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Objective: Anemia predicts poor outcome following aneurysmal subarachnoid hemorrhage (SAH). We hypothesized that this association would be stronger among patients with more severe SAH, since these patients are likely to be more vulnerable to secondary brain injury in the form of reduced cerebral oxygen delivery.Methods: Daily nadir hemoglobin (Hb) concentrations over 2 weeks following SAH were retrieved in 245 consecutive patients, and compared between those with a favorable versus unfavorable outcome. The analysis was repeated with patients dichotomized as follows: WFNS score 4-5 vs. 1-3; modified Fisher score (MFS) 4 vs. 0-3; and vasospasm present vs. absent. Mixed effect models and multivariable analysis using the generalized estimating equation were employed to assess correlated data with repeated measures.Results: Patients with an unfavorable outcome consistently had lower Hb concentrations, especially between days 6-11 following SAH (P ranging from <0.001 to 0.009), as well as a greater fall in Hb over time (beta = -0.07, P < 0.001). This was true regardless of WFNS score, MFS, or the presence or absence of vasospasm. However, the effect was somewhat more pronounced among patients with higher WFNS and modified Fisher scores.Conclusion: Lower Hb levels are associated with worse outcomes regardless of SAH severity or the development of vasospasm. This finding may imply that a lower Hb concentration is largely a marker for a greater degree of systemic illness, rather than necessarily causing direct harm. However, the association is somewhat stronger among patients with more severe SAH. Thus, if there is a benefit for maintaining higher Hb levels with transfusions or erythropoietin, it may be more pronounced among these patients. [ABSTRACT FROM AUTHOR]

A 38-year-old female with a history of nausea, vomiting, headache, and neck pain underwent suboccipital craniectomy and CI laminectomy for resection of a cervical-medullary junction hemangioblastoma. Posterior tibial nerve somatosensory evoked potentials (SSEPs), median nerve SSEPs, and transcranial electrical motor evoked potentials (TCeMEPs) from arm and leg muscles were recorded bilaterally during the surgical procedure. Total intravenous anesthesia (TIVA) was used for anesthesia. Neuromuscular blockade levels were monitored with train of four (TOF). At the end of resection, left upper median nerve SSEP responses were lost. Postoperative sensory exam revealed a profound lack of fine touch and proprioception in the left arm, with intact motor strength. Magnetic resonance imaging (MRI) revealed no evidence of hemorrhage or edema. The patient slowly regained some sensory function over the next several days before being discharged home. At the time of discharge the patient continued to have markedly decreased sensation in the left arm, but was otherwise intact. In this case, SSEP was an effective method to predict sensory loss in one extremity in the presence of intact TCeMEP responses. [ABSTRACT FROM AUTHOR]

MR-guided focused ultrasound (MRgFUS) allows for the incisionless treatment of intracranial lesions in an outpatient setting. While this is currently approved for the surgical treatment of essential tremor and Parkinson's disease, advancements in imaging and ultrasound technology are allowing for the expansion of treatment indications to other intracranial diseases. In addition, these advancements are also making MRgFUS treatments easier, safer, and more efficacious., Competing Interests: Disclosure The authors describe no commercial or financial disclosures associated with this work., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Focused Ultrasound Foundation was created to improve the lives of millions of people worldwide by accelerating the development of this noninvasive technology. The Foundation works to clear the path to global adoption by organizing and funding research, fostering collaboration, and building awareness among patients and professionals. Since its establishment in 2006, the Foundation has become the largest nongovernmental source of funding for focused ultrasound research. For more information, visit http://www.fusfoundation.org ., (© 2021. The Author(s).)

Oncology and cerebrovascular disease constitute two of the most common diseases afflicting the central nervous system. Standard of treatment of these pathologies is based on multidisciplinary approaches encompassing combination of interventional procedures such as open and endovascular surgeries, drugs (chemotherapies, anti-coagulants, anti-platelet therapies, thrombolytics), and radiation therapies. In this context, therapeutic ultrasound could represent a novel diagnostic/therapeutic in the armamentarium of the surgeon to treat these diseases. Ultrasound relies on mechanical energy to induce numerous physical and biological effects. The application of this technology in neurology has been limited due to the challenges with penetrating the skull, thus limiting a prompt translation as has been seen in treating pathologies in other organs, such as breast and abdomen. Thanks to pivotal adjuncts such as multiconvergent transducers, magnetic resonance imaging (MRI) guidance, MRI thermometry, implantable transducers, and acoustic windows, focused ultrasound (FUS) is ready for prime-time applications in oncology and cerebrovascular neurology. In this review, we analyze the evolution of FUS from the beginning in 1950s to current state-of-the-art. We provide an overall picture of actual and future applications of FUS in oncology and cerebrovascular neurology reporting for each application the principal existing evidences.

OBJECTIVE In appropriate candidates, the treatment of medication-refractory mesial temporal lobe epilepsy (MTLE) is primarily surgical. Traditional anterior temporal lobectomy yields seizure-free rates of 60%-70% and possibly higher. The field of magnetic resonance-guided focused ultrasound (MRgFUS) is an evolving field in neurosurgery. There is potential to treat MTLE with MRgFUS; however, it has appeared that the temporal lobe structures were beyond the existing treatment envelope of currently available clinical systems. The purpose of this study was to determine whether lesional temperatures can be achieved in the target tissue and to assess potential safety concerns. METHODS Cadaveric skulls with tissue-mimicking gels were used as phantom targets. An ablative volume was then mapped out for a "virtual temporal lobectomy." These data were then used to create a target volume on the InSightec ExAblate Neuro system. The target was the amygdala, uncus, anterior 20 mm of hippocampus, and adjacent parahippocampal gyrus. This volume was approximately 5cm 3 . Thermocouples were placed on critical skull base structures to monitor skull base heating. RESULTS Adequate focusing of the ultrasound energy was possible in the temporal lobe structures. Using clinically relevant ultrasound parameters (power 900 W, duration 10 sec, frequency 650 kHz), ablative temperatures were not achieved (maximum temperature 46.1°C). Increasing sonication duration to 30 sec demonstrated lesional temperatures in the mesial temporal lobe structures of interest (up to 60.5°C). Heating of the skull base of up to 24.7°C occurred with 30-sec sonications. CONCLUSIONS MRgFUS thermal ablation of the mesial temporal lobe structures relevant in temporal lobe epilepsy is feasible in a laboratory model. Longer sonications were required to achieve temperatures that would create permanent lesions in brain tissue. Heating of the skull base occurred with longer sonications. Blocking algorithms would be required to restrict ultrasound beams causing skull base heating. In the future, MRgFUS may present a minimally invasive, non-ionizing treatment of MTLE.

Purpose: In the ongoing endeavor of fine-tuning, the clinical application of transcranial MR-guided focused ultrasound (tcMRgFUS), ex-vivo studies wlkiith whole human skulls are of great use in improving the underlying technology guiding the accurate and precise thermal ablation of clinically relevant targets in the human skull. Described here are the designs, methods for fabrication, and notes on utility of three different ultrasound phantoms to be used for brain focused ultrasound research., Methods: Three different models of phantoms are developed and tested to be accurate, repeatable experimental options to provide means to further this research. The three models are a cadaver, a gel-filled skull, and a head mold containing a skull and filled with gel that mimics the brain and the skin. Each was positioned in a clinical tcMRgFUS system and sonicated at 1100 W (acoustic) for 12 s at different locations. Maximum temperature rise as measured by MR thermometry was recorded and compared against clinical data for a similar neurosurgical target. Results are presented as heating efficiency in units (°C/kW/s) for direct comparison to available clinical data. The procedure for casting thermal phantom material is presented. The utility of each phantom model is discussed in the context of various tcMRgFUS research areas., Results: The cadaveric phantom model, gel-filled skull model, and full head phantom model had heating efficiencies of 5.3, 4.0, and 3.9 °C/(kW/s), respectively, compared to a sample clinical heating efficiency of 2.6 °C/(kW/s). In the seven research categories considered, the cadaveric phantom model was the most versatile, though less practical compared to the ex-vivo skull-based phantoms., Conclusions: Casting thermal phantom material was shown to be an effective way to prepare tissue-mimicking material for the phantoms presented. The phantom models presented are all useful in tcMRgFUS research, though some are better suited to a limited subset of applications depending on the researchers needs.

Object: In biological tissues, it is known that the creation of gas bubbles (cavitation) during ultrasound exposure is more likely to occur at lower rather than higher frequencies. Upon collapsing, such bubbles can induce hemorrhage. Thus, acoustic inertial cavitation secondary to a 220-kHz MRI-guided focused ultrasound (MRgFUS) surgery is a serious safety issue, and animal studies are mandatory for laying the groundwork for the use of low-frequency systems in future clinical trials. The authors investigate here the in vivo potential thresholds of MRgFUS-induced inertial cavitation and MRgFUS-induced thermal coagulation using MRI, acoustic spectroscopy, and histology., Methods: Ten female piglets that had undergone a craniectomy were sonicated using a 220-kHz transcranial MRgFUS system over an acoustic energy range of 5600-14,000 J. For each piglet, a long-duration sonication (40-second duration) was performed on the right thalamus, and a short sonication (20-second duration) was performed on the left thalamus. An acoustic power range of 140-300 W was used for long-duration sonications and 300-700 W for short-duration sonications. Signals collected by 2 passive cavitation detectors were stored in memory during each sonication, and any subsequent cavitation activity was integrated within the bandwidth of the detectors. Real-time 2D MR thermometry was performed during the sonications. T1-weighted, T2-weighted, gradient-recalled echo, and diffusion-weighted imaging MRI was performed after treatment to assess the lesions. The piglets were killed immediately after the last series of posttreatment MR images were obtained. Their brains were harvested, and histological examinations were then performed to further evaluate the lesions., Results: Two types of lesions were induced: thermal ablation lesions, as evidenced by an acute ischemic infarction on MRI and histology, and hemorrhagic lesions, associated with inertial cavitation. Passive cavitation signals exhibited 3 main patterns identified as follows: no cavitation, stable cavitation, and inertial cavitation. Low-power and longer sonications induced only thermal lesions, with a peak temperature threshold for lesioning of 53°C. Hemorrhagic lesions occurred only with high-power and shorter sonications. The sizes of the hemorrhages measured on macroscopic histological examinations correlated with the intensity of the cavitation activity (R2 = 0.74). The acoustic cavitation activity detected by the passive cavitation detectors exhibited a threshold of 0.09 V·Hz for the occurrence of hemorrhages., Conclusions: This work demonstrates that 220-kHz ultrasound is capable of inducing a thermal lesion in the brain of living swines without hemorrhage. Although the same acoustic energy can induce either a hemorrhage or a thermal lesion, it seems that low-power, long-duration sonication is less likely to cause hemorrhage and may be safer. Although further study is needed to decrease the likelihood of ischemic infarction associated with the 220-kHz ultrasound, the threshold established in this work may allow for the detection and prevention of deleterious cavitations.

Objective: Gamma Knife radiosurgery (GKRS) is a minimally invasive technique employed in the treatment of intracranial arteriovenous malformations (AVMs). Patients experience a low incidence of complications following treatment. As long-term follow-up data became available, some late adverse effects have been reported. However, the exact incidence of radiosurgically induced neoplasia is not known., Methods: At University of Virginia, imaging and clinical outcomes of 1309 patients with intracranial AVMs treated with GKRS have been reviewed. AVM patients underwent magnetic resonance imaging (MRI) every 6 months for 2 years and then annually following GKRS. When the nidi were no longer visible on magnetic resonance imaging, angiography was performed to verify the obliteration of AVMs. Patients were thereafter recommended to continue MRIs every 3-5 years to detect any long-term complications. A subset of 812, 358, and 78 patients had neuroimaging and clinical follow-up of at least 3, 10, and 15 years, respectively., Results: The authors report the occurrence of 3 cases of radiosurgically induced neoplasia. More than 10 years after GKRS, 2 patients were found to have an incidental, uniformly enhancing, dural-based mass lesion near the site of the AVM with radiologic characteristics of a meningioma. As the lesions have shown no evidence of mass effect, they are being followed with serial neuroimaging. A third patient was found to have neurologic decline from a tumor in immediate proximity to an AVM previously treated with proton beam radiosurgery and GKRS. The patient underwent resection, demonstrating a high-grade glioma. The 3-, 10-, and 15-year incidence of a radiation-induced tumor is 0% (0/812), 0.3% (1/358), and 2.6% (2/78), respectively. The cumulative rate of radiosurgically induced tumors in those with a minimum of 10-year follow-up is 3 in 4692 person-years or 64 in 100,000 person-years. Thus, patients had a 0.64% chance of developing a radiation-induced tumor within ≥10 years following GKRS. If we calculate rates based on a subset of 78 patients with neuroimaging and clinical follow-up of ≤15 years, the cumulative rate was 3.4%. These are the second, third, and fifth reported cases of radiation-induced tumors following GKRS for an AVM., Conclusions: Although radiosurgery is generally considered a safe modality in the treatment of AVMs, radiation-induced neoplasia is a rare but serious adverse event. The possibility of GKRS-induced tumors underscores the necessity of long-term follow-up in AVM patients receiving radiosurgery., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Despite the frequency with which ventriculoperitoneal shunts are placed, ventricular catheter revision rates remains as high as 30%-40% at 1 year. Many neurosurgeons place ventricular catheters "blindly" depending on anatomical landmarks and personal experience. To determine whether intraoperative ultrasonography is beneficial for ventricular catheter placement, we performed a historical cohort study comparing shunts placed with intraoperative ultrasound (US) guidance to those placed blindly., Methods: We reviewed all shunts placed by the Department of Neurosurgery at the University of Virginia from January 2005 to January 2007. During that time 211 patients underwent 242 shunts, with US use determined by surgeon's preference. Ninety-two shunts were placed by the use of US guidance, and 150 were placed without US. Adults received 176 shunts, 56 with US. Children received 66 shunts, 36 with US. Mean follow-up was 21.6 months. The primary end points examined were shunt revision, ventricular catheter revision (VCR), and acute VCR (revision within 1 week for an improperly-placed catheter)., Results: The use of US was associated with a statistically significant decrease in shunt revisions (odds ratio 0.492; 95% confidence interval 0.253-0.958). Of the shunts placed with US guidance, 21.7% required revision, compared with 29.3% without US. VCRs and acute VCRs occurred in 9.8% and 2.2%, respectively, for US shunts, compared with 14% and 5.3% without US. Pediatric revision rates were 30.6% with US versus 53.3% without, whereas adult rates were 16.1% and 23.3%, respectively. The benefit of US was more profound for occipital shunts., Conclusions: The use of US for the placement of permanent cerebrospinal fluid shunt catheters is associated with a decreased risk of shunt revision., (Copyright © 2014 Elsevier Inc. All rights reserved.)

In preparing a patient for a trans-cranial magnetic resonance (MR)-guided focused ultrasound procedure, current practice is to shave the patient's head on treatment day. Here we present an initial attempt to evaluate the feasibility of trans-cranial focused ultrasound in an unshaved, ex vivo human head model. A human skull filled with tissue-mimicking phantom and covered with a wig made of human hair was sonicated using 220- and 710-kHz head transducers to evaluate the feasibility of acoustic energy transfer. Heating at the focal point was measured by MR proton resonance shift thermometry. Results showed that the hair had a negligible effect on focal spot thermal rise at 220 kHz and a 17% drop in temperature elevation when using 710 kHz.

Background and Purpose: The vasoconstrictor endothelin-1 (ET-1) has been implicated in the pathogenesis of cerebral vasospasm following subarachnoid hemorrhage (SAH). Previous results showed that CGS 26303, an endothelin converting enzyme (ECE) inhibitor, effectively prevented and reversed arterial narrowing in animal models of SAH. In the present study, we assessed the effect of CGS 26303 on neurological deficits in SAH rats. The involvement of vasoactive pathways downstream of ET-1 signaling in SAH was also investigated., Methods: Sprague-Dawley rats were divided into five groups (n = 6/group): (1) normal control, (2) SAH, (3) SAH+vehicle, (4) SAH+CGS 26303 (prevention), and (5) SAH+CGS 26303 (reversal). SAH was induced by injecting autologous blood into cisterna magna. CGS 26303 (10 mg/kg) was injected intravenously at 1 and 24 hr after the initiation of SAH in the prevention and reversal protocols, respectively. Behavioral changes were assessed at 48 hr after SAH. Protein expression was analyzed by Western blots., Results: Deficits in motor function were obvious in the SAH rats, and CGS 26303 significantly improved the rate of paraplegia. Expressions of rho-kinase-II and membrane-bound protein kinase C- δ and rhoA were significantly increased, while those of soluble guanylyl cyclase α 1 and β 1 as well as protein kinase G were significantly decreased in the basilar artery of SAH rats. Treatment with CGS 26303 nearly normalized these effects., Conclusions: These results demonstrate that the rhoA/rho-kinase and sGC/cGMP/PKG pathways play pivotal roles in cerebral vasospasm after SAH. It also shows that ECE inhibition is an effective strategy for the treatment of this disease.

Introduction: Posterior circulation perforator artery aneurysms are sparsely reported in the literature. The natural history of these rare lesions remains unclear and their diagnosis and management are not well-defined., Methods: We reviewed our institution's medical records and performed a comprehensive literature search for cases of posterior circulation perforator aneurysms. Diagnostic imaging, management and clinical outcomes were the primary components of interest., Results: Our first case was a 58-year-old patient who developed an infarct after attempted endovascular treatment of a basilar perforator artery aneurysm, the second case was a 55-year-old patient with a posterior cerebral artery perforator aneurysm who did well with conservative management and the third case was a 68-year-old patient who suffered an infarct after successful Onyx embolization of a superior cerebellar artery perforator aneurysm. From the literature we identified four case reports and four case series, all describing aneurysmal lesions of the basilar perforator arteries, giving a total of 17 cases including those from our institution. All cases presented with subarachnoid hemorrhage although 47% of initial vascular imaging studies failed to reveal the aneurysm. Cumulatively, 41% of patients were treated with microsurgery, 35% were treated with endovascular therapy and 24% were managed conservatively with subsequent spontaneous aneurysm resolution at a mean interval of 10 months after rupture., Conclusions: Perforator aneurysms of the posterior circulation are diagnostic and therapeutic challenges. Both microsurgical and endovascular treatment of posterior circulation perforator aneurysms are technically difficult, necessitating comprehensive management by an experienced cerebrovascular team.

Object: Intravenous sodium nitrite has been shown to prevent and reverse cerebral vasospasm in a primate model of subarachnoid hemorrhage (SAH). The present Phase IIA dose-escalation study of sodium nitrite was conducted to determine the compound's safety in humans with aneurysmal SAH and to establish its pharmacokinetics during a 14-day infusion. Methods In 18 patients (3 cohorts of 6 patients each) with SAH from a ruptured cerebral aneurysm, nitrite (3 patients) or saline (3 patients) was infused. Sodium nitrite and saline were delivered intravenously for 14 days, and a dose-escalation scheme was used for the nitrite, with a maximum dose of 64 nmol/kg/min. Sodium nitrite blood levels were frequently sampled and measured using mass spectroscopy, and blood methemoglobin levels were continuously monitored using a pulse oximeter., Results: In the 14-day infusions in critically ill patients with SAH, there was no toxicity or systemic hypotension, and blood methemoglobin levels remained at 3.3% or less in all patients. Nitrite levels increased rapidly during intravenous infusion and reached steady-state levels by 12 hours after the start of infusion on Day 1. The nitrite plasma half-life was less than 1 hour across all dose levels evaluated after stopping nitrite infusions on Day 14., Conclusions: Previous preclinical investigations of sodium nitrite for the prevention and reversal of vasospasm in a primate model of SAH were effective using doses similar to the highest dose examined in the current study (64 nmol/kg/min). Results of the current study suggest that safe and potentially therapeutic levels of nitrite can be achieved and sustained in critically ill patients after SAH from a ruptured cerebral aneurysm.

Intracerebral hemorrhage remains a significant cause of morbidity and mortality. Current surgical therapies aim to use a minimally invasive approach to remove as much of the clot as possible without causing undue disruption to surrounding neural structures. Transcranial MR-guided focused ultrasound (MRgFUS) surgery is an emerging technology that permits a highly concentrated focal point of ultrasound energy to be deposited to a target deep within the brain without an incision or craniotomy. With appropriate ultrasound parameters it has been shown that MRgFUS can effectively liquefy large-volume blood clots through the human calvaria. In this review the authors discuss the rationale for using MRgFUS to noninvasively liquefy intracerebral hemorrhage (ICH), thereby permitting minimally invasive aspiration of the liquefied clot via a small drainage tube. The mechanism of action of MRgFUS sonothrombolysis; current investigational work with in vitro, in vivo, and cadaveric models of ICH; and the potential clinical application of this disruptive technology for the treatment of ICH are discussed.

Object: Intracerebral hemorrhage (ICH) is a major cause of death and disability throughout the world. Surgical techniques are limited by their invasive nature and the associated disability caused during clot removal. Preliminary data have shown promise for the feasibility of transcranial MR-guided focused ultrasound (MRgFUS) sonothrombolysis in liquefying the clotted blood in ICH and thereby facilitating minimally invasive evacuation of the clot via a twist-drill craniostomy and aspiration tube., Methods and Results: In an in vitro model, the following optimum transcranial sonothrombolysis parameters were determined: transducer center frequency 230 kHz, power 3950 W, pulse repetition rate 1 kHz, duty cycle 10%, and sonication duration 30 seconds. Safety studies were performed in swine (n = 20). In a swine model of ICH, MRgFUS sonothrombolysis of 4 ml ICH was performed. Magnetic resonance imaging and histological examination demonstrated complete lysis of the ICH without additional brain injury, blood-brain barrier breakdown, or thermal necrosis due to sonothrombolysis. A novel cadaveric model of ICH was developed with 40-ml clots implanted into fresh cadaveric brains (n = 10). Intracerebral hemorrhages were successfully liquefied (> 95%) with transcranial MRgFUS in a highly accurate fashion, permitting minimally invasive aspiration of the lysate under MRI guidance., Conclusions: The feasibility of transcranial MRgFUS sonothrombolysis was demonstrated in in vitro and cadaveric models of ICH. Initial in vivo safety data in a swine model of ICH suggest the process to be safe. Minimally invasive treatment of ICH with MRgFUS warrants evaluation in the setting of a clinical trial.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) has the potential to create a shift in the treatment paradigm of several intracranial disorders. High-resolution MRI guidance combined with an accurate method of delivering high doses of transcranial ultrasound energy to a discrete focal point has led to the exploration of noninvasive treatments for diseases traditionally treated by invasive surgical procedures. In this review, the authors examine the current intracranial applications under investigation and explore other potential uses for MRgFUS in the intracranial space based on their initial cadaveric studies.

Object: Transcranial MR-guided focused ultrasound surgery (MRgFUS) is evolving as a treatment modality in neurosurgery. Until now, the trigeminal nerve was believed to be beyond the treatment envelope of existing high-frequency transcranial MRgFUS systems. In this study, the authors explore the feasibility of targeting the trigeminal nerve in a cadaveric model with temperature assessments using computer simulations and an in vitro skull phantom model fitted with thermocouples., Methods: Six trigeminal nerves from 4 unpreserved cadavers were targeted in the first experiment. Preprocedural CT scanning of the head was performed to allow for a skull correction algorithm. Three-Tesla, volumetric, FIESTA MRI sequences were performed to delineate the trigeminal nerve and any vascular structures of the cisternal segment. The cadaver was positioned in a focused ultrasound transducer (650-kHz system, ExAblate Neuro, InSightec) so that the focus of the transducer was centered at the proximal trigeminal nerve, allowing for targeting of the root entry zone (REZ) and the cisternal segment. Real-time, 2D thermometry was performed during the 10- to 30-second sonication procedures. Post hoc MR thermometry was performed on a computer workstation at the conclusion of the procedure to analyze temperature effects at neuroanatomical areas of interest. Finally, the region of the trigeminal nerve was targeted in a gel phantom encased within a human cranium, and temperature changes in regions of interest in the skull base were measured using thermocouples., Results: The trigeminal nerves were clearly identified in all cadavers for accurate targeting. Sequential sonications of 25-1500 W for 10-30 seconds were successfully performed along the length of the trigeminal nerve starting at the REZ. Real-time MR thermometry confirmed the temperature increase as a narrow focus of heating by a mean of 10°C. Postprocedural thermometry calculations and thermocouple experiments in a phantom skull were performed and confirmed minimal heating of adjacent structures including the skull base, cranial nerves, and cerebral vessels. For targeting, inclusion of no-pass regions through the petrous bone decreased collateral heating in the internal acoustic canal from 16.7°C without blocking to 5.7°C with blocking. Temperature at the REZ target decreased by 3.7°C with blocking. Similarly, for midcisternal targeting, collateral heating at the internal acoustic canal was improved from a 16.3°C increase to a 4.9°C increase. Blocking decreased the target temperature increase by 4.4°C for the same power settings., Conclusions: This study demonstrates focal heating of up to 18°C in a cadaveric trigeminal nerve at the REZ and along the cisternal segment with transcranial MRgFUS. Significant heating of the skull base and surrounding neural structures did not occur with implementation of no-pass regions. However, in vivo studies are necessary to confirm the safety and efficacy of this potentially new, noninvasive treatment.

Object: In randomized clinical trials of subarachnoid hemorrhage (SAH) in which the primary clinical outcomes are ordinal, it has been common practice to dichotomize the ordinal outcome scale into favorable versus unfavorable outcome. Using this strategy may increase sample sizes by reducing statistical power. Authors of the present study used SAH clinical trial data to determine if a sliding dichotomy would improve statistical power., Methods: Available individual patient data from tirilazad (3552 patients), clazosentan (the Clazosentan to Overcome Neurological Ischemia and Infarction Occurring After Subarachnoid Hemorrhage trial [CONSCIOUS-1], 413 patients), and subarachnoid aneurysm trials (the International Subarachnoid Aneurysm Trial [ISAT], 2089 patients) were analyzed. Treatment effect sizes were examined using conventional fixed dichotomy, sliding dichotomy (logical or median split methods), or proportional odds modeling. Whether sliding dichotomy affected the difference in outcomes between the several age and neurological grade groups was also evaluated., Results: In the tirilazad data, there was no significant effect of treatment on outcome (fixed dichotomy: OR = 0.92, 95% CI 0.80-1.07; and sliding dichotomy: OR = 1.02, 95% CI 0.87-1.19). Sliding dichotomy reversed and increased the difference in outcome in favor of the placebo over clazosentan (fixed dichotomy: OR = 1.06, 95% CI 0.65-1.74; and sliding dichotomy: OR = 0.85, 95% CI 0.52-1.39). In the ISAT data, sliding dichotomy produced identical odds ratios compared with fixed dichotomy (fixed dichotomy vs sliding dichotomy, respectively: OR = 0.67, 95% CI 0.55-0.82 vs OR = 0.67, 95% CI 0.53-0.85). When considering the tirilazad and CONSCIOUS-1 groups based on age or World Federation of Neurosurgical Societies grade, no consistent effects of sliding dichotomy compared with fixed dichotomy were observed., Conclusions: There were differences among fixed dichotomy, sliding dichotomy, and proportional odds models in the magnitude and precision of odds ratios, but these differences were not as substantial as those seen when these methods were used in other conditions such as head injury. This finding suggests the need for different outcome scales for SAH.

Magnetic resonance-guided focused ultrasound surgery (MRgFUS) is a novel combination of technologies that is actively being realized as a noninvasive therapeutic tool for a myriad of conditions. These applications are reviewed with a focus on neurological use. 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.

Background: Patients undergoing neurosurgical clipping or endovascular coiling of a ruptured aneurysm may differ in their risk of vasospasm., Objective: Because clot clearance affects vasospasm, we tested the hypothesis that clot clearance differs in patients depending on method of aneurysm treatment., Methods: Exploratory analysis was performed on 413 patients from CONSCIOUS-1, a prospective randomized trial of clazosentan for the prevention of angiographic vasospasm in patients with aneurysmal subarachnoid hemorrhage (SAH). Clot clearance was measured by change in Hijdra score between baseline computed tomography and one performed 24 to 48 hours after aneurysm treatment. Angiographic vasospasm was assessed by the use of catheter angiography 7 to 11 days after SAH, and delayed ischemic neurological deficit (DIND) was determined clinically. Extended Glasgow Outcome Score (GOSE) was assessed 3 months after SAH, and poor outcome was defined as death, vegetative state, or severe disability. Multivariable ordinal and binary logistic regression were used., Results: There was no significant difference in the rate of clot clearance between patients undergoing clipping or coiling (P = .56). Coiling was independently associated with decreased severity of angiographic vasospasm (odds ratio [OR] 0.53, 95% confidence interval [CI] 0.33-0.86), but not with DIND or GOSE. Greater clot clearance decreased the risk of severe angiographic vasospasm (OR 0.86, 95% CI 0.81-0.91), whereas higher baseline Hijdra score predicted increased angiographic vasospasm (OR 1.17, 95% CI 1.11-1.23) and poor GOSE (OR 1.09, 95% CI 1.04-1.14)., Conclusion: Aneurysm coiling and increased clot clearance were independently associated with decreased severity of angiographic vasospasm in multivariate analysis, although no differences in clot clearance were seen between coiled and clipped patients.

Background and Purpose: The long-standing concept that delayed cerebral infarction after aneurysmal subarachnoid hemorrhage results exclusively from large artery vasospasm recently has been challenged. We used data from the CONSCIOUS-1 trial to determine the relationship between angiographic vasospasm and cerebral infarction after subarachnoid hemorrhage., Methods: We performed a post hoc exploratory analysis of the CONSCIOUS-1 data. All patients underwent catheter angiography before treatment and 9±2 days after subarachnoid hemorrhage. CT was performed before and after aneurysm treatment, and 6 weeks after subarachnoid hemorrhage. Angiograms and CT scans were assessed by centralized blinded review. Angiographic vasospasm was classified as none/mild (0%-33% decrease in arterial diameter), moderate (34%-66%), or severe (≥67%). Infarctions were categorized as secondary to angiographic vasospasm, other, or unknown causes. Logistic regression was conducted to determine factors associated with infarction., Results: Complete data were available for 381 of 413 patients (92%). Angiographic vasospasm was none/mild in 209 (55%) patients, moderate in 118 (31%), and severe in 54 (14%). Infarcts developed in 6 (3%) of 209 with no/mild, 12 (10%) of 118 patients with moderate, and 25 (46%) of 54 patients with severe vasospasm. Multivariate analysis found a strong association between angiographic vasospasm and cerebral infarction (OR, 9.3; 95% CI, 3.7-23.4). The significant association persisted after adjusting for admission neurological grade and aneurysm size. Method of aneurysm treatment was not associated with a significant difference in frequency of infarction., Conclusions: A strong association exists between angiographic vasospasm and cerebral infarction. Efforts directed at further reducing angiographic vasospasm are warranted.

Cerebral vasospasm after aneurysmal subarachnoid hemorrhage (aSAH) is a frequent but unpredictable complication associated with poor outcome. Current vasospasm therapies are suboptimal; new therapies are needed. Clazosentan, an endothelin receptor antagonist, has shown promise in phase 2 studies, and two randomized, double-blind, placebo-controlled phase 3 trials (CONSCIOUS-2 and CONSCIOUS-3) are underway to further investigate its impact on vasospasm-related outcome after aSAH. Here, we describe the design of these studies, which was challenging with respect to defining endpoints and standardizing endpoint interpretation and patient care. Main inclusion criteria are: age 18-75 years; SAH due to ruptured saccular aneurysm secured by surgical clipping (CONSCIOUS-2) or endovascular coiling (CONSCIOUS-3); substantial subarachnoid clot; and World Federation of Neurosurgical Societies grades I-IV prior to aneurysm-securing procedure. In CONSCIOUS-2, patients are randomized 2:1 to clazosentan (5 mg/h) or placebo. In CONSCIOUS-3, patients are randomized 1:1:1 to clazosentan 5, 15 mg/h, or placebo. Treatment is initiated within 56 h of aSAH and continued until 14 days after aSAH. Primary endpoint is a composite of mortality and vasospasm-related morbidity within 6 weeks of aSAH (all-cause mortality, vasospasm-related new cerebral infarction, vasospasm-related delayed ischemic neurological deficit, neurological signs or symptoms in the presence of angiographic vasospasm leading to rescue therapy initiation). Main secondary endpoint is extended Glasgow Outcome Scale at week 12. A critical events committee assesses all data centrally to ensure consistency in interpretation, and patient management guidelines are used to standardize care. Results are expected at the end of 2010 and 2011 for CONSCIOUS-2 and CONSCIOUS-3, respectively.

Background: Intraventricular hemorrhage (IVH) predicts worse outcomes following aneurysmal subarachnoid hemorrhage (SAH). One potential mechanism is that IVH predisposes to the development of delayed ischemic neurological deficits (DINDs). No previous studies have evaluated the association between IVH volume (in milliliters) and subsequent development of DINDs or poor outcomes., Objective: To assess the association between the volume of IVH and the subsequent development of DINDs, delayed cerebral infarction, death, and poor neurological outcomes, specifically among patients with concomitant SAH and IVH., Methods: We performed a cohort study involving 152 consecutive patients with concomitant SAH and IVH. To determine volume of IVH, we used the IVH Score, shown to correlate well with computerized volumetric assessment. To determine the relative quantity of subarachnoid blood, we applied the SAH Sum Score. Multivariate logistic regression was used to adjust for potential confounders., Results: There was no significant association between IVH volume and the development of DINDs or delayed infarction. In contrast, patients with poor neurological outcomes had significantly larger baseline IVH volume (mean, 11.8 mL vs 3.8 mL, P = .001). In the multivariate analysis, IVH volume was an independent predictor of poor outcomes (OR per mL: 1.11 [1.04-1.18]). Patients in the highest quartile for IVH volume were far more likely to progress to poor outcome compared with those in the lowest quartile (OR 4.09 [1.32-12.65]). Interobserver agreement in the determination of IVH Score was moderate to good., Conclusions: IVH volume is an independent predictor of poor neurological outcomes, even after adjusting for the amount of subarachnoid blood. The pathophysiology of this association does not appear to involve an increased risk of DINDs or delayed infarction. Measures aimed at accelerating IVH clearance, such as intraventricular thrombolysis, merit further evaluation.

Involvement of the nervous system is not uncommon in patients with multiple myeloma, with polyneuropathy and myelopathy predominating. Intracranial involvement producing neurological symptoms, however, is distinctly uncommon. Massive intraparenchymal hemorrhage from a previously unrecognized intracranial plasmacytoma is exceedingly rare. The authors report the case of a 57-year-old male who presented with sudden onset of severe headache, rapid onset of right-sided weakness and deterioration in level of consciousness while at work. Two years earlier the patient had completed treatment for multiple myeloma and was considered to be in remission, with a recent bone marrow biopsy that was negative, and complete normalization of serum protein electrophoresis. Imaging studies revealed a massive intracerebral hemorrhage with the possibility of an underlying lesion, and the patient was taken for emergent hematoma evacuation and tumor resection. The patient made an excellent recovery and was treated with intracranial radiation. Even in patients with multiple myeloma without evidence of systemic disease following successful treatment, the possibility of unrecognized lesions lingers. The onset of new symptoms referable to potential intracranial pathology in this setting should prompt consideration of intracranial plasmacytoma in the differential diagnosis., (2009. Published by Elsevier B.V.)

Objective: Ischemic stroke and intracranial hemorrhage remain a persistent scourge in Western civilization. Therefore, novel therapeutic modalities are desperately needed to expand the current limitations of treatment. Sonothrombolysis possesses the potential to fill this void because it has experienced a dramatic evolution from the time of early conceptualization in the 1960s. This process began in the realm of peripheral and cardiovascular disease and has since progressed to encompass intracranial pathologies. Our purpose is to provide a comprehensive review of the historical progression and existing state of knowledge, including underlying mechanisms as well as evidence for clinical application of ultrasound thrombolysis., Methods: Using MEDLINE, in addition to cross-referencing existing publications, a meticulous appraisal of the literature was conducted. Additionally, personal communications were used as appropriate., Results: This appraisal revealed several different technologies close to broad clinical use. However, fundamental questions remain, especially in regard to transcranial high-intensity focused ultrasound. Currently, the evidence supporting low intensity ultrasound's potential in isolation, without tissue plasminogen, remains uncertain; however, possibilities exist in the form of microbubbles to allow for focal augmentation with minimal systemic consequences. Alternatively, the literature clearly demonstrates, the efficacy of high-intensity focused ultrasound for independent thrombolysis., Conclusion: Sonothrombolysis exists as a promising modality for the noninvasive or minimally invasive management of stroke, both ischemic and hemorrhagic. Further research facilitating clinical application is warranted.

Object: Several studies have indicated that short-term mortality risk is higher among patients who are admitted on the weekends. This "weekend effect" has been observed among patients admitted with a variety of diagnoses, including myocardial infarction, pulmonary embolism, ruptured abdominal aortic aneurysm, and stroke. This study examines the relationship between short-term mortality risk and weekend admission among patients hospitalized following subarachnoid hemorrhage (SAH)., Methods: This retrospective cohort study examines mortality outcomes among patients included in the Nationwide Inpatient Sample (NIS) for 2004. Patients included in the cohort were identified using the International Classification of Diseases, 9th revision, Clinical Modification (ICD-9-CM) code for SAH. Multivariable logistic regression analyses and Cox proportional hazard regression analyses are used to measure the association of weekend admission on mortality for patients with SAH, adjusted for differences in patient characteristics that also contribute to mortality risk., Results: Weekend admissions occurred among 27.5% of the 5667 patients with SAH in the NIS database. Weekend admission was not a statistically significant independent predictor of death in the SAH study population at 7 days (OR 1.07, 95% CI 0.91-1.25), 14 days (OR 1.01, 95% CI 0.87-1.17), or 30 days (OR 1.03, 95% CI 0.89-1.19)., Conclusions: Weekend admission is not associated with significantly increased short-term mortality risk among patients hospitalized with SAH.

Fusiform aneurysms of the basilar artery present difficult challenges for the treating physician. On one hand, these aneurysms are difficult and dangerous to treat. On the other, the relatively high rupture rate, risk of thromboemboli, and the frequent presence of mass effect on the brainstem often demand treatment rather than observation. While conservative treatment may be reasonable in an elderly patient, the relative resiliency and the larger lifetime cumulative risks of pediatric patients are compelling arguments for treatment. With the advancement of endovascular techniques some of these lesions have become treatable without the high morbidity and mortality rates associated with open surgical treatment, albeit with risks of their own. The authors present the case of a fusiform aneurysm arising from a severely tortuous basilar artery in a 22-month-old boy. The aneurysm was successfully treated using flow diversion by placing multiple intracranial stents without coil embolization. This allowed for thrombosis of the aneurysm and resolution of the mass effect on the brainstem without compromising blood flow to the brainstem.

The treatment of intracranial dural arteriovenous fistulas (AVF) has progressed considerably over the past few decades. With the introduction of new embolic materials and refinement of endovascular techniques, lesions that in the past may have required extensive surgery, or were considered untreatable, have increasingly become curable. Despite improvements in technology, not every condition is amenable to an endovascular treatment, including those patients with preexisting vascular abnormalities that preclude an endovascular approach. In these cases, the patient may be left with suboptimal treatment options with higher associated risks. The authors here report on the treatment of a dural AVF in a pediatric patient in whom prior procedures rendered his cerebrovascular anatomy unnavigable using traditional endovascular techniques. To circumvent these vascular abnormalities the patient underwent combined surgical/endovascular treatment that included surgical exposure and cannulation of the cervical carotid artery, as well as simultaneous femoral artery access, with subsequent successful transarterial embolization of the dural AVF.

Object: Cerebral vasospasm remains a major complication in patients who have suffered a subarachnoid hemorrhage (SAH). Previous studies have shown that 17beta-estradiol (E2) attenuates experimental SAH-induced cerebral vasospasm. Moreover, E2 has been shown to reduce neuronal apoptosis and secondary injury following cerebral ischemia. Adenosine A1 receptor (AR-A1) expression is increased following ischemia and may represent an endogenous neuroprotective effect. This study was designed to evaluate the efficacy of E2 in preventing cerebral vasospasm and reducing secondary injury, as evidenced by DNA fragmentation and AR-A1 expression, following SAH., Methods: A double-hemorrhage model of SAH in rats was used, and the degree of vasospasm was determined by averaging the cross-sectional areas of the basilar artery 7 days after the first SAH. A cell death assay was used to detect apoptosis. Changes in the protein expression of AR-A1 in the cerebral cortex, hippocampus, and dentate gyrus were compared with levels in normal controls and E2-treated groups (subcutaneous E2, 0.3 mg/ml)., Results: The administration of E2 prevented vasospasm (p < 0.05). Seven days after the first SAH, DNA fragmentation and protein levels of AR-A1 were significantly increased in the dentate gyrus. The E2 treatment decreased DNA fragmentation and prevented the increase in AR-A1 expression in the dentate gyrus. There were no significant changes in DNA fragmentation and the expression of AR-A1 after SAH in the cerebral cortex and hippocampus in the animals in the control and E2-treated groups., Conclusions: The E2 was effective in attenuating SAH-induced cerebral vasospasm, decreasing apoptosis in the dentate gyrus, and reducing the expression of AR-A1 in the dentate gyrus after SAH. Interestingly, E2 appears to effectively prevent cerebral vasospasm subsequent to SAH as well as attenuate secondary injury by reducing both apoptosis and a compensatory increase in AR-A1 expression in the dentate gyrus.

Background: The effects of both hyperglycemia and hypoglycemia are deleterious to patients with neurologic injury., Methods: On January 1, 2002, the neurointensive care unit at the University of Virginia Health System initiated a strict glucose control protocol (goal glucose < 120 mg/dl). The authors conducted an impact study to determine the effects of this protocol on patients presenting with aneurysmal subarachnoid hemorrhage., Results: Among the 834 patients admitted between 1995 and 2007, the in-hospital mortality was 11.6%. The median admission glucose for survivors was lower (135 vs. 176 mg/dl); however, on multivariate analysis, increasing admission glucose was not associated with a statistically significant increase in the risk of death (P = 0.064). The median average glucose for survivors was also lower (116 vs. 135 mg/dl). This was significant on multivariate analysis (P < 0.001); however, the effect was small (odds ratio, 1.045). Implementation of the strict glucose protocol decreased median average glucose (121 vs. 116 mg/dl, P < 0.001) and decreased the incidence of hyperglycemia. Implementation of the protocol had no effect on in-hospital mortality (11.7% vs. 12.0%, P = 0.876 [univariate], P = 0.132 [multivariate]). Protocol implementation was associated with an increased incidence of hypoglycemia (P < 0.001). Hypoglycemia was associated with a substantially increased risk of death on multivariate analysis (P = 0.009; odds ratio = 3.818)., Conclusions: The initiation of a tight glucose control regimen lowered average glucose levels but had no effect on overall in-hospital mortality.

The field of magnetic resonance imaging-guided high-intensity focused ultrasound surgery (MRgFUS) is a rapidly evolving one, with many potential applications in neurosurgery. The first of 3 articles on MRgFUS, this article focuses on the historical development of the technology and its potential applications in modern neurosurgery. The evolution of MRgFUS has occurred in parallel with modern neurological surgery, and the 2 seemingly distinct disciplines share many of the same pioneering figures. Early studies on focused ultrasound treatment in the 1940s and 1950s 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 the lack of sophisticated imaging technology, resulted in limited growth of high-intensity focused ultrasound for neurosurgery. More recently, technological advances have permitted the combination of high-intensity focused ultrasound along with magnetic resonance imaging guidance to provide an opportunity to effectively treat a variety of central nervous system disorders. Although challenges remain, high-intensity focused ultrasound-mediated neurosurgery may offer the ability to target and treat central nervous system conditions that were previously extremely difficult to address. The remaining 2 articles in this series will focus on the physical principles of modern MRgFUS as well as current and future avenues for investigation.

Introduction: Bilateral pulmonary infiltrates occur frequently following aneurysmal subarachnoid hemorrhage (SAH), and may be associated with worse outcomes. The etiology, natural history, and prognosis of infiltrates occurring soon after SAH may differ from the characteristics of infiltrates developing at a later time., Methods: We performed a retrospective cohort study involving 245 consecutive patients with a ruptured cerebral aneurysm to assess the association between "early" (< or = 72 h) or "late" (>72 h) bilateral pulmonary infiltrates and subsequent death or neurologic impairment. We used logistic regression models to adjust for baseline differences in age, level of consciousness, amount of blood on computed tomography, and the presence or absence of clinical vasospasm., Results: Sixty-seven patients (27%) developed bilateral pulmonary infiltrates. Of these, 36 (54%) had early infiltrates, 24 (36%) had late infiltrates, and 7 (10%) had both. Twenty-eight patients (11% of entire cohort) met criteria for acute respiratory distress syndrome (ARDS). Patients with early infiltrates were more likely to have presented with stupor or coma than patients who developed infiltrates later (64% vs. 29%, P < 0.01). In multivariable analysis, late pulmonary infiltrates were strongly predictive of poor outcome (OR 5.0, 95% CI 1.9-13.6, P < 0.01), while early infiltrates were not (OR 1.2, 95% CI 0.5-3.0, P = 0.66)., Conclusions: Bilateral pulmonary infiltrates after SAH most often occur within three days of aneurysm rupture. However, only infiltrates occurring beyond this time are independently associated with poor outcome. Increased emphasis on the prevention of late pulmonary complications has the potential to improve outcomes in SAH.

Object: Delayed cerebral ischemia is a major cause of morbidity and death following aneurysmal subarachnoid hemorrhage and requires timely intervention for a successful outcome to be achieved. In this study the investigators compared the commonly used Fisher scale with 2 newer radiographic scales for the prediction of vasospasm, delayed infarction, and poor outcome., Methods: This was a single-center, retrospective cohort study involving 271 consecutive patients with a ruptured cerebral aneurysm. Without knowledge of subsequent events, admission CT scans were each assigned scores by using 3 different grading schemes: the Fisher, modified Fisher, and Claassen scales. For each of the scales, the relationship between an increasing score and the risk of later complications was assessed in univariate and multiple logistic regression analyses., Results: With the Fisher scale, the risk of complications was relatively high when the score was 3, but not for other scores. In contrast, using the other scales, there was a more linear relationship between a rising score and the frequency of complications. This was particularly true for the modified Fisher scale, in which each stepwise increase was associated with an escalating risk of vasospasm, delayed infarction, and poor prognosis. Kappa scores measuring interobserver variability among 4 CT readers were also slightly better with the newer scales., Conclusions: Although the modified Fisher and Claassen scales have yet to be prospectively validated, the authors' findings suggest that the clinical performance of these systems is superior to that of the Fisher scale.

Cerebral vasospasm lingers as the leading preventable cause of death and disability in patients who experience aneurysmal subarachnoid hemorrhage. Despite the potentially devastating consequences of cerebral vasospasm, the mechanisms behind it are incompletely understood. Nitric oxide, endothelin-1, bilirubin oxidation products and inflammation appear to figure prominently in its pathogenesis. Therapies directed at many of these mechanisms are currently under investigation and hold significant promise for an ultimate solution to this substantial problem.

Objective: The development of delayed ischemia caused by cerebral vasospasm remains a common cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage. Preliminary studies suggest that 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) may decrease the risk of vasospasm, but additional study is required., Methods: Beginning in May 2006, our treatment protocol for patients presenting with subarachnoid hemorrhage was altered to routinely include the use of 80 mg of simvastatin per day for 14 days. Before this time, only patients with other indications for statins were treated. The charts of 203 consecutive patients over a period of 27 months were retrospectively reviewed, and 150 patients were included in the analysis, of whom 71 patients received statins. These patients were compared with 79 untreated patients to determine whether or not the use of statins was associated with a reduction in the occurrence of vasospasm, delayed infarction, or poor outcome (death, vegetative state, or severe disability)., Results: Patients who were treated with statins and those who were not had similar baseline characteristics, although more patients in the former group were managed with endovascular coil embolization. There were no statistically significant differences in the proportion of patients developing at least moderate radiographic vasospasm (41% with statins versus 42% without, P = 0.91), symptomatic vasospasm (32% with statins versus 25% without, P = 0.34), delayed infarction (23% with statins versus 28% without, P = 0.46), or poor outcome (39% with statins versus 35% without, P = 0.61). After adjustment for differences in baseline characteristics, including the method of aneurysm treatment, statins were still not significantly protective., Conclusion: The addition of statins to standard care was not associated with any reduction in the development of vasospasm or improvement in outcomes after aneurysmal subarachnoid hemorrhage. If there is a benefit to statin use, it may be smaller than suggested by previous studies. However, further randomized controlled trials are awaited.

Objective: Selective adenosine 2A receptor agonists, such as ATL-146e, are known to be potent anti-inflammatory agents devoid of systemic side effects and have been used clinically in a number of disease states. However, adenosine 2A receptor agonists have not been studied in the treatment of cerebral vasospasm after subarachnoid hemorrhage. The present study investigated the efficacy of ATL-146e in the prevention of leukocyte infiltration and attenuation of posthemorrhagic vasospasm., Methods: The rodent femoral artery model of vasospasm was used. Forty male Sprague-Dawley rats were randomly assigned to four different groups (vehicle, 1 ng/kg/min, 10 ng/kg/min, or 100 ng/kg/min ATL-146e administered via subcutaneous osmotic minipump). Vasospasm was evaluated at posthemorrhage Day 8 (period of peak constriction) by calculating the lumen cross-sectional area (expressed as percent change in luminal area: ratio of blood-exposed vessel to normal saline-exposed vessel) and radial wall thickness. Immunostaining with anti-CD45 monoclonal antibody to detect leukocytes was used to evaluate localized inflammation., Results: Significant vasospasm was noted in the vehicle-treated (blood-exposed) control group (78.5%, P < 0.001; expressed as a ratio of luminal area of the saline [no blood] control), but not in the ATL-146e-treated groups (lumen ratio to control: 105.0, 83.4, and 91.3% for the 1, 10, and 100 ng/kg/min groups, respectively). Additionally, infiltration of inflammatory cells was reduced significantly and radial wall thickness was decreased in the ATL-146e-treated groups compared with the vehicle-treated control group., Conclusion: Selective activation of the adenosine 2A receptor with ATL-146e prevented posthemorrhagic vasospasm and reduced leukocyte infiltration in this experimental model. This agent is worthy of further investigation and lends credence to the hypothesis supporting a role for inflammation in the pathogenesis of cerebral vasospasm after subarachnoid hemorrhage.

Object: Impaired endothelium-dependent relaxation is present in vasospastic cerebral vessels after subarachnoid hemorrhage (SAH) and may result from deficient production of endothelial nitric oxide synthase (eNOS) or increased production and/or activity of inducible NOS (iNOS). Accumulating evidence demonstrates that adenosine A2A receptors increase the production of NO by human and porcine arterial endothelial cells, which in turn leads to vasodilation. This study was designed to examine the effects of an adenosine A2A receptor agonist, (2(4-[2-carboxyethyl]phenyl)ethylamino)-5'-N-ethylcarboxamidoadenosine (CGS 21680), in the prevention of SAH-induced vasospasm., Methods: . Experimental SAH was induced in Sprague-Dawley rats by injecting 0.3 ml of autologous blood into the cisterna magna of each animal. Intraperitoneal injections of CGS 21680 or vehicle were administered 5 minutes and 24 hours after induction of SAH. The degree of vasospasm was determined by averaging measurements of cross-sectional areas of the basilar artery (BA) 48 hours after SAH. Expression of eNOS and iNOS in the BA was also evaluated. Prior to perfusion-fixation, there were no significant differences among animals in the control and treated groups in any physiological parameter that was recorded. The CGS 21680 treatment significantly attenuated SAH-induced vasospasm. Induction of iNOS mRNA and protein in the BA by the SAH was significantly diminished by administration of CGS 21680. The SAH-induced suppression of eNOS mRNA and protein was also relieved by the CGS 21680 treatment., Conclusions: This is the first evidence that adenosine A2A receptor agonism is effective in preventing SAH-induced vasospasm without significant complications. The beneficial effect of adenosine A2A receptor agonists may be, at least in part, related to the prevention of augmented expression of iNOS and the preservation of normal eNOS expression following SAH. Adenosine A2A receptor agonism holds promise in the treatment of cerebral vasospasm following SAH and merits further investigation.

Object: Adhesion molecules, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin, are important mediators of inflammation, and their levels are elevated in the serum of patients following aneurysmal subarachnoid hemorrhage (SAH). The investigators previously found that CGS 26303 is effective in preventing and reversing arterial narrowing in a rabbit model of SAH. The purpose of the present study was to examine whether levels of adhesion molecules are altered after treatment with CGS 26303 in this animal model., Methods: New Zealand White rabbits were each injected with 3 ml of autologous blood in the cisterna magna, and intravenous treatment with CGS 26303 (30 mg/kg) was initiated 1 hour later. The compound was subsequently administered at 12, 24, and 36 hours post-SAH. Blood samples were collected at 48 hours post-SAH to measure ICAM-1, VCAM-1, and E-selectin levels. After the rabbits had been killed by perfusion-fixation, the basilar arteries (BAs) were removed and sliced, and their cross-sectional areas were measured. Treatment with CGS 26303 attenuated arterial narrowing after SAH. Morphologically, corrugation of the internal elastic lamina of BAs was prominently observed in the SAH only and vehicle-treated SAH groups, but not in the CGS 26303-treated SAH group or in healthy controls. There were no significant differences in the levels of VCAM-1 among the four groups. The levels of E-selectin were increased in all animals subjected to SAH (those in the SAH only, SAH plus vehicle, and SAH plus CGS 26303 groups) compared with healthy controls (no SAH); however, the levels of ICAM-1 in the SAH only and SAH plus vehicle groups were significantly elevated (p < 0.001), and treatment with CGS 26303 reduced ICAM-1 to control levels following SAH., Conclusions: These results show that ICAM-1 may play a role in mediating SAH-induced vasospasm and that a reduction of ICAM-1 levels after SAH may partly contribute to the antispastic effect of CGS 26303.