Edin Nevzati

Use of Fluorescence to Guide Resection or Biopsy of Primary Brain Tumors and Brain Metastases

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.

Estrogen Induces Nitric Oxide Production Via Nitric Oxide Synthase Activation in Endothelial Cells

INTRODUCTION 17β-estradiol (E2) has been found to induce vasodilation in the cardiovascular system and at physiological levels, resulting in prevention of cerebral vasospasm following subarachnoid hemorrhage (SAH) in animal models. The goal of this study was to analyze the cellular mechanism of nitric oxide (NO) production and its relation to E2, in vitro in brain and peripheral endothelial cells. METHODS Human umbilical endothelial cells (HUVEC) and brain endothelial cells (bEnd.3) were treated with estradiol (E2, 0.1, 10, 100, and 1,000 nM), and supernatant was collected at 0, 5, 15, 30, 60, and 120 min for nitric oxide metabolome (nitrite, NO₂) measurements. Cells were also treated with E2 in the presence of 1400W, a potent eNOS inhibitor, and ICI, an antagonist of estradiol receptors (ERs). Effects of E2 on eNOS protein expression were assessed with Western blot analysis. RESULTS E2 significantly increased NO2 levels irrespective of its concentration in both cell lines by 35 % and 42 % (p < 0.05). The addition of an E2 antagonist, ICI (10 μM), prevented the E2-induced increases in NO2 levels (11 % p > 0.05). The combination of E2 (10 nM) and a NOS inhibitor (1400W, 5 μM) inhibited NO2 increases in addition (4 %, p > 0.05). E2 induced increases in eNOS protein levels and phosphorylated eNOS (eNOS(p)). CONCLUSIONS This study indicates that E2 induces NO level increases in cerebral and peripheral endothelial cells in vitro via eNOS activation and through E2 receptor-mediated mechanisms. Further in vivo studies are warranted to evaluate the therapeutic value of estrogen for the treatment of SAH-induced vasospasm.

The Rabbit Shunt Model of Subarachnoid Haemorrhage

Aneurysmal subarachnoid haemorrhage (SAH) is a disease with devastating complications that leads to stroke, permanent neurological deficits and death. Clinical and ex-perimental work has demonstrated the importance of the contribution of delayed cerebral vasospasm (DCVS) indepen-dent early events to mortality, morbidity and functional out-come after SAH. In order to elucidate processes involved in early brain injury (EBI), animal models that reflect acute events of aneurysmal bleeding, such as increase in intracranial pressure (ICP) and decrease in cerebral perfusion pressure, are needed. In the presented arterial shunt model, bleeding is initially driven by the pressure gradient between mean arterial blood pressure and ICP. SAH dynamics (flow rate, volume and duration) depend on physiological reactions and local anatomical intrathecal (cistern) conditions. During SAH, ICP reaches a plateau close to diastolic arterial blood pressure and the blood flow stops. Historical background, anaesthesia, perioperative care and monitoring, SAH induction, technical considerations and advantages and limitations of the rabbit blood shunt SAH model are discussed in detail. Awareness of technical details, physiological characteristics and appropriate monitoring methods guarantees successful implementation of the rabbit blood shunt model and allows the study of both EBI and DCVS after SAH.

Validation and accuracy of intraoperative CT scan using the Philips AlluraXper FD20 angiography suite for assessment of spinal instrumentation

Abstract Background: With the concept of the hybrid operating room gaining popularity, the authors adapted a hybrid angiographic suite with intraoperative computed tomography (iCT) to evaluate accuracy of pedicle screw placement in spinal fusion. This retrospective review examines how well iCT detected extrapedicular screw violation, to then allow repositioning and potentially avoid revision surgery. Methods: A total of 36 consecutive patients underwent pedicle screw placement in posterior cervical, thoracic, and lumbosacral spinal fusions. All patients underwent iCT in the Philips AlluraXper FD20 angiography suite in the lumbar spine XperCT mode and postoperative conventional computed tomography (CT) scanning. Primary endpoints included the sensitivity and specificity of iCT in detecting pedicular violation characterized as minor, moderate, or severe when compared with postoperative CT. Secondary endpoint included the incidence of replaced screws during surgery and number of revision surgeries. Results: Of 241 screws placed in 16 males and 20 females, iCT detected severe pedicle violation in 25 screws (10.4%); 16 screws were then repositioned during surgery. Sensitivity and specificity of iCT to detect severe screw malposition were 92.3% and 99.1%, respectively. No revision surgeries were performed in this series. Conclusions: In our series, iCT had high sensitivity and specificity in detecting severe screw malposition. As a valuable adjunct for intraoperative assessment of pedicle screw position, immediate intraoperative correction of misplaced screws then eliminated any revision surgery for our patients.

Evaluation of a filament perforation model for mouse subarachnoid hemorrhage using 7.0 Tesla MRI

The filament perforation model (FPM) in mice is becoming increasingly popular to elucidate the molecular pathogenesis of neuronal injury after subarachnoid hemorrhage (SAH). We evaluated brain MRI in a mouse FPM. A total of 28 male C57Bl/6J mice were used. Seventeen animals underwent SAH induction by FPM. In two animals, transient middle cerebral artery occlusion (MCAo) was induced. Nine mice served as controls. T1-weighted images (T1WI), T2-weighted images (T2WI), T2(∗)-weighted images (T2*WI) and apparent diffusion coefficient maps were acquired at day 0 and at various time points following SAH (range: day 1-6 after SAH). Cerebral blood flow (CBF) analysis by (14)C-iodoamphetamine ((14)C-IMP) autoradiography was conducted in nine animals. Hemorrhage could be best confirmed using T2*WI. The degree of hemorrhage varied. All animals evaluated for ⩾2days were hydrocephalic, which was best seen on T2WI. T2-hyperintensity of the corpus callosum and external capsule, indicating white matter (WM) injury, was present after SAH. Ventricle and WM injury volumes were statistically significantly higher at day 3 compared to day 0. Territorial ischemia was detectable in MCAo but not in SAH. Markedly hypointense cortical veins were visible in the hyperacute and delayed phase after SAH on T2*WI. The (14)C-IMP analysis indicated decreased CBF after SAH. MRI is feasible and useful in evaluating pathophysiological changes over time. T2*WI seems best for SAH detection and grading. The chronological change of hydrocephalus and WM injury could be analyzed. T2*WI illustrated specific signal changes of cortical veins, possibly caused by increased oxygen extraction fraction due to decreased CBF.

An Interlaminotomy New Zealand White Rabbit Model to Evaluate Novel Epidural Strategies.

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.

Systematic Review of In Vivo Animal Models of Subarachnoid Hemorrhage: Species, Standard Parameters, and Outcomes

In preclinical models, modification of experimental parameters associated with techniques of inducing subarachnoid hemorrhage (SAH) can greatly affect outcomes. To analyze how parameter choice affects the relevance and comparability of findings, we systematically reviewed 765 experimental studies of in vivo animal SAH models (2000–2014). During the last decade, we found marked increases in publications using smaller species and models for simulating acute events after SAH. Overall, the fewer types of species and models used did not correlate with an increased standardization in the experimental characteristics and procedures. However, by species, commonly applied, reliable parameters for each experimental SAH technique were identified in mouse, rat, rabbit, and dog models. Our findings can serve as a starting point for discussion toward a more uniform performance of SAH experiments, development of preclinical SAH common data elements, and establishment of standardized protocols for multicenter preclinical trials.

Biodegradable Magnesium Stent Treatment of Saccular Aneurysms in a Rat Model - Introduction of the Surgical Technique

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.

Intraoperative Visualization of Bilateral Thrombosis in the Posterior Inferior Cerebellar Artery Apparent in the Telovelomedullary Segment

Unilateral posterior inferior cerebellar artery (PICA) thrombosis is frequent. However, bilateral PICA thrombosis is rare. Herein we report about an intraoperative visualization of a bilateral thrombosis of the telovelomedullary segment of the PICA. A 74-year-old woman was admitted to our department on day two of a bilateral PICA thrombosis with developing cerebellar infarction. Her Glasgow Coma Scale score dropped from 15 to 13, and cranial computed tomography revealed compression of the fourth ventricle with consecutive occlusive hydrocephalus. After the insertion of an external ventricular drainage, the patient underwent urgent suboccipital decompressive craniectomy with removal of infarcted cerebellar tonsils, which allowed the bilateral visualization of the thrombosed telovelomedullary segments. The surgical access may offer surgical therapeutic options in a hyperacute occlusion, such as thromb-/embolectomy or bypass procedures.