Microvascular Shunts, Intracranial Pressure, and the Impact of Drag-Reducing Polymers.

In the 50 years of my membership in ISOTT, I, Edwin M Nemoto, have enjoyed the application of many of the technologies developed in our society including microelectrodes for pH, PO2, and near-infrared spectroscopy (NIRS) in the measurement of tissue oxygenation and metabolism. The greatest joy has been the number of great scientists I have had the pleasure of knowing and exchanging scientific ideas with across the United States, Europe, and Asia. This will be the enduring legacy of ISOTT for me personally as we continue beyond our half-century existence.Every organ in our body, including the tegmentum, is endowed with microvascular shunts (MVS), which may be involved in physiological regulation, i.e. temperature regulation or pathophysiological responses to tissue injury and oedema. MVS that open in response to increased capillary resistance and tissue oedema in the brain, heart, kidneys, liver, and muscles conduct neither nutrient nor gas exchange with tissue promoting tissue oedema in a vicious cycle. Pharmacologic arteriolar vasodilation cannot correct the MVS flow as may occur after a stroke or traumatic brain injury because pan arteriolar vasodilation would shunt flow to the normal tissue and away from the injured brain in a "reverse" steal or a "Robin Hood" phenomenon. A high molecular weight (4000 kDa) drag-reducing polymer (DRP) of polyethylene oxide or Lamiflo™ enhances blood flow by altering the physical dynamics of red blood cells (RBC) and blood flow, increasing the shear rate in the microvasculature and capillaries where shear rate is highest as it is inversely proportional to the 3rd power of blood vessel diameter. The shear rate sensed on the endothelium through the glycocalyx exerts precise control of endothelial function, including endothelial water permeability, nitric oxide synthase activity, lymphocyte adhesion to and transport across the endothelium, and microglial activation, all in response to low endothelial shear rate. DRP has proven effective in reversing MVS flow and increasing capillary flow in haemorrhagic shock, myocardial ischaemia, stroke, renal ischaemia, traumatic brain injury, stroke, sepsis, and Alzheimer's Disease. Our aim is to establish the universality of MVS in the pathogenesis of vascular disease and in taking DRP to clinical treatment of vascular diseases.

Evaluating the Status of the Injured Brain: Cerebrovascular Reserve (CVR) Is Not Equivalent to Induced Cerebrovascular Reactivity (iCVRx) and Induced Pressure Reactivity (iPRx) in Defining the Critical Cerebral Perfusion Pressure (CPP).

Methods evaluating the status of the injured brain have evolved over the past 63 years since Lundberg first reported clinical measurement of intracranial pressure (ICP) to evaluate the status of the injured brain (Lundberg, Acta Psychiatr Scand Suppl. 36:1-193, 1960). Subsequent evaluation involved measurement of the autoregulatory capacity of the brain by measuring cerebral blood flow (CBF) with decreasing mean arterial pressure (MAP) to define the critical CPP where the vasodilatory capacity of the cerebral circulation is exceeded and CBF begins to fall (CPP of 50 mmHg). A seminal advance was made by Marmarou (Marmarou et al., J Neurosurg. 48:332-344, 1978) who measured brain compliance by injecting a bolus of saline into the intracranial catheter while measuring the rise in intracranial pressure (ICP) otherwise known as induced pressure reactivity (iPRx). Seeking to utilise continuous measurement of iPRx in traumatic brain injury (TBI) patients with continuous monitoring of ICP, the ICP response to arterial pulsations was developed to evaluate the optimal CPP patients with raised ICP by the arterial pulsations-based iPRx. A similar approach was made with Doppler measurement of CBF with arterial pulsations for iCVRx to guide optimal CPP (CPPopt). Both iPRx and iCVRx are associated with microvascular shunts (MVS) and can accurately measure the critical CPP, whereas the CBF autoregulation curve by decreasing MAP does not. Sophisticated continuous multimodal monitoring established with ICM+ algorithms successfully identifies CPPopt for ICP control and identifies CBF dysregulation as related to outcome, but does not provide insights into the mechanisms involved in the loss of CBF autoregulation as related to increased ICP and potentially effective treatments (Froese et al., Neurocrit Care. 34:325-335, 2021).

Cerebrovascular Reserve (CVR) and Stages of Hemodynamic Compromise.

The concept of hemodynamic compromise (HC) is used to detect brain regions under ischemic stress by impaired ability to dilate in response to a vasodilatory challenge for cerebrovascular reserve (CVR). The vasodilatory challenges are either inhaled CO2 or a carbonic anhydrase inhibitor acetazolamide (AZ) with measurements of cerebral blood flow (CBF) before and during the challenge. The rationale for CVR is that the brain under ischemic stress is vasodilated and the increase in CBF is attenuated. However, regional oxygen extraction fraction (OEF) by positron emission tomography (PET) is the gold standard for measurement of HC. We showed a strong correlation between CVR and OEF and the OEF response (OEFR) before and after vasodilation in patients with acute ischemic stroke. These observations suggest that CVR measurements alone identify brain regions under ischemic stress without the need for expensive, time consuming and difficult PET OEF.

ACCESS to Better Health and Clear Skies: Telemedicine and Greenhouse Gas Reduction.

Introduction: This study estimates the reduction in greenhouse gas (GHG) emissions resulting from 2,020 neuro-emergent telemedicine consultations. We then estimate potential GHG reduction if the program was expanded nationwide. Materials and Methods: Travel distances in miles were calculated for each avoided patient transfer using hospital location data and ArcGIS® tools. Potential GHG reductions from program expansion were calculated based on state and national stroke Diagnosis-Related Groups (DRGs). Along with average flight distance from a rural hospital to closest level one trauma center. Results: Participation in the Access to Critical Cerebral Emergent Support Services (ACCESS) from May 2015 to July 2017 resulted in 2,020 consultations. Of these consultations, there was a 70% (1,414) reduction in patient transfers. Emission reduction totaled 618,772 kg of carbon dioxide equivalents (CO2e) (618.77 metric tons) or 0.306 metric tons of CO2e per patient. Expanding the program across New Mexico and similar U.S. areas resulted in potential reductions of 4,307 (IQR 3,386-5,274) and 213,279 (IQR 169,320-263,570) metric tons of CO2e. Conclusion: Transport accounts for 26% of global CO2 emissions and is one of the few industrial sectors where emissions are still growing. What makes this study more impactful is that aviation's emissions are not part of the Kyoto Protocol and little is being done in this sector. GHG reduction was not the main intention of the ACCESS program, but it has shown to be a significant by-product.

Microsurgical Vascular Manipulation in Aneurysm Surgery and Delayed Ischemic Injury.

BACKGROUND: The role of aggressive surgical manipulation with clot evacuation, arachnoid dissection, and papaverine-guided adventitial dissection of large vessels during ruptured aneurysm surgery in reducing vasospasm is controversial. Here we describe a single-institution experience in aneurysm surgery outcomes with and without aggressive surgery. METHODS: We performed retrospective analysis of all patients >18 years of age with subarachnoid hemorrhage (SAH) from anterior circulation aneurysms between 2008 and 2013 at the University of New Mexico Hospital. Vasospasm was characterized on days 3 through 14 after SAH based on: (1) angiography, (2) vasospasm requiring angiographic intervention, (3) development of delayed ischemic neurologic deficit (DIND), and (4) radiological appearance of new strokes. RESULTS: Of 159 patients, 114 (71.6%) had "aggressive" and 45 (28.3%) had standard microsurgery. More than 60% of patients presented with a Hunt and Hess score of ≥3 and a Fisher grade (FG) of 4. Compared with standard surgery, there was a statistically significant decrease in the incidence of DIND in patients undergoing aggressive surgery (18.4% vs 37.8%, p=0.01). Moreover, there was a reduction in the number of new strokes by 30% in the aggressive surgery group with moderate or higher degrees of vasospasm (46.0% vs 76.5%, p=0.06). In the same group with FG 4 SAH, however, this difference was more than 50% (30% vs 64.7%, p=0.02). CONCLUSIONS: We conclude that aggressive surgical manipulation during aneurysm surgery results in lower incidence of DIND and new strokes. This effect is most pronounced in patients with FG 4 SAH.

The Utility of Cerebral Blood Flow Assessment in TBI.

Over the past few decades, intracranial monitoring technologies focused on treating and preempting secondary injury after traumatic brain injury (TBI) have experienced considerable growth. A physiological measure fundamental to the management of these patients is cerebral blood flow (CBF), which may be determined directly or indirectly. Direct measurement has proven difficult previously; however, invasive and non-invasive CBF monitors are now available. This article reviews the history of CBF measurements in TBI as well as the role of CBF in pathologies associated with TBI, such as cerebral autoregulation, hyperemia, and cortical spreading depression. The limitations of various CBF monitors are reviewed in order to better understand their role in TBI management.

Co-prescription of naloxone as a Universal Precautions model for patients on chronic opioid therapy-Observational study.

BACKGROUND: The epidemic of lethal prescription opioid overdose is one of the most pressing public health problems in the United States. In an ambulatory clinic setting, current practice guidelines suggest that health care providers should screen patient's aberrant drug-related behaviors. Given the difficulty of predicting which patients on chronic opioid therapy (COT) will experience opioid overdose, a new paradigm of harm reduction is called for. In previous studies, naloxone, an opioid antagonist, was given only to high-risk patients. However, if naloxone is co-prescribed in a Universal Precautions manner for all patients receiving COT, this may have a significant impact on intentional and unintentional opioid overdose deaths. METHODS: Adult patients treated with COT for chronic noncancer pain are eligible study participants at the University of New Mexico Pain Center. The primary goal of this 1-year study was to develop an efficient Universal Precautions model for co-prescribing of naloxone with COT in the ambulatory clinic setting. Outcome measures included demographic data, detailed medical and substance use history, current morphine equivalent dose (MED), other "high-risk" medications used, and opioid misuse risk. RESULTS: One hundred and sixty-four patients were enrolled in this study. All subjects were educated about the risks of opioid overdose and provided naloxone rescue kits. No overdoses occurred in the study population. Follow-up data illustrated that approximately 57% of the cohort had depressive disorder, the median MED was 90 mg/day, and the median Current Opioid Misuse Measure score (COMM) was 5.0. CONCLUSIONS: The ambulatory co-prescribing of naloxone in a Universal Precautions model for all patients prescribed COT can be adopted as a useful public health intervention. This study illustrates a model that can be used to educate patients, caregivers, and an interdisciplinary team of health care professionals in an academic medical center.

Critical cerebral perfusion pressure at high intracranial pressure measured by induced cerebrovascular and intracranial pressure reactivity.

OBJECTIVES: The lower limit of cerebral blood flow autoregulation is the critical cerebral perfusion pressure at which cerebral blood flow begins to fall. It is important that cerebral perfusion pressure be maintained above this level to ensure adequate cerebral blood flow, especially in patients with high intracranial pressure. However, the critical cerebral perfusion pressure of 50 mm Hg, obtained by decreasing mean arterial pressure, differs from the value of 30 mm Hg, obtained by increasing intracranial pressure, which we previously showed was due to microvascular shunt flow maintenance of a falsely high cerebral blood flow. The present study shows that the critical cerebral perfusion pressure, measured by increasing intracranial pressure to decrease cerebral perfusion pressure, is inaccurate but accurately determined by dopamine-induced dynamic intracranial pressure reactivity and cerebrovascular reactivity. DESIGN: Cerebral perfusion pressure was decreased either by increasing intracranial pressure or decreasing mean arterial pressure and the critical cerebral perfusion pressure by both methods compared. Cortical Doppler flux, intracranial pressure, and mean arterial pressure were monitored throughout the study. At each cerebral perfusion pressure, we measured microvascular RBC flow velocity, blood-brain barrier integrity (transcapillary dye extravasation), and tissue oxygenation (reduced nicotinamide adenine dinucleotide) in the cerebral cortex of rats using in vivo two-photon laser scanning microscopy. SETTING: University laboratory. SUBJECTS: Male Sprague-Dawley rats. INTERVENTIONS: At each cerebral perfusion pressure, dopamine-induced arterial pressure transients (~10 mm Hg, ~45 s duration) were used to measure induced intracranial pressure reactivity (Δ intracranial pressure/Δ mean arterial pressure) and induced cerebrovascular reactivity (Δ cerebral blood flow/Δ mean arterial pressure). MEASUREMENTS AND MAIN RESULTS: At a normal cerebral perfusion pressure of 70 mm Hg, 10 mm Hg mean arterial pressure pulses had no effect on intracranial pressure or cerebral blood flow (induced intracranial pressure reactivity = -0.03 ± 0.07 and induced cerebrovascular reactivity = -0.02 ± 0.09), reflecting intact autoregulation. Decreasing cerebral perfusion pressure to 50 mm Hg by increasing intracranial pressure increased induced intracranial pressure reactivity and induced cerebrovascular reactivity to 0.24 ± 0.09 and 0.31 ± 0.13, respectively, reflecting impaired autoregulation (p < 0.05). By static cerebral blood flow, the first significant decrease in cerebral blood flow occurred at a cerebral perfusion pressure of 30 mm Hg (0.71 ± 0.08, p < 0.05). CONCLUSIONS: Critical cerebral perfusion pressure of 50 mm Hg was accurately determined by induced intracranial pressure reactivity and induced cerebrovascular reactivity, whereas the static method failed.

Role of microvascular shunts in the loss of cerebral blood flow autoregulation.

Historically, determination of the critical cerebral perfusion pressure (CPP) was done in animals by a progressive lowering of arterial pressure yielding a nominal critical CPP of 60 mmHg. Subsequently, it was shown that if the CPP was decreased by increasing intracranial pressure (ICP), critical CPP fell to 30 mmHg. This discrepancy was unexplained. We recently provided evidence that the decrease in critical CPP was due to microvascular shunting resulting in maintained cerebral blood flow (CBF) at a lower CPP. We demonstrated by a progressive increase in ICP in rats using two-photon laser scanning microscopy (2PLSM) that the transition from capillary to microvascular shunt flow is a pathological process. We surmise that the loss of CBF autoregulation revealed by decreasing arterial pressure occurs by dilation of normal cerebral blood vessels whereas that which occurs by increasing ICP is due to microvascular shunting. Our observations indicate that the loss of CBF autoregulation we observed in brain injured patients that changes on an hourly or daily basis reflects an important pathophysiological process impacting on outcome that remains to be determined.

Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.

BACKGROUND AND PURPOSE: The authors present an overview of the current evidence and management recommendations for evaluation and treatment of adults with acute ischemic stroke. The intended audiences are prehospital care providers, physicians, allied health professionals, and hospital administrators responsible for the care of acute ischemic stroke patients within the first 48 hours from stroke onset. These guidelines supersede the prior 2007 guidelines and 2009 updates. METHODS: Members of the writing committee were appointed by the American Stroke Association Stroke Council's Scientific Statement Oversight Committee, representing various areas of medical expertise. Strict adherence to the American Heart Association conflict of interest policy was maintained throughout the consensus process. Panel members were assigned topics relevant to their areas of expertise, reviewed the stroke literature with emphasis on publications since the prior guidelines, and drafted recommendations in accordance with the American Heart Association Stroke Council's Level of Evidence grading algorithm. RESULTS: The goal of these guidelines is to limit the morbidity and mortality associated with stroke. The guidelines support the overarching concept of stroke systems of care and detail aspects of stroke care from patient recognition; emergency medical services activation, transport, and triage; through the initial hours in the emergency department and stroke unit. The guideline discusses early stroke evaluation and general medical care, as well as ischemic stroke, specific interventions such as reperfusion strategies, and general physiological optimization for cerebral resuscitation. CONCLUSIONS: Because many of the recommendations are based on limited data, additional research on treatment of acute ischemic stroke remains urgently needed.

Microvascular shunts in the pathogenesis of high intracranial pressure.

Hyperemia in the infarcted brain has been -suggested for years by "red veins" reported by neurosurgeons, shunt peaks in radioactive blood flow clearance curves, and quantitative cerebral blood flow using stable xenon CT. Histological characterization of infarcted brain revealed capillary rarefaction with prominent microvascular shunts (MVS). Despite abundant histological evidence, the presence of cerebrovascular shunts have been largely ignored, perhaps because of a lack of physiological evidence demonstrating the transition from capillary flow to MVS flow. Our studies have shown that high intracranial pressure induces a transition from capillary to microvascular shunt flow resulting in cerebral hypoperfusion, tissue hypoxia and brain edema, which could be delayed by increasing cerebral perfusion pressure. The transition from capillary to microvascular shunt flow provides for the first time a physiological basis for evaluating the optimal cerebral perfusion pressure with increased intracranial pressure. It also provides a physiological basis for evaluating the effectiveness of various drugs and therapies in reducing intracranial pressure and the development of brain edema and tissue hypoxia after brain injury and ischemia. In summary, the clear-cut demonstration of the transition from capillary to MVS flow provides an important method for evaluating various therapies for the treatment of brain edema and loss of autoregulation.

Unifying theory of carotid plaque disruption based on structural phenotypes and forces expressed at the lumen/wall interface.

OBJECTIVES: To integrate morphological, haemodynamic and mechanical analysis of carotid atheroma driving plaque disruption. MATERIALS AND METHODS: First, we analysed the phenotypes of carotid endarterectomy specimens in a photographic dataset A, and matched them with the likelihood of preoperative stroke. Second, laser angioscopy was used to further define the phenotypes in intact specimens (dataset B) and benchmark with histology. Third, representative vascular geometries for each structural phenotype were analysed with Computational Fluid Dynamics (CFD), and the mechanical strength of the complicated atheroma to resist penetrating forces was quantified (n=14). RESULTS: In dataset A (n=345), ulceration (fibrous cap disruption) was observed in 82% of all plaques, intraplaque haemorrhage in 68% (93% subjacent to an ulcer) and false luminal formation in 48%. At least one of these 'rupture' phenotypes was found in 97% of symptomatic patients (n=69) compared with 61% in asymptomatic patients. In dataset B (n=30), laser angioscopy redemonstrated the structural phenotypes with near-perfect agreement with histology. In CFD, haemodynamic stress showed a large pulse magnitude, highest upstream to the point of maximal stenosis and on ulceration the inflow stream excavates the necrotic core cranially and then recirculates into the true lumen. Based on mechanical testing (n=14), the necrotic core is mechanically weak and penetrated by the blood on fibrous cap disruption. CONCLUSIONS: Fibrous cap ulceration, plaque haemorrhage and excavation are sequential phenotypes of plaque disruption resulting from the chiselling effect of haemodynamic forces over unmatched mechanical tissue strength. This chain of events may result in thromboembolic events independently of the degree of stenosis.

Failure of cerebral hemodynamic selection in general or of specific positron emission tomography methodology?: Carotid Occlusion Surgery Study (COSS).

BACKGROUND AND PURPOSE: The Carotid Occlusion Surgery Study (COSS) was an improvement over the Extracranial-Intracranial Bypass Study, which did not utilize physiological selection. To assess possible reasons for early closure of the COSS trial, we reviewed COSS methods used to identify high-risk patients and compared results with separate quantitative data. METHODS: Increased oxygen extraction fraction (OEF) by positron emission tomography is a gold standard for ischemia, but the specific thresholds and equivalency of the semiquantitative OEF ratio utilized in COSS and quantitative OEF are at issue. RESULTS: The semiquantitative hemispheric OEF ratio used in COSS did not identify the same group of patients as did quantitative OEF using a threshold of 50%. CONCLUSIONS: The failure of COSS is likely caused by a failure of the semiquantitative, hemispheric OEF ratio method rather than by the selection for bypass based on hemodynamic compromise.

MicroRNA Analysis of Human Stroke Brain Tissue Resected during Decompressive Craniectomy/Stroke-Ectomy Surgery.

BACKGROUND: Signaling pathways mediated by microRNAs (miRNAs) have been identified as one of the mechanisms that regulate stroke progression and recovery. Recent investigations using stroke patient blood and cerebrospinal fluid (CSF) demonstrated disease-specific alterations in miRNA expression. In this study, for the first time, we investigated miRNA expression signatures in freshly removed human stroke brain tissue. METHODS: Human brain samples were obtained during craniectomy and brain tissue resection in severe stroke patients with life-threatening brain swelling. The tissue samples were subjected to histopathological and immunofluorescence microscopy evaluation, next generation miRNA sequencing (NGS), and bioinformatic analysis. RESULTS: miRNA NGS analysis detected 34 miRNAs with significantly aberrant expression in stroke tissue, as compared to non-stroke samples. Of these miRNAs, 19 were previously identified in stroke patient blood and CSF, while dysregulation of 15 miRNAs was newly detected in this study. miRNA direct target gene analysis and bioinformatics approach demonstrated a strong association of the identified miRNAs with stroke-related biological processes and signaling pathways. CONCLUSIONS: Dysregulated miRNAs detected in our study could be regarded as potential candidates for biomarkers and/or targets for therapeutic intervention. The results described herein further our understanding of the molecular basis of stroke and provide valuable information for the future functional studies in the experimental models of stroke.

Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group.

BACKGROUND AND PURPOSE: In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. METHODS: An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. RESULTS: It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. CONCLUSIONS: The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

The impact of a telehealth web-based solution on neurosurgery triage and consultation.

INTRODUCTION: To enhance the quality of neurosurgery consultations, triage, and transport decisions between a Level I trauma service neurosurgery program at the University of New Mexico Hospital and referring hospitals, a secure Health Insurance Portability and Accountability Act (HIPAA)-compliant Web-based system was developed, to which digital neurological images could be sent for review by a neurosurgeon for consultation or patient transfer. Based upon prior experience of neurosurgery, it was predicted that 25% of transfer requests would be avoided if the neurosurgeons reviewed the computerized tomography scans at the time of a transfer request. In addition, it was predicted in 25% of the case that changes in management recommendations would take place independent of the transfer decision. METHODS: The program was designed to allow referring hospitals to transmit digital images to the Web site, providing consulting doctors with additional patient information. This project analyzed the neurosurgeons' responses to questions designed to determine if transport or management decisions were altered when using this telehealth program in response to a request for consultation or transfer from a rural facility. RESULTS: Analysis of the responses of the consulting neurosurgeons revealed that, after viewing the images, 44% of the potential transfers were avoided and 44% of consulted cases resulted in management recommendation changes independent of the transfer decision. CONCLUSIONS: Use of the system resulted in improved triage and changes in transfer or management recommendations. A significant number of potential transfers were avoided, resulting in transport cost avoidance, more effective use of resources, and more appropriate use of the neurosurgery service as well as improved patient preparation.

Radiographic assessment of vasospasm after aneurysmal subarachnoid hemorrhage: the physiological perspective.

OBJECTIVES: Vasospasm following aneurysmal subarachnoid hemorrhage is ascribed to be the cause of morbidity and mortality in 10-30% of patients. Vascular narrowing following SAH defined by angiography (along with non-invasive vascular imaging such as CT angiography) is, however, present in most patients. We seek to describe the need for understanding the clinically relevant syndrome of delayed ischemic neurological deficit (DIND) and to describe various perfusion techniques which in addition to vascular imaging studies, are needed to fully understand when delayed neurological deficits are due to due vasospasm induced ischemia. METHODS: The literature regarding various perfusion techniques as they relate to vasospasm and DIND was reviewed. RESULTS: There are many techniques which offer some data regarding cerebral blood flow in the setting of DIND. Truly quantitative techniques such as positron emission tomography and xenon CT offer powerful tools to identify areas at increased risk for infarction. Xenon CT is a practical technique which may be performed at the bedside and may be used to assess cerebral blood flow response to a changing variable. DISCUSSION: Perfusion techniques offer clinical data which may be applied to the care of an individual patient so that treatment may be tailored to that patient's physiological needs. This allows the clinician to pursue a rational strategy for diagnosis and treatment of a patient with a delayed neurological deficit following aneurysmal SAH.

Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease: A Review.

Importance: Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality. Observations: We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies that provide insight into CCM pathogenesis and indicate molecular mechanisms as potential therapeutic targets. These studies report dysregulated cellular pathways shared between CCM, cardiovascular diseases, and cancer. They also suggest the potential effectiveness of proper drug repurposing in association with, or as an alternative to, targeted interventions. Conclusions and Relevance: We propose methods to exploit specific molecular pathways to design patient-tailored therapeutic approaches in CCM, with the aim to alter its natural progression. In this scenario, the lack of effective pharmacologic options remains a critical barrier that poses an unfulfilled and urgent medical need.

MRI-Guided High-Intensity Focused Ultrasound as an Emerging Therapy for Stroke: A Review.

Stroke, either ischemic or hemorrhagic, accounts for significantly high morbidity and mortality rates around the globe effecting millions of lives annually. For the past few decades, ultrasound has been extensively investigated to promote clot lysis for the treatment of stroke, myocardial infarction, and acute peripheral arterial occlusions, with or without the use of tPA or contrast agents. In the age of modern minimal invasive techniques, magnetic resonance imaging-guided high-intensity focused ultrasound is a new emerging modality that seems to promise therapeutic utilities for both ischemic and hemorrhagic stroke. High-intensity focused ultrasound causes thermal heating as the tissue absorbs the mechanical energy transmitted by the ultrasonic waves leading to tissue denaturation and coagulation. Several in-vitro and in-vivo studies have demonstrated the viability of this technology for sonothrombolysis in both types of stroke and have warranted clinical trials. Apart from safety and efficacy, initiation of trials would further enable answers regarding its practical application in a clinical setup. Though this technology has been under study for treatment of various brain diseases for some decades now, relatively very few neurologists and even neurosurgeons seem to be acquainted with it. The aim of this review is to provide basic understanding of this powerful technology and discuss its clinical application and potential role as an emerging viable therapeutic option for the future management of stroke.