Penetrating arterioles branch into an extensive network of capillaries. Capillaries are not found around large vessels providing 50% of the extracted O2. Majority of the remaining O2 is extracted from the first few order capillaries during rest and also from high-branching-order capillaries during activation. This requires a final step of regulation after the arterioles to match the focal demand by nearby tissue, which appears to be mediated by microvascular pericytes. The coupling of flow with metabolism demands a close interaction between the endothelia, pericytes, astrocytes, and perimicrovascular nerves. Pericytes are also required for the formation and maintenance of the blood–brain barrier (BBB). Microvessels are vulnerable to injury; the damage induced by ischemia limits reperfusion after recanalization (no reflow) and disrupts the BBB. Increasing evidence suggests that microvascular dysfunction also plays a role in the pathophysiology of dementia, small vessel disease, and, in the adverse effects of diabetes and hypertension on brain.
Migraine headache affects millions of people and is usually benign. It has been linked with stroke through genetic and vascular studies and epidemiologic observations. Migraine with aura doubles the risk of stroke in women and young adults and is associated with cardiac risk factors, patent foramen ovale, dissection, and small-vessel ischemic stroke. Migraine produces a cortical spreading depression, increases platelet aggregation, causes vasomotor and oligemic instability, and activates inflammatory cascades that may predispose to ischemic stroke. White matter abnormalities on magnetic resonance angiography of the brain of patients with migraine may represent subcortical silent infarctions. The aura of migraine may be prolonged and mimic transient ischemic attack or stroke, acutely complicating emergent treatment decisions. Rare syndromes with stroke and migraine as core manifestations may be difficult to recognize and definitively diagnose. There is immediate need for awareness of the intersecting symptoms of these two conditions for appropriate diagnosis, treatment, and prevention.
Magnetic resonance imaging (MRI) provides a powerful (neuro)imaging modality for the diagnosis and outcome prediction after (acute) stroke. Since MRI allows noninvasive, longitudinal, and three-dimensional assessment of vessel occlusion (with magnetic resonance angiography (MRA)), tissue injury (with T1-, T2-, T2∗-, and/or diffusion-weighted MRI), and hemodynamics (with perfusion MRI), it offers a valuable tool for (pre)clinical and experimental studies on stroke pathology, treatment, and recovery. Combined MRI protocols that inform of different aspects of stroke pathophysiology enable the delineation of irreversibly damaged tissue and, potentially salvageable, tissue at risk of infarction, based on concepts like the perfusion-diffusion mismatch, or by predictive modeling of infarct probability. These approaches can aid in the selection of patients who could respond favorably to thrombolysis or thrombectomy. Furthermore, structural and functional MRI of the progression of affected tissue may contribute to the monitoring and characterization of effects of (experimental) therapeutic interventions aimed at improving outcome after stroke.
Aneurysmal rupture leading to subarachnoid hemorrhage (SAH) represents a dire clinical entity with profound neurologic and systemic manifestations. Despite several advances in microsurgical and endovascular technology, mortality rates remain high, and survivors often suffer substantial neurologic morbidity. In these patients, presentation can range from a moderate acute onset headache to a near-comatose state. Optimal care relies on accurate and prompt diagnosis to minimize the deleterious effects of the subarachnoid blood on the central nervous system (CNS) and to eliminate the risk of rerupture. The acute care of these patients focuses on the prevention of a rerupture with either open surgical or endovascular intervention. Subsequent intensive care of these patients is driven by the prevention of vasospasm, hydrocephalus, and management of acute medical issues associated with SAH. The care of SAH requires a concerted effort of multispecialty physicians for the prompt recognition, treatment, and management of this profound disease entity.
A dissection is a hematoma within the arterial wall, that can be spontaneous or the result of trauma. Cervicocephalic arterial dissections are a common cause of cerebrovascular disease, particularly in younger patients in whom atherosclerosis is less prevalent. The clinical presentation of dissections is variable. The pain fibers within the arterial wall are compressed by dissection causing ipsilateral headaches or neck pain, sometimes as the only symptom. Dissections of the cervicocephalic arteries can also result in an ischemic stroke or a subarachnoid hemorrhage. The arterial hematoma can result in a flow-limited lesion or an intramural thrombus, either of which can lead to brain ischemia. Dissection in intracranial vessels can also result in a "pseudoaneurysm" (dissecting aneurysm) that can cause a subarachnoid hemorrhage if it ruptures. Prevention of further ischemic events is typically done with antithrombotic agents, and endovascular procedures in complicated cases. Brain ischemia secondary to cervicocephalic arterial dissections has generally a better prognosis than ischemia due to atherosclerotic cerebrovascular disease.
This chapter describes various aspects of primary platelet disorders. Platelets are small biconcave cells that are essential for adequate hemostasis. Platelet disorders can lead to both hemorrhagic and ischemic strokes. Platelet abnormalities can be divided into quantitative abnormalities or qualitative abnormalities of platelet function. Primary thrombocythemia is a rare myeloproliferative disorder in which platelets are produced in excess. The diagnosis of primary thrombocythemia requires exclusion of other causes of increased platelets such as carcinoma and infection. Treatment of primary thrombocythemia can include plateletpheresis and chemotherapy. Cessation of smoking may also lessen the frequency of thrombotic events. Idiopathic thrombocytopenic purpura is an autoimmune disorder in which IgM and IgG antibodies attack the platelet glycoprotein membrane, diminishing the lifespan of the platelet. Platelet dysfunction is seen in nearly all patients undergoing cardiopulmonary bypass (CPB). Most of these abnormalities of platelet aggregation and activation are reversible soon after cessation of CPB. Hemorrhagic complications are often due to additional variables affecting hemostasis during surgery such as the use of heparin. The treatment of bleeding complications may include platelet transfusion and desmopressin.
Ischemic tolerance was originally induced by in situ ischemic preconditioning (PreC, i.e., before ischemia). This classic concept of ischemic PreC has now evolved into ischemic postconditioning (PostC, i.e., after ischemia), remote PreC and PostC, and remote perconditioning (PerC, i.e., during ischemia). In addition, ischemic tolerance induced by ischemic PreC and PostC can be triggered by many nonischemic stressors. Each type of ischemic conditioning has specific therapeutic time windows, and unique protective mechanisms. PreC adapts the brain to resist brain injury induced by a subsequent severe stroke; PostC alters reperfusion after a stroke to attenuate the brain injury it caused. In contrast, remote conditioning exerts its effect on the brain via various factors produced in the remote ischemic organ. Despite these differences, the protective mechanisms of in situ and remote conditioning converge on some similar cellular and molecular mechanisms at a later stage after stroke.
Ischemic stroke presents several opportunities for medical intervention, distinguished by their relative timing: (1) primary prevention of a stroke; (2) control of tissue damage in the acute ischemic stroke setting; and (3) secondary prevention following a transient ischemic attack or stroke.
As cancer and stroke are, respectively, the second and fifth leading causes of mortality in the United States, it is not surprising to encounter a patient with these concomitant diagnoses. Various cerebrovascular disorders can occur within the oncological population, complicating the overall clinical course, treatment, and long-term outcome of cancer patients. Detailed investigation and precise diagnosis of cerebrovascular disorders in cancer patients is important for several reasons. Early recognition of acute stroke may allow the cancer patient access to interventional thrombolytic, surgical, and endovascular therapies, and improve overall patient outcome. Secondary stroke prevention therapies are also guided by the etiology of the particular cerebrovascular event. Additionally, diagnostic workups in young or cryptogenic stroke patients without overt cancer can lead to the first recognition of the underlying malignancy. This chapter presents an overview of cerebrovascular complications from cancer.
Eicosanoids, enzymatically generated oxidation products of arachidonic acid, contribute to cerebrovascular disease in diverse ways that we are only beginning to fully understand. With the advent of improved analytical techniques and increased knowledge of the metabolic pathways by which eicosanoids are generated in the brain following an ischemic event, it has become possible to specifically target both the enzymes that generate eicosanoids, as well as the receptors they act upon. This chapter will highlight the contributions of cyclooxygenases, lipoxygenases, and members of the cytochrome P450 family of proteins to stroke-induced brain pathology, as well as illustrate ways to target eicosanoid pathways for stroke therapy.
Since most mRNA and microRNA (miRNA) are known, and can be assessed using arrays or RNAseq, they offer unique insight into the molecular biology of ischemic stroke and hemorrhage. Although no one blood mRNA or miRNA can diagnose stroke or hemorrhage, panels or profiles of mRNAs/miRNA can distinguish ischemic stroke from intracerebral hemorrhage and control patients. There are also specific profiles of mRNA and miRNA in blood for large-vessel, cardioembolic, and lacunar causes of stroke that can be used to predict the causes of cryptogenic stroke. There are also specific profiles for patients with ischemic compared with nonischemic transient neurological events, and profiles within 3 h of a stroke that predict which patients will develop hemorrhagic transformation following tissue plasminogen activator.
Cerebral angiography was introduced and expanded by the Portuguese neurologist Egas Moniz close to a century ago. Significant morbidity and mortality lead to a transition to iodinated solution as contrast media, leading to satisfactory technical results. Despite the original "distrust" and controversy regarding this method and its future, cerebral angiography not only remains the gold standard for the diagnosis of vascular conditions affecting the craniocervical and cerebral vessels, but has also developed itself into a very sophisticated interventional field. This chapter discusses indications, risks, periprocedural care, as well as recent advancements in the field of cerebral angiography.
Regulation of cerebral blood flow (CBF) is determined mainly by changes in diameter of resistance vessels in brain. The moment-to-moment changes in vessel diameter are primarily the function of vascular muscle. Vascular muscle receives, integrates, and responds to mechanical forces as well as signals from other cell types. In this chapter, we summarize some recent advances regarding the regulation of vascular tone in cerebral arteries and the microcirculation. We discuss myogenic tone and myogenic reactivity in the context of autoregulation, along with the impact of transient receptor potential channels. Major mechanisms of vasodilation are presented including the nitric oxide system, the impact of potassium channels, and effects of reactive oxygen species. Lastly, as proof of principle, we discuss the pathobiology of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy as an example of how a functional defect in vascular muscle can adversely affect CBF with resulting effects on brain function.
Two-photon microscopy enables the study of blood flow in the brain capillary network, with measurements of red blood cell speed and flux within individual capillaries. This chapter provides some practical guidance for conducting such measurements in models such as rodents. The vasculature can be visualized by intravenous dye injection, which shows blood cells in silhouette. Although most two-photon microscopes do not take images quickly enough to quantify flow speed in full-frame images, by limiting scanning to lines along the center of the vessels, these microscopes can capture red blood cell motion in nearly all the vessels in the rodent cortex. Several automated algorithms are available to extract cell speeds from such datasets. Images can also be used to identify capillaries that are stalled and have no moving red blood cells. Additional exogenous dyes or expression of fluorescent proteins can provide many complementary structural and functional measurement capabilities.
Cerebral edema, a buildup of fluid in the brain, occurs in many neurological conditions, including ischemic and hemorrhagic stroke. It is a major, potentially life-threatening, condition. This chapter discusses the mechanisms underlying cytotoxic (parenchymal cell injury) and vasogenic (vascular injury) edema after stroke. It particularly focuses on ion and water movements within the brain under normal and pathological conditions. Therapies for brain edema are limited and have not changed substantially in decades. It is hoped that a greater understanding of underlying mechanisms will lead to new approaches.
The Rho/Rho kinase (ROCK) pathway is a key molecular switch for many diverse cellular processes implicated in increasing the risk and worsening the outcome of cerebrovascular diseases including acute ischemic or hemorrhagic stroke, as well as chronic cerebrovascular dysfunction. ROCK inhibitors have been uniformly efficacious in animal models of focal or global cerebral ischemia, and subarachnoid hemorrhage, as well as in traumatic injury where they have improved neuroplasticity and recovery. However, there has been a conspicuous lag in clinical translation in part due to clinically unacceptable side effects of relatively poor selectivity of existing compounds toward ROCK over other kinases, and toward either one of the two known ROCK isoforms. Nevertheless, significant progress has been made over the past decade in both developing more selective compounds and characterizing their efficacy and safety profile in animal models that early phase clinical trials are anticipated.
