Stroke is an enormous public health problem as it is one of the leading causes of both death and disability worldwide. The word “stroke” is used by different groups of people in different ways, often leading to confusion. To avoid this, it can be helpful to distinguish the syndromes from the disorders related to the term.
A stroke syndrome involves the sudden onset of symptoms or signs that match a focal area of the central nervous system, without features suggesting a nonvascular cause. Technically, this includes the spinal cord and retinae, but the word “stroke” is used mainly for events involving the brain. The word “focal” in this context is important, and clinicians often divide syndromes of the central nervous system into those that are focal and those that are nonfocal. A focal syndrome may involve one lobe of the cerebrum or a small area of the brain stem or cerebellum, whereas a nonfocal, or diffuse, brain syndrome usually involves most of the cerebral cortex on both sides. Stroke commonly involves focal brain syndromes and rarely involves diffuse brain syndromes, which are more commonly caused by the large number of conditions that can cause syndromes such as syncope or delirium. Some sudden-onset, focal central nervous system syndromes may appear similar to stroke syndromes, except for features suggesting a nonvascular cause, such as the tonic or clonic motor activity that may occur with seizures.
The disorders that usually cause stroke syndromes are divided into two categories: ischemic stroke and hemorrhagic stroke. Ischemia involves insufficient blood flow, and hemorrhage involves bleeding. Ischemic stroke is more common, and is usually caused by the sudden occlusion of a cerebral artery, most often from a thrombus (blood clot), although there are other mechanisms by which cerebral ischemia may occur. Hemorrhagic stroke is divided into spontaneous intracerebral (also called “intraparenchymal”) hemorrhage, which is bleeding into the brain tissue, and spontaneous subarachnoid hemorrhage, which is bleeding into the cerebrospinal fluid that surrounds the brain and spinal cord. Bleeding into these spaces and other intracranial spaces may also occur with trauma, but most clinicians do not use the word “stroke” for traumatic intracranial hemorrhage.
Focal cerebral ischemia may cause a temporary stroke syndrome because of dysfunction of brain tissue from lack of blood flow, but then perfusion may be restored before infarction occurs. Infarction is irreversible tissue injury from ischemia. The term “transient ischemic attack” is used for this situation, but an older and a newer definition are both in common use. The older definition was a stroke syndrome that completely resolves within 24 hours. This definition was developed before modern brain imaging techniques, which then led to the realization that many of the patients had visible cerebral infarction on scans. The new definition is a stroke syndrome that resolves rapidly without evidence of cerebral infarction on testing. Transient ischemic attack is often described to patients as a “mini-stroke.”
Many patients have misunderstandings about stroke, often confusing it with cardiac events, or other neurological events such as seizures or “pinched nerves.” This is understandable but unfortunate, because it causes many patients to have a delay in presentation to medical attention that may lead to missed treatment opportunities. On the clinical side, it is also not uncommon for stroke patients to be initially misdiagnosed, because there are a large number of stroke syndromes that may occur, often with clinical features that heavily overlap with other disorders. The optimal strategies for tests and treatments of different stroke patient populations are evolving rapidly, and the following information will describe the fundamentals for approaching this increasingly complex area of medicine.
There is historical evidence that stroke was recognized as a cause of death and disability since antiquity. However, because advanced age is one of the strongest risk factors for stroke, its incidence likely has increased gradually over time as life expectancy has increased.
Stroke, like all diseases, was probably attributed to supernatural causes integral with the dominant religion of the people involved. For example, authors have speculated about possible cases of stroke in the Bible, such as when Saul was struck blind on the road to Damascus (Bullock, 1978), or the child of the Shunammite woman: “And he said unto his father, my head, my head. And he said to a lad, carry him to his mother. And when he had taken him, and brought him to his mother, he sat on her knees till noon, and then died” (Mathew & Pandian, 2010).
What could be described as the first medical descriptions of stroke are attributed to the person or people called Hippocrates in the fourth and fifth centuries BCE (Nilsen, 2010). In addition to describing contralateral weakness from traumatic brain injury, there are also descriptions of cases with spontaneous abnormal speech with right-sided paralysis (Nilsen, 2010). The term apoplexy was used for these cases, which translated as “struck with violence,” presumably referring to the suddenness of the syndrome onset (Nilsen, 2010). An alternative, and more colorful, translation is “struck with violence as if by a thunderbolt” (Quest, 1990). The word “apoplexy” gradually dwindled into use for hemorrhage into some organs, and the word “stroke” replaced it, initially appearing in English in 1599; the term “cerebrovascular accident” also developed as a synonym at some point (Nilsen, 2010). The Hippocratic writings described cases of attacks of numbness preceding apoplexy, which were likely transient ischemic attacks, and cases of sudden headaches followed by deterioration of consciousness and death, which were likely hemorrhagic stroke (Quest, 1990). Apoplexy was attributed to “heating of cranial vessels with subsequent flow of phlegm or black bile to the head” (Quest, 1990). In the second century BCE, Aretaeus of Cappadocia hypothesized that apoplexy could be caused by abnormal blood flow (Quest, 1990). In the second century CE, Galen proposed that phlegm blocked the flow of animal spirits through brain arteries (Quest, 1990). These ideas largely held for the next millennium, and common treatments included bloodletting, purging, and vomiting based on these humoral concepts of disease (Caplan, 2004; Nilsen, 2010; Quest, 1990).
Multiple developments occurred in the 17th century. Nymman suggested cardioembolism as a cause of apoplexy, Wepfer described brain hemorrhage and cerebral arterial occlusion, and Willis refined cerebrovascular anatomy and described transient ischemic attack. In the 18th and 19th centuries, increasingly accurate distinctions developed about the kinds and causes of stroke through clinical, pathological, and laboratory descriptions by many, including Morgagni, Baillie, Cheyne, Bright, Cooper, Virchow, Serres, Abercrombie, Charcot, Duret, Bouchard, and Osler (Caplan, 2004; Nilsen, 2010; Quest, 1990).
Advances accumulated rapidly during the 20th century, involving too many people to name here (Caplan, 2004; Nilsen, 2010; Quest, 1990). Vascular imaging developed, first with direct injection angiography, then later with catheter angiography, as well as brain imaging with computed tomography and magnetic resonance imaging. Preventive treatments for stroke became widespread, including an understanding of lifestyle risk factors, treatments for vascular risk factors, antithrombotic agents, and surgical treatments such as carotid endarterectomy. All of this history has led up to now, which is the era of expanding acute stroke treatments involving reperfusion for ischemic stroke, as well as critical care and surgical interventions seeking to improve outcomes for both ischemic and hemorrhagic stroke patients.
Stroke occurs because of a disruption of the brain’s blood supply. Broadly, there are three general mechanisms by which this disruption occurs; these involve the heart, the blood vessels, or the blood. The specific diseases affecting each of these three components of the cerebrovascular system are discussed in the etiology section.
Heart: Strokes arising because of heart disease are almost always ischemic; they are due to embolism of clot (and rarely, other material) from the heart into a cerebral artery.
Blood vessels: Occlusion of a cervical or cerebral artery causes brain ischemia, whereas blood vessel rupture causes hemorrhage.
Blood: Coagulopathies result in an excessive tendency toward either thrombosis of a cervical or cerebral blood vessel or hemorrhage into or around the brain.
Atrial fibrillation: The most common cardiac condition leading to stroke is atrial fibrillation. In this condition, the heart’s atria do not contract regularly, but rather quiver continuously. Blood flow within the fibrillating atria is turbulent, which can lead to clot formation. Pieces of clot can then break loose, travel into the brain, and lodge in the cerebral circulation; this causes ischemic stroke.
Ventricular thrombosis: Occasionally, thrombus forms in the left ventricle rather than the left atrium and then embolizes into the brain. A common cause of this is myocardial infarction, where the ventricle’s contractions are not well coordinated, leading to turbulent blood flow and thrombus formation.
Patent foramen ovale (PFO): The foramen ovale is an opening between the right and the left atria of the heart. In utero, it is normally patent, allowing deoxygenated blood to bypass the not-yet-functioning lungs and to instead be oxygenated via the placenta. The foramen normally closes at birth, but remains somewhat patent in approximately 25% of people. In a person with a venous thrombus, most commonly a deep venous thrombosis of the leg, the clot may migrate through the venous system and into the right atrium. Instead of being carried into the pulmonary arteries (causing a pulmonary embolism), the clot can instead traverse the PFO, enter the left atrium, and then be carried into the cerebral circulation, causing an ischemic stroke.
Endocarditis: Endocarditis refers to inflammation of the heart’s valves. It can be infective or noninfective. Infective endocarditis is caused by a variety of bacteria. It arises when bacteria enter the bloodstream, often because of poor dentition, intravenous drug abuse, or an immunocompromised state. Pieces of infective debris can dislodge from the heart, causing ischemic stroke. The noninfective endocarditides, often called “marantic” or “Libman–Sacks” endocarditis, are associated with cancer and rheumatological conditions, respectively.
Intracardiac tumor: Much less common than the just-listed conditions are the formation of tumors within the heart. These include papillary fibroelastomas and atrial myxomas. Fragments of the tumor can break loose and travel into the brain, causing vascular occlusion and ischemic stroke.
Atherosclerosis: Atherosclerosis is an extremely common disease and a leading cause of stroke. It can occur in any vascular bed (coronary, visceral, peripheral, etc.), and the cerebral circulation is a common site of involvement. Embolization of atheromatous debris or, more commonly, associated thrombus, from the aortic arch, carotid or vertebral arteries, or the intracerebral vessels deeper into the brain leads to ischemic stroke. Atherosclerosis can also cause occlusion of the larger arteries in the neck and brain via thrombosis (i.e., the clot occludes the vessel at that location and does not embolize further).
Lipohyalinosis: Lipohyalinosis is a pathology of the microvasculature—the smallest arteries deep within the brain. The arteries essentially degenerate and either become occluded, leading to small (lacunar) infarcts, or they rupture, leading to intracerebral hemorrhage.
Amyloid angiopathy: Amyloid angiopathy is another pathology of the microvasculature. It is characterized by the deposition of a protein called “amyloid” in the walls of the brain’s arteries. It is very similar to the amyloid deposited in the brain parenchyma in patients with Alzheimer’s disease, and the two conditions often coexist. The classic manifestation of cerebral amyloid angiopathy is intracerebral hemorrhage, often in lobar locations, as opposed to the hemorrhages of lipohyalinosis, which occur in the basal ganglia, brain stem, thalamus, and cerebellum. Amyloid angiopathy has other, less common, clinical manifestations as well.
Saccular aneurysm: Saccular aneurysms are outpouchings of the larger cerebral vessels that run in the subarachnoid space at the base of the brain. Rupture of these aneurysms causes subarachnoid hemorrhage.
Dissection: Dissection is a relatively common cause of stroke in younger patients. It involves disruption of the arterial wall, with blood tracking in between the wall’s layers and compromising flow through the lumen of the vessel. Clots can form at the site of disruption or elsewhere in the artery because of turbulent blood flow. Dissections can arise as a complication of trauma (e.g., motor vehicle accidents or sports injuries) or spontaneously.
Vascular malformation: These include arteriovenous malformations (AVMs), cavernous angiomas, and developmental venous anomalies. Rupture of these lesions (most commonly, AVMs) leads to intracerebral hemorrhage.
Vasospasm: Vasospasm is a narrowing of the artery owing to contraction of its muscular wall. The impairment of blood flow past the narrowing results in cerebral ischemia. There are two main causes of vasospasm:
Subarachnoid hemorrhage: One of the most feared complications of aneurysmal subarachnoid hemorrhage is delayed cerebral ischemia. The presence of blood in the subarachnoid space, through which the major cerebral arteries course, results, via an unknown mechanism, in vasospasm and thus cerebral ischemia. This is typically delayed by a few days to a few weeks after the subarachnoid hemorrhage.
Reversible cerebral vasoconstriction syndrome (RCVS): RCVS is characterized by sudden, severe headache, the absence of subarachnoid hemorrhage, and the finding of arterial narrowing on vascular imaging that normalizes upon repeat imaging. It is associated with many conditions, including various drug exposures, the postpartum state, neurosurgical procedures, and sexual activity, among others.
Vasculitis: Inflammation of the arteries is termed “vasculitis.” Vasculitis of the brain can be primary, meaning that it arises alone, or it can be part of a rheumatological disorder such as polyarteritis nodosa, Wegener’s granulomatosis, or Churg–Strauss syndrome. When larger arteries are involved, the inflammation can cause narrowing of the vessels that looks like vasospasm and leads to thrombosis and thromboembolism. Involvement of the microvasculature can cause either vascular occlusion and ischemic stroke or vascular rupture and intracerebral hemorrhage.
Anticoagulation: The most common coagulopathy is that caused by therapeutic anticoagulation, usually to prevent thromboembolism in patients with atrial fibrillation. When the intensity of anticoagulation is too high, hemorrhage can occur in any brain compartment—usually intracerebral or subdural hemorrhage.
Prothrombotic drugs: Drugs with prothrombotic effects include estrogens (found in oral contraceptives and hormone replacement therapies), testosterone, tamoxifen, bevacizumab, and glucocorticoids. These are associated mostly with venous thromboembolism, including cerebral venous sinus thrombosis.
Antiphospholipid antibodies: Patients with a lupus anticoagulant, particularly anticardiolipin or anti–beta 2-glycoprotein I antibodies, are hypercoagulable. Such antibodies arise in the setting of lupus and other rheumatological conditions, but can also occur alone. Unlike most other hypercoagulable states, antiphospholipid antibodies are most strongly associated with arterial rather than venous thrombosis.
Other acquired prothrombotic states:
Pregnancy: Pregnancy is a relatively hypercoagulable state, causing mostly venous thromboembolism.
Malignancy: Malignancy is also a relatively prothrombotic state. It is associated with both venous and arterial thrombosis.
Trauma: Trauma, especially major trauma, is associated with venous thromboembolism.
Hereditary thrombophilias: These include deficiencies of antithrombin or proteins C or S and mutations in the factor V and prothrombin genes. Such thrombophilias are most closely associated with venous thromboembolism.