What's a Stroke?
Stroke, or cerebral infarction, is a sudden disruption of cerebral blood flow caused by occlusion or rupture of brain vessels. This alteration of the cerebral vascular system can be transitory, or permanent if it does not resolve itself spontaneously or through therapeutic action.
The cerebral damage caused by a stroke is immediate and can range from mild to severe, depending on how fast it is diagnosed and treated, the type of infarct and the patient’s evolution. Stroke symptoms can include sudden numbness or paralysis in the face or body, typically in one side only, as well as loss of equilibrium or sight, severe headache, dizziness, impaired speech and understanding. These neurological deficits depend on the brain’s area affected (Gunel and Lifton, 1996).
a) Definition of Stroke
In recent years, death rates from cardiovascular diseases (CVDs) have declined, yet the burden remains high for healthcare systems, with a 2005 overall rate of 280 per 100 000 habitants. About 795 000 people experience a new or recurrent stroke each year, making it the third cause of death in industrialized countries, behind myocardial infarction and cancer. Although the incidence of stroke is lower in women than men, with a death rate of 170 per 100 000 habitants (vs. 350 for men), it is the first cause of mortality in women. The incidence is approximately 100 times higher in the aging population, than in the young one. Stroke is also the first cause of adult disability and incapacity and it is estimated that 4/5 families will be somehow affected by stroke over the course of a lifetime (Lloyd-Jones et al., 2009).
Stroke can be categorized in two subtypes: (1) ischemic, caused by an occlusion of a cerebral vessel, or (2) hemorrhagic, caused by a bleeding in the brain (Figure 1).
Ischemic stroke can be classified as a large vessel disease, resulting from an embolism, when the obstruction of blood vessels is caused by a blood clot formed in the heart, or from a thrombosis, when a blood clot is formed locally often as a result of atherosclerosis, or a small vessel disease, associated with lipohyalinosis of small intracranial blood vessels observed as lacunae and leukoaraoisis on magnetic resonance imaging (MRI). The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) criteria is commonly used nowadays to classify patients with ischemic stroke into 5 core etiologic subgroups (Adams, Jr. et al., 1993): (1) atherothrombotic or large artery atherosclerosis (LAA); (2) cardioembolic (CE); (3) lacunar or small artery occlusion (SAO), if the artery diameter is less than 1.5 cm; (4) stroke of other determined cause (OC), including neoplasias, infections, dissections, malformations, etc; (5) stroke of undetermined cause (UND), if no cause was found despite an extensive evaluation or could not be determined because more than one plausible cause was found. Subtype definitions are based on risk factor profiles, clinical features and results of diagnostic tests, including CT scan, MRI, vascular imaging (carotid duplex, transcranial Doppler), electrocardiogram, echocardiography (transesophageal or transthoracic), assessment of prothrombotic syndromes and postmortem examination.
Hemorrhagic stroke is the sudden rupture and bleeding of a brain vessel, usually small arteries or arterioles. It represents 10 to 20% of all strokes and although its prognostic is usually rather bad, with a 30-days mortality rate of 45%, its molecular mechanisms are still little known. There are two types of hemorrhagic stroke, depending if bleeding occurs in the brain tissue, called intracerebral hemorrhage (ICH), or if blood leaks into the space surrounding the brain, called subarachnoid hemorrhage (SAH). Both subtypes generate similar symptoms, including partial or total loss of consciousness, nausea, severe headache, light intolerance or hemiplegia, but generally result from different causes. SAH can be due to ruptured aneurysms (a ballooning of the arterial wall) and vascular malformations. The most common diagnostic procedures for hemorrhagic stroke are CT scan, MRI and cerebral angiogram.
Figure 1. Schematic representation of the two subtypes of stroke (adapted from Cuadrado, 2009).
a) Treatments and prevention
Blood deprivation provoked by a stroke can lead to serious damage of the cerebral parenchymal tissue if measures are not taken promptly. Indeed, the absence of oxygen and glucose leads to rapid cell death in the core of the infarct and release of toxic chemicals in the surrounding area, the ischemic penumbra (Figure 2). The infarct core is injured irreversibly, so the central premise of stroke acute treatment is to rescue the penumbra. Amazingly, 42% of stroke patients wait as long as 24 hours before presenting for medical treatment, because of the poor public’s general knowledge regarding stroke (Paciaroni et al., 2009).
Figure 2. CT perfusion imaging of (A) cerebral blood volume (B) mean transit time in a patient with ischemic stroke in the right middle cerebral artery territory (C) the predicted irreversibly damaged core infarction (in red) and the potentially salvable ischemic penumbra (in green) (adapted from Paciaroni et al., 2009).
Treatment of ischemic stroke
The only approved treatment by the federal drug administration (FDA) for ischemic stroke during the acute phase is the administration of recombinant tissue plasminogen activator (rt-PA). Although rt-PA (sold under the brand name Activase) treatment was approved for acute heart attacks in the late 80’s, the FDA approved it to treat stroke in 1996 and nowadays, it is only administered to less than 5% of stroke patients in developed countries. The
reasons for this low percent are a small therapeutic window (<4.5 hours since symptoms onset) and exclusion of patients treated with anticoagulants, with evidence of hemorrhagic complications, with elevated blood pressure or sugar, recent surgery, low platelet count, end-stage liver or kidney disorders (Hacke and Lichy, 2008). t-PA occurs naturally in the body and presents fibrinolytic properties. It can form a complex with endogenous plasminogen to bind and destroy fibrin, dissolving the clot and provoking recanalization of the artery. However, its half-life is short in human blood, 5 to 10 minutes, since it rapidly binds to the plasminogen activator inhibitor (PAI-1), forming a t-PA/PAI-1 complex that is degraded by low-density lipoprotein receptor-related protein 1 (LRP1) (Gravanis and Tsirka, 2008).
There are two ways to administer rt-PA, intravenously (IV) or intra-arterially, although only the intravenous route has received FDA approval. The IV method needs significant amounts of rt-PA, because the drug becomes diluted in the blood stream as it travels to the site of blockage. The intra-arterial administration is faster and has been used by cardiologists for years. A thin, flexible catheter is introduced into the artery and steered up to the area of the clot where rt-PA is injected. The latter has a wider time window than the IV method and requires less rt-PA, thus reducing the possibility of adverse effects. Indeed, neurotoxic effects and hemorrhagic transformations (HT) can be caused by thrombolytic therapy (Figure 3). Symptomatic HTs can be classified as hemorrhagic infarct (HI) type one (HI-1), type two (HI-2), parenchymal hematoma (PH) type 1 (PH-1) and type two (PH-2), according to the gravity of the event. These complications affect about 5% of rt-tPA treated patients and show very high mortality rates. While t-PA can dissolve the clot that causes a blood vessel blockage, the interruption in blood flow causes an oxygen imbalance which results in massive free radical damage, which can be reduced by simultaneous administration of antioxidants.
Figure 3. MRI showing hemorrhagic transformation of an infarct in the left middle cerebral artery territory. (1) T1-weighted of a wedge-shaped hypointense area with a few isointense and hyperintense areas within it. (2) T2-weighted image showing predominantly hyperintense lesion with a few hypointense and isointense areas. (3) Gradient-echo image with marked blooming, suggestive of hemorrhage (adapted from http://emedicine.medscape.com/)
A new promising acute therapy for ischemic stroke is the combined use of sonolysis and microbubbles. The microbubbles injected are sub-micron sized lipid shells, encapsulating an inert biocompatible gas, and they can penetrate a blood clot where the application of ultrasounds will provoke their expansion and contraction, resulting in the breaking of the clot into very small particles (Molina et al., 2006). The MERCI retriever (Mechanical Embolus Removal in Cerebral Ischemia), a cork-screw shaped device, is the first FDA approved mechanical device for the treatment of ischemic stroke. A catheter is inserted into a patient’s leg artery and guided through the circulatory system to the brain until the clot is reached. At the clot, the retriever is deployed from inside the catheter and slowly rotated to ensnare the clot as a corkscrew would ensnare a cork. The entire apparatus is then withdrawn from the body.
In some cases, surgery may be needed to remove obstruction of the blood vessel. Generally, carotid artery stenosis is treated with carotid angioplasty, combined with the placement of a stent, which permits to mechanically widen the obstructed blood vessel. The stents, or tightly folded balloons, are passed into the narrowed locations and inflated to a fixed size using pressures 75 to 500 times normal blood pressure (6 to 20 atmospheres). Carotid endarterectomy can also be used. This procedure involves clamping of the internal, common and external carotid arteries, opening of the lumen of the internal carotid artery, and removing of the atheromatous plaque. A temporary shunt is created to ensure blood supply to the brain during the procedure, performed under general or local anesthesia. The latter allows direct monitoring of neurological status by intra-operative verbal contact and testing of grip strength. With general anesthesia, indirect methods of assessing cerebral perfusion must be used, such as electroencephalography, transcranial doppler analysis and carotid artery stump pressure monitoring. When intervention is not possible, the stroke team focuses on preserving as much of the brain as possible. This can be achieved in several ways, including some that are still investigational and not yet widely available, like hypothermia (Linares and Mayer, 2009).
Treatment of hemorrhagic stroke
Treatment of hemorrhagic stroke depends on the underlying cause of the hemorrhage and the extent of damage to the brain, and includes medication and surgical intervention. In patients with hypertension-induced ICH, initial treatment involves the use of antihypertensive agents. If the hemorrhage results from the use of anticoagulants, these medications are discontinued immediately and Protamine or vitamin K may be given to reduce bleeding. Antioxidants may be beneficial for the treatment of hemorrhagic stroke. In Europe, Hydergine is administered on an acute-care basis for the prevention of brain damage following stroke, but it has not been approved by the FDA, although it was approved in the treatment of other diseases. In patients with ruptured aneurysms, surgery is usually performed, by placing a metal clip around the base of the aneurysm, or by packing the aneurysm if the damaged area is difficult to approach. This method, also called embolization, uses microcoils (small and flexible wire coils), that are inserted into the aneurysm using a catheter. Blood cells are attracted to the coil and promote clot formation. Patients with ICH may also benefit from a surgical evacuation of the hematoma, but it is contra-indicated in patients ≥ 75 years old, who have significant pre-existing disease, or who arrive at the hospital in very poor condition (Towfighi et al., 2005).
Primary and secondary prevention of stroke are typically based on reducing the prevalence of risk factors and include treatments by anti-platelets (Trental, Ticlid), anticoagulants (Heparin, Coumadin), aspirin, neuroprotective agents (Hydergine, Piracetam), Ginkgo Biloba, melatonin or statins (Atorvastatin, Simvastatin).
c) Risk factors
A good understanding and management of stroke risk factors is essential to reduce its incidence in the general population. They can be divided in four groups, depending on their ability to be modified (Table 1) Goldstein and Hankey, 2006.
Firstly, social characteristics, such as socioeconomic factors, geographic location, season and climate have been related to stroke. Indeed, there is some evidence that people of low social class, income and educational level have a higher risk of stroke. Moreover, in the United States, stroke is more common in the south eastern area than in others, in the so-called “stroke belt” states, and in periods of extremely hot or cold temperatures.
Secondly, life style factors such as smoking, excessive alcohol consumption, diet, physical activity, use of oral contraceptives and anticoagulation treatment have been identified in recent years. Cigarette smoking is especially important since nicotine and carbon monoxide in cigarette smoke can highly damage the cardiovascular system and a combined use of oral contraceptives can greatly increase the risk. Excessive drinking set as an average of one drink per day for women and two drinks per day for men, as well as binge drinking can provoke high blood pressure, obesity, dyslipidemia, heart failure and stroke. Certain kinds of drug abuses, like cocaine or intravenous drugs are associated with important cardiovascular complications.
Thirdly, a multitude of abnormal physiological traits have been associated with stroke, such as atrial fibrillation, asymptomatic carotid stenosis, transient ischemic attacks, migraine, left-ventricular hypertrophy, sickle-cell disease, hypertension, diabetes mellitus, hypercholesterolemia, hyperhomocysteinemia, hyperfibrinogenemia, amyloid angiopathy and obesity. High blood pressure is the most prominent of those, and stroke risk is directly related to blood pressure. Effective treatment for hypertension is thus a key factor in the prevention of stroke. Diabetes mellitus is also an independent risk factor, although it is often strongly related to hypertension, obesity and dyslipidemia, hence multiplying the risk. Carotid artery disease and heart disease, particularly atrial fibrillation, are very strongly related to stroke, showing twice as much risk as healthy people. Previous stroke and transient ischemic attacks are strong predictors of stroke, with an estimated 10 times more risk between persons of the same and gender. Other secondary risk factors have been described, like risk factors for cardiovascular diseases obesity, physical inactivity, high red blood cell count and dyslipidemia. Among survivors of a stroke, heart attack is a frequent cause of death.
Table 1. Principal risk factors for stroke classified by their ability to be modified.
Finally, the last group includes inherent biological traits. Advanced age is particularly important and the chance of suffering a stroke doubles for each decade of life after 55. Men also show a 20% higher risk of stroke compared to women, although mortality is higher in women, in part because of birth control use or pregnancy that also present stroke risk. Race and ethnic origins have also been related to stroke, and African-Americans show a much higher risk of death and disability than Caucasians, partly because they have more risk of ICH and show a greater incidence of high blood pressure, diabetes and obesity. Additionally, in the last decades, evidence has been provided supporting a role for genetic background in ischemic stroke as well as hemorrhagic stroke. Indeed, in the early 90’s, a twin study on 2700 male twin pairs showed a five fold significant increase in the prevalence of stroke among monozygotic compared with dizygotic twin pairs (proband concordance rate of 18% vs. 4% respectively) (Brass et al., 1992). These results were confirmed later with another study on about 1000 twin pairs, showing that the heritability estimates were moderate, with 32% of liability for stroke mortality (Bak et al., 2002). Moreover, the Framingham Offspring Study and the Family Heart Study both showed that parental history of stroke increased the risk of stroke, be it maternal (relative risk of 1.5) or paternal (relative risk of 2.5) and that this familial aggregation could not be explained by conventional risk factors only (Kiely et al., 1993; Liao et al., 1997). Furthermore, an increasing number of monogenic (or single gene) disorders causing stroke are being described, and there is growing evidence that polygenic factors are important in the risk of sporadic stroke (Tournier-Lasserve, 2002). However, there is no clear agreements on which are the common genetic risk factors for the polygenic form of the disease.
The goal of the GeneStroke project is to identify those genetic risk factors.
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