncture site were 167 ± 22 min, 26 ± 6 min and 11 ± 5 min, respectively. The mortality rate was 6% (n=4). The morbidity rate was 7.5% (n=5), and in-stent thrombosis was found in 4 cases (n=2 early, n=2 late in stent thrombosis). The results demonstrate the feasibility of standardized stent occlusion of saccular sidewall aneurysms in rats - with low rates of morbidity and mortality. This stent embolization procedure combines the opportunity to study novel concepts of stent or flow diverter based devices as well as the molecular aspects of healing.

Objective To evaluate implant accuracy and cosmetic outcome of a new intraoperative patient-specific cranioplasty method after convexity meningioma resection. Methods The patient's own bone flap served as a template to mold a negative form with the use of polymethyl methacrylate (PMMA). The area of bone invasion was determined and broadly excised under white light illumination with a safety margin of at least 1 cm. The definitive replica was cast within the remaining bone flap frame and the imprint. Clinical and radiologic follow-up examinations were performed 3 months after surgery. Results Four women and two men (mean age 51.4 years ± 12.8) underwent reconstruction of bone flap defects after meningioma resection. Mean duration of intraoperative reconstruction of the partial bone flap defects was 19 minutes ± 4 (range 14–24 minutes). Implant sizes ranged from 17–35 cm2 (mean size 22 cm2 ± 8). Radiologic and clinical follow-up examinations revealed excellent implant alignment and favorable cosmesis (visual analogue scale for cosmesis [VASC] = 97 ± 5) in all patients. Conclusions Patient-specific reconstruction of partial bone flap defects after convexity meningioma resection using the presented intraoperative PMMA cast method resulted in excellent bony alignment and a favorable cosmetic outcome. Relatively low costs and minimized operation time for adjustment and insertion of the cranioplasty implant justify use of this method in small bony defects as well.

The Central Brain Tumor Registry of the USA estimates the annual incidence of primary brain and central nervous system (CNS) tumors at 7.3/100,000 for malignant and 13.3/100,000 for nonmalignant tumors. A true comparison of incidence numbers across different time periods and countries is difficult given the inconsistency of data collection methods and the diversity in diagnostic criteria. Available diagnosis rates for malignant gliomas spanning the last three decades do not allow the determination of an increase or decline of age adapted incidence (Ohgaki and Kleihues, Acta Neuropathol 109:93–108, 2005; Ostrom et al., Neuro Oncol 16:896–913, 2014), despite remarkable changes of environment and lifestyle in industrial nations.

Medulloblastoma is a malignant embryonic brain tumor arising in the posterior fossa and typically occurring in pediatric patients. Current multimodal treatment regimes have significantly improved the survival rates; however, a marked heterogeneity in therapy response is observed, and one third of all patients die within 5 years after diagnosis. Large-scale genetic and transcriptome analysis revealed four medulloblastoma subgroups (WNT, SHH, Group 3, and Group 4) associated with different demographic parameters, tumor manifestation, and clinical behavior. Future treatment protocols will integrate molecular classification schemes to evaluate subgroup-specific intensification or de-escalation of adjuvant therapies aimed to increase tumor control and reduce iatrogenic induced morbidity. Furthermore, the identification of genetic drivers allows assessing target therapies in order to increase the chemotherapeutic armamentarium. This review highlights the biology behind the current classification system and elucidates relevant aspects of the disease influencing forthcoming clinical trials.

Patients with spontaneous non-aneurysmal subarachnoid hemorrhage (non-aSAH) are considered to have a benign illness in contrast to patients with aSAH. The occurrence of the systemic inflammatory response syndrome has been linked to worse outcomes in patients with aSAH. We analyzed systemic interleukin (IL)-6, a proinflammatory cytokine, to determine whether its concentration differs between patients with non-aSAH and those with aSAH, reflecting the more benign illness. Daily systemic IL-6 levels were measured in the acute phase in 11 patients with non-aneurysmal perimesencephalic SAH (pmSAH), with bleeding strictly located around the midbrain, and in nine patients with non-aneurysmal non-perimesencephalic (non-pmSAH), with hemorrhage extending into adjacent cisterns (group 1). IL-6 levels were compared with those from patients suffering from aSAH with cerebral vasospasm (CVS) (group 2) and without CVS (group 3). The mean IL-6 level (±standard error of the mean) was significantly lower in group 1 compared to group 2 (9.9 ± 1.9 vs. 29.1 ± 6.7 pg/mL, p = 0.018). The difference in mean IL-6 level between group 1 and 3 fell short of significance (9.9 ± 1.9 vs. 14.9 ± 1.1 pg/mL, p = 0.073). Patients in group 1 had a significantly better outcome (Glasgow Outcome Scale score 4–5) compared to group 2 (p < 0.001) and a trend towards better outcome compared to group 3 (p = 0.102). A subgroup analysis revealed a higher mean IL-6 concentration in patients with non-pmSAH compared to patients with pm-SAH (p = 0.001). We concluded that systemic IL-6 concentration reflects the severity of the inflammatory stress response and course of the illness. The more benign illness and good prognosis of patients with pmSAH or non-pmSAH in contrast to patients with aSAH is reflected by the lower concentrations of IL-6.

5-aminolevulinic acid (5-ALA) has gained importance as an intraoperative photodynamic diagnostic agent for the extirpation of malignant gliomas. The application of this technique for resection of meningiomas has barely been explored. The aim of this study was to evaluate the utility of 5-ALA-induced fluorescence as a visual tool in meningioma resection and its correlation with histological findings.A total of 33 consecutive patients undergoing resection of intracranial meningiomas from December 2007 to August 2009 were included in this study. After confirmation of normal liver function, 5-ALA was administered orally (20 mg/kg) within 3-5 h prior to skin incision. All cases were operated on using standard microsurgical and neuronavigation-guided techniques. Intraoperative 440 nm fluorescence was applied periodically during and at the end of resection in order to detect tumor-infiltrated sites. The fluorescence of the tumor was evaluated intraoperatively by the surgeon and confirmed by subsequent video analysis.A total of 32 (97%) patients presented with benign meningiomas (WHO I-II). In 1 (3%) patient, histological anaplastic signs (WHO III) could be demonstrated. 5-ALA-induced fluorescence of the tumor was confirmed in a total of 31 (94%) patients. The fluorescence did not correlate with the histological findings (n = 30 WHO I-II, n = 1 WHO grade III) or with preoperative brain edema and administration of steroids. A total resection could be postoperatively demonstrated in 25 (76%) patients. No adverse effects attributable to 5-ALA occurred.5-ALA-induced fluorescence is a useful and promising intraoperative tool for the visualization of meningioma tissue. The novel findings demonstrated in this study in terms of high fluorescence and poor correlation with histological findings highlight the usefulness of this technique as a routine visual tool to achieve optimal resection of meningiomas.

Recent advances in the development of high-throughput genotyping platforms allow for the unbiased identification of genes and genomic sequences related to heritable traits. In this study, we analyzed human short-term memory, which refers to the ability to remember information over a brief period of time and which has been found disturbed in many neuropsychiatric conditions, including schizophrenia and depression. We performed a genome-wide survey at 909 622 polymorphic loci and report six genetic variations significantly associated with human short-term memory performance after genome-wide correction for multiple comparisons. A polymorphism within SCN1A (encoding the alpha subunit of the type I voltage-gated sodium channel) was replicated in three independent populations of 1699 individuals. Functional magnetic resonance imaging during an n-back working memory task detected SCN1A allele-dependent activation differences in brain regions typically involved in working memory processes. These results suggest an important role for SCN1A in human short-term memory.

Conditions with chronically elevated glucocorticoid levels are usually associated with declarative memory deficits. Considerable evidence suggests that long-term glucocorticoid exposure may cause cognitive impairment via cumulative and long-lasting influences on hippocampal function and morphology. However, because elevated glucocorticoid levels at the time of retention testing are also known to have direct impairing effects on memory retrieval, it is possible that such acute hormonal influences on retrieval processes contribute to the memory deficits found with chronic glucocorticoid exposure. To investigate this issue, we examined memory functions and hippocampal volume in 24 patients with rheumatoid arthritis who were treated either chronically (5.3 ± 1.0 years, mean ± SE) with low to moderate doses of prednisone (7.5 ± 0.8 mg, mean ± SE) or without glucocorticoids. In both groups, delayed recall of words learned 24 h earlier was assessed under conditions of either elevated or basal glucocorticoid levels in a double-blind, placebo-controlled crossover design. Although the findings in this patient population did not provide evidence for harmful effects of a history of chronic prednisone treatment on memory performance or hippocampal volume per se, acute prednisone administration 1 h before retention testing to either the steroid or nonsteroid group impaired word recall. Thus, these findings indicate that memory deficits observed under chronically elevated glucocorticoid levels result, at least in part, from acute and reversible glucocorticoid effects on memory retrieval.

OBJECT Choroid plexus carcinomas (CPCs) are rare brain tumors originating from the ventricular choroid plexus. They account for 2%–4% of all pediatric brain tumors and are most frequently seen in very young children. This pediatric proclivity, in combination with a marked vascularity, renders an aggressive resection a difficult and often dangerous endeavor. Blood losses of several total blood volumes in small children are not uncommon, sometimes forcing the neurosurgeon to abort the procedure, often leaving residual tumor. Great extent of tumor resection is an accepted beneficial factor for overall survival. Therefore, a second resection usually follows the administration of adjuvant chemotherapy. Second-look surgery appears to be associated with markedly decreased blood loss. Histological examination of specimens obtained at a second intervention shows decreased vascularity and fibrotic changes in tumor tissue. At the Hospital for Sick Children in Toronto, this empirical finding led to the strategy of neoadjuvant chemotherapy to minimize blood loss and maximize cytoreduction. The authors undertook this study to assess the potentially beneficial effect of neoadjuvant chemotherapy on blood loss during surgery for CPCs. METHODS In this retrospective cohort review, the demographic, clinical, and treatment parameters of 22 consecutive patients diagnosed with CPC are presented. All underwent surgical treatment at the Hospital for Sick Children from 1982 to 2013. Special attention was given to the impact of neoadjuvant chemotherapy on extent of resection and intraoperative blood loss. Extent of resection was calculated based on perioperative neuroimaging, and amount of blood loss was estimated based on transfusion parameters and perioperative changes in hematocrit. RESULTS Ten patients did not receive neoadjuvant chemotherapy, and 12 were treated with 2–5 cycles of ICE (ifosfamide, carboplatin, etoposide) chemotherapy in a neoadjuvant fashion. The 22 patients included in the study underwent a total of 37 tumor resection surgeries. In all of the cases in which neoadjuvant chemotherapy was used, at least a near-total resection (> 95% of tumor volume) was achieved. Patients who underwent gross-total resection had prolonged overall survival. Of the 37 resections, 18 were performed after chemotherapy. Mean blood loss in the neoadjuvant chemotherapy group was 22% of total estimated blood volume as opposed to 96% in patients without preoperative chemotherapy. CONCLUSIONS In children with CPC, the administration of neoadjuvant chemotherapy decreases intraoperative blood loss and increases extent of resection with a significant positive effect on overall survival.

OBJECTIVE The New Zealand White (NZW) rabbit model is an established animal model for examining surgical methods to prevent epidural scar formation after spine surgery. As most approaches include complete laminectomy of the rabbit vertebra, this procedure is associated with high morbidity and mortality rates. We examined a less invasive technique, the microsurgical interlaminotomy, for testing epidural substance application in the rabbit spine. METHODS Surgery was performed in the cadaver rabbit spine to evaluate the approach before performing it in NZW rabbits. All surgical procedures were performed under an operation microscope. Female rabbits with a mean weight of 4770 g ± 240 g were used. Neurologic symptoms were analyzed based on predefined scores. After resection of the spinal process, the caudal part of the upper lamina was resected using a drill and a 1-mm Kerrison punch. The yellow ligament was resected resulting in a dural exposure of ∼ 5 × 10 mm. RESULTS Eight pilot interlaminotomies were performed on three cadaveric spines to establish the surgical approach. Twenty-one NZW rabbits were then operated on using the interlaminotomy model. Three rabbits (14.3%) died during surgery due to anesthesia-related complications. Two rabbits (9.5%) showed partial paresis of the lower extremities and one (4.8%) a complete paraplegia. The remaining 15 rabbits (71.4%) had an uneventful recovery without neurologic symptoms. The mean surgical duration was 88 +/- 28 minutes. CONCLUSION The rabbit interlaminotomy model is associated with few neurologic deficits and a relatively short operating time.

Human memory is a polygenic trait. We performed a genome-wide screen to identify memory-related gene variants. A genomic locus encoding the brain protein KIBRA was significantly associated with memory performance in three independent, cognitively normal cohorts from Switzerland and the United States. Gene expression studies showed that KIBRA was expressed in memory-related brain structures. Functional magnetic resonance imaging detected KIBRA allele–dependent differences in hippocampal activations during memory retrieval. Evidence from these experiments suggests a role for KIBRA in human memory.

OBJECTIVE Application of Medishield to the nerve root is common during spinal surgery to create a mechanical barrier from pain mediators and reduce scar formation. However, Medishield's signal characteristics on magnetic resonance imaging (MRI) have not yet been examined. METHODS Microsurgical interlaminotomy was performed on 2 lower lumbar segments in 17 adult New Zealand white rabbits. After dural exposure, applications of 1 mL (autologous blood clot or Medishield) were randomized for each level. On postoperative days 1 through 3, various MRI sequences in 1.5T were performed including T1-weighted, T2-w, T1-gadolinium-weighted, susceptibility-weighted and turbo inversion recovery magnitude (TIRM) sequence. Signaling characteristics were analyzed by 3 blinded observers. Inter-rater agreement was calculated using Fleiss's kappa coefficient (κ). Positive and negative likelihood ratios in detecting Medishield by MRI were determined. RESULTS Of 24 MRIs performed, TIRM sequence identified Medishield with the highest likelihood ratio. Medishield's positive likelihood ratio was highest (5.8) on postoperative day 1 with interobserver agreement of 93% (κ = 0.75); these rates declined to 2.5 and 1.4 on postoperative days 2 and 3 with interobserver agreements of 71% (κ = 0.43) and 83% (κ = 0.67), respectively. Medishield adherence was confirmed in each rabbit by histologic examinations. CONCLUSION Understanding that radiologic detection of Medishield diminished over time as its signal characteristics became less distinguishable from a blood clot is essential in clinical practice. Medishield was detected on postoperative day 1 but not 2 days later after hemodynamic changes had occurred. These results may provide a guide for postoperative findings, such as differential diagnosis of hematoma.

The recently introduced rabbit blood shunt subarachnoid haemorrhage model is based on the two standard procedures of subclavian artery cannulation and transcutaneous cisterna magna puncture. An extracorporeal shunt placed in between the arterial system and the subarachnoid space allows examiner-independent SAH in a closed cranium. Despite its straightforwardness, it is worth examining some specific features and characteristics of the model. We outline technical considerations to successfully perform the model with minimal mortality and morbidity. In addition, we discuss outcome measures, advantages and limitations, and the applicability of the model for the study of early brain injury and delayed cerebral vasospasm after SAH.

The recently introduced rabbit blood shunt subarachnoid haemorrhage model is based on the two standard procedures of subclavian artery cannulation and transcutaneous cisterna magna puncture. An extracorporeal shunt placed in between the arterial system and the subarachnoid space allows examiner-independent SAH in a closed cranium. Despite its straightforwardness, it is worth examining some specific features and characteristics of the model. We outline technical considerations to successfully perform the model with minimal mortality and morbidity. In addition, we discuss outcome measures, advantages and limitations, and the applicability of the model for the study of early brain injury and delayed cerebral vasospasm after SAH.

Introduction: Focused ultrasound (FUS) can penetrate soft tissue noninvasively and induce physiological effects deep within target tissues. MR-image guidance, lesioning precision, sparing of healthy tissue and absence of ionizing radiation make FUS an ideal modality for brain interventions. Based on the encouraging results in treating patients with chronic pain or movement disorders through thermal ablation of thalamic and subthalamic targets, noninvasive transcranial MR guided focused ultrasound (tcMRgFUS) recently received CE marking for functional neurosurgery. Here, we report the world’s first successful application of noninvasive tcMRgFUS for tumor ablation in a patient suffering from a centrally located malignant glioma. Case Report: A 63 year old patient presented in our clinic with tumor recurrence in the left thalamic and subthalamic region five years after first surgery for a glioblastoma. After giving informed written consent he was included in our ongoing clinical phase-1 study on the feasibility and safety of tcMRgFUS for the treatment of brain tumors. Due to the location of the tumor within eloquent brain areas and considering previous radiotherapy and various cycles of different chemotherapeutics, surgical resection was excluded as a treatment option. The tcMRgFUS procedure was performed using the ExAblate Neuro® system (InSightec Ltd, Haifa, Israel) integrated into a clinical 3T MR system (GE Healthcare, Little Chalfont, UK). The patient received local anesthesia for positioning a stereotactic frame (Integra LifeSciences Corporation, New Jersey, USA), and prophylactic administration of paracetamol and ondansetron for preventing pain or nausea. Post-interventional assessment included follow-up MRI immediately after and on days 1, 5 and 21 after the procedure. The patient was awake and responsive during the whole intervention with stable neurological assessment and without additional medication needed. In the 3 hours lasting procedure, a total of 25 sonications were applied with up to 19'550 Joules of acoustic energy. 17 sonications reached ablative temperatures of over 55°C with a maximum of 65°C, as recorded by intraoperative realtime MR thermometry. MRI scans acquired immediately after the intervention revealed significant lesions to the sonicated tumor tissue that were particularly well visible in DWI and ADC maps. Later on, contrast-enhanced MRI showed well-circumscribed volumes of non-perfused tissue, indicative for ablated tumor tissue. As expected from earlier experience, perifocal edema developed around the thermal lesions, but gradually disappeared during the follow-up period. Neurological examination on day 5 revealed improvement of the preexisting right arm paresis while no additional neurological deficits were observed. Conclusion: The successful ablation of a brain tumor demonstrates the feasibility of noninvasive tcMRgFUS tumor surgery. Further clinical interventions in the context of our ongoing clinical phase I study will be needed to assess the safety and efficacy of tcMRgFUS for brain tumor treatment and its relevance for future treatment strategies against brain tumors.

Aneurysm volume is routinely approximated calculating cylindrical volumes. Exact aneurysm volume assessment is crucial for liquid polymer embolization. The aim of this study was to compare simple cylindrical volume approximations with direct multiplanar reconstruction (MPR) segmentational volumetry in a saccular/complex experimental rabbit bifurcation aneurysm model.In 12 female New Zealand white rabbits, saccular, broad-based, bilobular, and bisaccular aneurysms (three of each) were created using the rabbit venous pouch bifurcation model. Contrast-enhanced magnetic resonance angiography (CE-MRA) was performed, and maximal intensity projection (MIP) reconstructions as well as an MPR dataset were acquired. Aneurysm width and length were measured in MIP images, and the volume was approximated calculating cylindrical volumes. Three-dimensional (3D) segmentational volumetry using the MPR dataset was performed in a semi-automated manner.Maximal intensity projection cylindrical volumes ranged from 53·6 to 503·5 mm(3) (mean 186·5±118 mm(3)). Multiplanar reconstruction segmentation-based volumes ranged from 74·7 to 581·0 mm(3) (mean 202·2±133 mm(3)). The mean relative difference between MIP cylindrical and MPR segmentation volume calculation was 24·7% (range -77·5 to +50·8%). Only 4 of 12 MPR segmentational volumes were within a 10% range of results calculated for MIP cylindrical volume, and 3 of those were in broad-based aneurysms.This descriptive study demonstrates that estimated MIP cylindrical volumes differ from those measured by MPR segmentation volumetry. With the increasing acquisition of 3D data as 3D-MRA and the increasing need for exact volume determination, studies on the accuracy of computational segmentational volumetry of CE-MRA are necessary.

Object The accurate discrimination between tumor and normal tissue is crucial for determining how much to resect and therefore for the clinical outcome of patients with brain tumors. In recent years, guidance with 5-aminolevulinic acid (5-ALA)–induced intraoperative fluorescence has proven to be a useful surgical adjunct for gross-total resection of high-grade gliomas. The clinical utility of 5-ALA in resection of brain tumors other than glioblastomas has not yet been established. The authors assessed the frequency of positive 5-ALA fluorescence in a cohort of patients with primary brain tumors and metastases. Methods The authors conducted a single-center retrospective analysis of 531 patients with intracranial tumors treated by 5-ALA–guided resection or biopsy. They analyzed patient characteristics, preoperative and postoperative liver function test results, intraoperative tumor fluorescence, and histological data. They also screened discharge summaries for clinical adverse effects resulting from the administration of 5-ALA. Intraoperative qualitative 5-ALA fluorescence (none, mild, moderate, and strong) was documented by the surgeon and dichotomized into negative and positive fluorescence. Results A total of 458 cases qualified for final analysis. The highest percentage of 5-ALA–positive fluorescence in open resection was found in glioblastomas (96%, n = 99/103). Among other tumors, 5-ALA–positive fluorescence was detected in 88% (n = 21/32) of anaplastic gliomas (WHO Grade III), 40% (n = 8/19) of low-grade gliomas (WHO Grade II), no (n = 0/3) WHO Grade I gliomas, and 77% (n = 85/110) of meningiomas. Among metastases, the highest percentage of 5-ALA–positive fluorescence was detected in adenocarcinomas (48%, n = 13/27). Low rates or absence of positive fluorescence was found among pituitary adenomas (8%, n = 1/12) and schwannomas (0%, n = 0/7). Biopsies of high-grade primary brain tumors showed positive rates of fluorescence similar to those recorded for open resection. No clinical adverse effects associated with use of 5-ALA were observed. Only 1 patient had clinically silent transient elevation of liver enzymes. Conclusions Study findings suggest that the administration of 5-ALA as a surgical adjunct for resection and biopsy of primary brain tumors and brain metastases is safe. In light of the high rate of positive fluorescence in high-grade gliomas other than glioblastomas, meningiomas, and a variety of metastatic cancers, 5-ALA seems to be a promising tool for enhancing intraoperative identification of neoplastic tissue and optimizing the extent of resection.

In experimental aneurysm models, long-term patency without spontaneous thrombosis is the most important precondition for analyses of embolization devices. We recently reported the feasibility of creating complex venous pouch bifurcation aneurysms in the rabbit with low morbidity, low mortality, and high short-term aneurysm patency. In order to further evaluate our model, we examined the long-term patency rate.Various sizes of complex bilobular, bisaccular, and broad-neck venous pouch aneurysms were surgically formed at an artificially created bifurcation of both common carotid arteries in 17 rabbits. Early aggressive anticoagulation was continued for 1 month. The rabbits were followed up using contrast-enhanced three-dimensional 1.5-T magnetic resonance angiography (CE-3D-MRA) at 1 month and up to 1 year after creation of the bifurcation.At 1-month follow-up, all but one of the created aneurysms and all parent vessels proved to be patent. Three animals (18%) were lost during follow-up for reasons unrelated to aneurysm surgery. At 1-year follow-up, one animal showed partial and one complete spontaneous aneurysm thrombosis (aneurysm patency rate: 86%). Six out of 42 parent vessels were occluded at that time (vessel patency rate: 86%).Complex bilobular, bisaccular, and broad-neck microsurgical aneurysm formation in the rabbit bifurcation model demonstrates a high long-term patency rate but is complicated by high rates of unrelated procedural mortality and morbidity. There is no need for prolonged (4 weeks) anticoagulation to achieve good long-term patency in complex venous pouch bifurcation aneurysms.

Objective Fluorescence-guided surgery for cranial meningioma has been reported to be useful. There are no reports about spinal cases using this technique. We report on a meningioma of the cervical spine for which fluorescence-guided surgery was used. Case Description A 78-year-old female patient with a meningioma located in the cervical spine underwent surgery using fluorescence guidance. After complete removal of the meningioma and removal and coagulation of the dural attachment (equal to Simpson grade II resection), a fluorescence-positive remnant could be identified and successfully removed. The remnant was found to harbor meningioma tissue on histological examination. Conclusions Fluorescence-guided microsurgery is helpful in achieving a total resection of spinal meningiomas, and might therefore reduce the risk of recurrence.

Human memory capacity is highly variable across individuals and is influenced by both genetic and environmental factors. A roughly 50% heritability estimate indicates that naturally occurring genetic variations have an important impact on this cognitive ability. Therefore, we investigated a functional variation of a memory-related serotonin receptor in 349 healthy young volunteers, and found 21% poorer memory performance in subjects with the rare variant.

BACKGROUND Recent clinical studies confirmed the high potential of MR-guided focused ultrasound (MRgFUS) in the field of functional neurosurgery. While its ability for precise thermo-ablation within soft tissue is widely recognized, the impact of high-intensity focused ultrasound (HIFU) on larger vessels is less explored. We used a bifurcation aneurysm model in rabbits to investigate the possible effects on the walls of vascular aneurysms and to assess the risk and prospect of this procedure for managing neurovascular disorders. METHODS Experimental bifurcation aneurysms were microsurgically created in New Zealand white rabbits and sonicated using MRgFUS. RESULTS A temperature of max. 54°C could be achieved close to the aneurysm, and the shape and size of the aneurysm were noticeably changed, as shown by MR angiography. CONCLUSIONS The presented rabbit model proved suitable and capable of being extended to acquire data on the effect of HIFU on aneurysms and larger vessels. The fact that HIFU led to an alteration of the aneurysm without inducing rupture encourages further investigations.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) allows for precise thermal ablation of target tissues. While this emerging modality is increasingly used for the treatment of various types of extracranial soft tissue tumors, it has only recently been acknowledged as a modality for noninvasive neurosurgery. MRgFUS has been particularly successful for functional neurosurgery, whereas its clinical application for tumor neurosurgery has been delayed for various technical and procedural reasons. Here, we report the case of a 63-year-old patient presenting with a centrally located recurrent glioblastoma who was included in our ongoing clinical phase I study aimed at evaluating the feasibility and safety of transcranial MRgFUS for brain tumor ablation. Applying 25 high-power sonications under MR imaging guidance, partial tumor ablation could be achieved without provoking neurological deficits or other adverse effects in the patient. This proves, for the first time, the feasibility of using transcranial MR-guided focused ultrasound to safely ablate substantial volumes of brain tumor tissue.