Chapter 1: Transient Ischemic Attack, Traumatic Brain Injury, and Ischemic Stroke: Risk Factors and Treatments

The overall burden of stroke in the number of people affected is increasing, especially in the younger age groups and in lower-to-middle-income countries.^1–3  Despite some improvements in stroke prevention and management in high-income countries, the growth and aging of the global population is leading to a rise in the number of young and old patients with stroke. Closely related to this is the increasing number of people, including young children, who are overweight or obese.⁴  Obesity is a risk factor for stroke on account of it leading to atherosclerosis, which promotes thrombosis and obstruction to the flow of blood.⁵  Moreover, there is an increasing prevalence of hypertension, which also leads to atherosclerosis, and this in turn can lead to blockage of small blood vessels in the brain, causing stroke.^6–8 

In people experiencing a transient ischemic attack (TIA), the incidence of subsequent stroke is as high as 11% over the next 7 days and 24–29% over the following 5 years.⁹  Unlike a stroke, the symptoms of a TIA can resolve within a few minutes or within 24 hours. However, brain injury may still occur in a TIA lasting only a few minutes.¹⁰  A strong association has been shown between traumatic brain injury (TBI) and later development of ischemic stroke, which remained significant even after several potential confounders, such as vascular risk factors and comorbidities, were taken into consideration. The association was similar in magnitude to that of hypertension, which is the leading stroke risk factor.^8,11 

Early definitions of stroke and TIA focused on the duration of symptoms and signs. More recently, using clinical observation and modern brain imaging, it has been shown that the duration and reversibility of brain ischemia are variable. While brain tissue deprived of needed nutrients undergoes irreversible damage (infarction) in most individuals, in some patients it can survive for a considerable period of time, which may be several hours or even, rarely, days. In 2009, an expert committee of the American Heart Association/American Stroke Association (AHA/ASA) published a scientific statement defining TIA as a transient episode of neurological dysfunction caused by focal brain, spinal cord, or retinal ischemia without acute infarction.¹²  The word ‘transient’ indicates a lack of permanence. However, modern brain imaging has shown that many patients in whom symptoms and signs of brain ischemia are clinically transient have evidence of brain infarction. Similarly, ischemia may produce symptoms and signs that are prolonged (and would qualify as strokes in older definitions) and yet no permanent brain infarction has occurred. In 2013, the AHA/ASA published a scientific statement defining ischemic stroke as an episode of neurological dysfunction caused by focal cerebral, spinal, or retinal infarction. Stroke caused by intracerebral hemorrhage was defined as rapidly developing clinical signs of neurological dysfunction attributable to a focal collection of blood within the brain parenchyma or ventricular system that is not caused by trauma. Likewise, stroke caused by subarachnoid hemorrhage was defined as rapidly developing clinical signs of neurological dysfunction and/or headache because of bleeding into the subarachnoid space between the arachnoid membrane and the pia mater of the brain or spinal cord, which is not caused by trauma.¹³  TBI has been defined as a non-degenerative, non-congenital insult to the brain from an external mechanical force, possibly leading to permanent or temporary impairment of cognitive, physical, and psychosocial functions, with an associated diminished or altered state of consciousness.¹⁴  It usually results from a violent blow or jolt to the head or body. The resulting brain damage can be focal or diffuse. A focal TBI is usually caused by sudden contact; diffuse injury is more likely to be caused by an acceleration/deceleration trauma. The severity of TBI is determined by the nature, speed, and location of the impact, and by complications such as hypotension, intracranial hemorrhage, or increased intracranial pressure. These complications may cause secondary injury hours or even days after the trauma.¹⁵ 

Precise estimates of the incidence and prevalence of TIAs are difficult to determine because of varying criteria used in epidemiological studies to identify TIA. Failure of recognition by both the public and health professionals of the transitory focal neurological symptoms associated with TIAs may also lead to significant underestimates. Given these limitations, the incidence of TIA in the United States has been estimated to be 200 000–500 000 per year, with a population prevalence of 2.3%, which equated to 5 million individuals in 1999.^12,16  TIA incidence markedly increases with age and varies by race–ethnicity. The prevalence rate varies depending on the age distribution of the study population. The Cardiovascular Health Study estimated a prevalence of TIA in men of 2.7% for 65–69 years of age and 3.6% for 75–79 years of age. For women, TIA prevalence was 1.6% for 65–69 years of age and 4.1% for 75–79 years of age.¹⁷  In the Atherosclerosis Risk in Communities Study, the overall prevalence of TIAs among adults 45–64 years of age was 0.4%.¹⁸  Among patients who present with stroke, the prevalence of prior TIA may range from 7% to 40% depending on how TIA is defined, which stroke subtypes are evaluated, and whether the study is a population-based series or a hospital-based series. Variability in the use of brain imaging and the type of diagnostic imaging used can also affect estimates of the incidence and prevalence of TIAs. For example, a revision of the TIA definition to include the absence of changes on magnetic resonance imaging could lead to a decrease in the incidence of TIAs by 33% and a resultant 7% increase in the number of cases labeled as stroke.¹⁹ 

Approximately 795 000 strokes occur each year in the United States.²⁰  In total, 10–20% of patients have a stroke within 90 days following a TIA, and in up to 50% of these patients the stroke occurs within 24–48 hours.²¹  In 2000, there were 167 661 deaths in the United States attributable to stroke, which was nearly 24% of stroke patients.²²  The AHA/ASA reported that among non-Hispanic blacks, the relative risk of stroke is four-times higher than among whites at 35–54 years of age and three-times higher at 55–64 years of age. Among Hispanics and American Indians/Alaska natives, the relative risk is about 1.3-times higher than in whites at 35–64 and 45–54 years of age, respectively.^22,23  Ischemic stroke accounts for 87% of all strokes and can be divided into two main types: thrombotic and embolic. Thrombotic disease accounts for about 60% of acute ischemic strokes.²⁴  It is estimated that 14–30% of ischemic strokes are cardioembolic in origin.^25,26  The incidence of cardioembolic strokes increases with age.²⁵ 

TBI is the greatest cause of mortality and disability in young adults in modern Western societies. In the United States, 1.6 million people sustain a TBI each year, approximately 50 000 people die from a TBI, and 125 000 people are disabled 1 year after injury. However, the exact facts and figures on the incidence, prevalence, and long-term consequences of TBI are uncertain, and it is likely the incidence figures have to be multiplied by 5 or even 10 in order to include every unregistered patient.¹⁵  TBI is strongly associated with several neurological disorders 6 months or more after injury.²⁷  Seizures are associated with most types of TBI. About 25% of patients with brain contusions or hematomas and about 50% of patients with penetrating head injuries will develop seizures within the first 24 hours of the injury.¹⁵ 

The most important of the non-modifiable risk factors associated with stroke is age. Stroke is most prevalent among the elderly and the majority of strokes occur in those aged >65 years.²⁶  Age-related risk also increases for TIA, except for those in the oldest category (≥85 years), where it may decrease slightly.²⁸ 

Men are at greater risk of stroke, with the incidence rate being 1.25-times higher than in women.²⁹  Some differences between the genders have also been noted for stroke subtype. Men have about a fourfold greater age-adjusted incidence rate of ischemic stroke due to large vessel atherosclerosis than women, which may account for their higher rate of undergoing carotid endarterectomy.³⁰ 

Significant differences in stroke frequency have been found for race. Black Americans have a higher incidence of stroke than whites. The age- and gender-adjusted ischemic stroke incidence for blacks is 246 per 100 000, compared with 147 per 100 000 for whites.³⁰  Racial differences have also been found for the distribution of stroke subtype. Stroke due to large vessel atherosclerosis occurs more often among whites (27 per 100 000) than blacks (17 per 100 000). Cardioembolic and small vessel infarcts were the two most important identifiable causes of ischemic stroke among black Americans, and most small vessel strokes in blacks can be attributed to hypertension and diabetes.³¹ 

Hypertension is the most important modifiable stroke risk factor, with an age-adjusted relative risk of approximately 3 and an attributable risk that may be as high as about 50%, depending on age.³²  The risk for stroke increases proportionately with increasing blood pressure, with systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥95 mm Hg constituting a relative risk of approximately 4. Even small improvements in the control of hypertension can reduce stroke risk significantly.³²  In the United States in 2011–2012, 29% of adults aged ≥18 years had hypertension, and this was similar among men and women. This figure varied considerably depending on ethnicity and race, with the age-adjusted prevalence being 42.1% for non-Hispanic blacks, 28.0% for non-Hispanic whites, 26.0% for Hispanics, and 24.7% for non-Hispanic Asians. Hypertension increases with age, and according to estimates in the United States in 2011–2012, in adults aged ≥60 years the prevalence was 65.0%.³³  The percentage of those with hypertension controlled to a blood pressure of <140 mm Hg systolic and <90 mm Hg diastolic was <50%.^34,35 

Diabetes mellitus is a potentially modifiable risk factor with a relative risk of ischemic stroke of 1.8–3.0.³⁶  In the United States in 2012, 29.1 million inhabitants had diabetes, of which 21.0 million were diagnosed and 8.1 million were undiagnosed. The rates of diagnosed diabetes varies in different subgroups of the population and was 15.9% for American Indians/Alaskan Natives, 13.2% for non-Hispanic blacks, 12.8% for Hispanics, 9.0% for Asian Americans, and 7.6% for non-Hispanic whites.³⁷  Diabetes is associated with the development of atherosclerosis, hypertension, obesity, abnormal blood lipid levels, and ultimately stroke.

Active cigarette smoking has been attributed to causing approximately 18% of ischemic strokes, and the risk increases twofold among heavy smokers compared with light smokers. Former smoking has an attributable risk of 6%, with the level of risk varying according to the time since quitting, and major risk reduction occurs within 2–4 years of smoking cessation.³⁸  Cigarette smoke may enhance platelet aggregation, increase coagulability, blood viscosity, and fibrinogen levels, and raise blood pressure.³⁹ 

Previous stroke is a major risk factor. The cumulative risk for recurrent stroke is 3–10% in the first 30 days and 5–14% in the first year. The 5-year estimated recurrence rate is 25–29% or higher.

TIA is a significant independent risk factor for ischemic stroke and has an average annual risk of approximately 4%.⁴⁰  The greatest risk is in the first year following a TIA. In addition to TIA, the presence of other risk factors, including older age (>60 years), diabetes mellitus, duration of a TIA event >10 minutes, and signs or symptoms of weakness and speech impairment are associated with increased risk of subsequent stroke. Half of all strokes occur within 23 days of the TIA, and the 90-day stroke risk is 11%.

The risk of stroke in patients with non-valvular atrial fibrillation is approximately 3–5% per year, and approximately two-thirds of strokes are cardioembolic.³⁸  Factors that increase risk in patients with atrial fibrillation include older age, prior TIA or stroke, hypertension, impaired left ventricular function, and diabetes mellitus.³⁸  Atrial fibrillation is implicated in approximately 24% of strokes in patients aged 80–89 years.⁴¹ 

Atherosclerosis of carotid arteries is implicated in 20–30% of ischemic strokes.⁴²  Both TIA and ischemic stroke are more frequent in patients with severe carotid artery stenosis (>75%), with an annual risk of 3% in those with 60–90% stenosis.³⁸ 

In the Framingham study, ischemic stroke occurred in 8% of men and 11% of women within 6 years of an acute myocardial infarction. Coronary artery bypass procedures and open heart surgery carry a risk of stroke, and perioperative stroke occurs in 1–7% of patients undergoing cardiac surgery.³⁸ 

Obesity and in particular abdominal obesity are associated with greater stroke risk, with the risk rising as body weight increases. The relative risk in overweight women ranges from 1.8 for a body mass index (BMI) of 27–29 kg m⁻² to a risk of 2.4 for a BMI of ≥32 kg m⁻².³⁸ 

Increased salt intake is associated with hypertension, and a decrease in salt intake may lower both blood pressure and the associated stroke risk.³⁹  A higher cereal fiber intake has been associated with a lower risk of total stroke and ischemic stroke.⁴³ 

Physical activity reduces the risk of cardiovascular disease. Light to moderate physical activities such as walking, jogging, and swimming provide a stroke reduction benefit.³⁸  Physical exercise may also have a beneficial effect on other risk factors, such as body weight and blood pressure.

Greater high-density lipoprotein cholesterol levels reduce the occurrence of both TIA and ischemic stroke. Elevated total serum cholesterol increases the incidence of thromboembolic stroke, while very low cholesterol levels are associated with an increase in hemorrhagic stroke risk.⁴⁴ 

In the Women's Health Initiative Study, a 41% increase in stroke rate occurred among women using hormone replacement therapy, beginning in the second year of therapy and persisting beyond the fifth year.⁴⁵ 

Two thrombolytic strategies have been efficacious in improving outcome after ischemic stroke: intravenous-administered tissue plasminogen activator (tPA)⁴⁶  and intra-arterial prourokinase.⁴⁷  Currently, tPA is the only FDA-approved treatment for ischemic stroke. Thrombolysis is necessary to restore blood flow to the affected area of the brain and prevent greater cell death. However, following reperfusion, there is frequently some cell death due to breakdown of the blood–brain barrier, excitotoxicity, infiltration of leukocytes, and production of free radicals. Neuroprotective agents reduce the loss of neuronal cells by being delivered to the ischemic penumbra, and are less likely to suffer irreversible injury at early time points than neurons in the infarct core. Intravenous tPA thrombolysis is recommended for all eligible patients. However, the criteria for eligibility for intravenous tPA are numerous and strict, which accounts for <10% of patients being eligible, and treatment should be started within 4.5 hours of symptom onset.⁴⁸  The use of intra-arterial tPA is recommended for patients who are no longer eligible for intravenous administration of tPA due to the time window restraints, but who are still within the 6-hour cut-off time for intra-arterial treatment. Also, patients who are excluded from intravenous tPA due to contraindications such as recent surgery may be eligible for intra-arterial treatment in the case of occlusion of middle cerebral artery (MCA) or another proximal cerebral artery.⁴⁹  Treatment of patients with intra-arterial prourokinase within 6 hours of the onset of acute ischemic stroke caused by MCA occlusion significantly improved clinical outcomes at 90 days, despite an increased frequency of early symptomatic intracranial hemorrhage.⁴⁷ 

The role of aspirin in the prophylaxis of ischemic cerebrovascular events and stroke has been well documented. Numerous studies and reviews have shown a highly significant risk reduction of 13% in the incidence of acute ischemic stroke when daily low-dose aspirin is taken, without a greatly significant increase in the incidence of hemorrhagic complications including stroke.⁵⁰  In 2012, a revised set of guidelines was published by the American College of Chest Physicians in which starting aspirin at doses of between 160 and 325 mg daily within 48 hours of the onset of symptoms of stroke in adults is recommended.⁵¹  The general consensus is that an initial 325 mg dose of aspirin should be given to most patients suffering from a stroke or TIA within 24 hours of the onset of stroke or as early as possible, but not before 24 hours have elapsed since thrombolytic therapy, except when contraindicated by evidence of intracranial hemorrhage, bleeding diathesis, recent surgery, and sensitivity to aspirin, among others. After the initial higher dose, subsequent daily low-dose aspirin might be more adequate than the higher dose, as there is no evidence suggesting that the higher dose provides better protection from further strokes and there is an associated greater risk of intracranial bleeding with chronic use of high-dose aspirin therapy compared to low-dose therapy.⁴⁹ 

The use of anticoagulants in the first stages of acute ischemic stroke has met with little success. The International Stroke Trial and the National Institute of Neurological Disorders and Stroke recommend against the use of anticoagulants such as heparin within 24 hours of treatment with tPA.⁵¹  This is due to the marked increase in symptomatic intracranial hemorrhage observed in the trials testing anticoagulants for acute ischemic stroke. Currently, no anticoagulant is recommended in the treatment of the acute stages of acute ischemic stroke. Patients with cardioembolic stroke need to receive oral prophylactic anticoagulation, particularly when associated with atrial fibrillation. Patients with mild stroke or TIA may be started on warfarin or newer agents such as dabigatran, titrating the dose to an international normalized ratio of between 2.0 and 3.0 after 48 hours if there is no contraindication. Patients with moderate to severe strokes should not receive anticoagulants after 2–4 weeks have passed.⁵² 

Due to a lack of large randomized clinical trials, current guidelines do not provide specific recommendations on statin initiation in acute ischemic stroke. A recent meta-analysis indicates that pre-stroke statin is associated with milder initial stroke severity, good functional outcome, and lower mortality. In addition, in-hospital statin use is associated with good functional outcome and lower mortality. In patients treated with thrombolysis, statin use is associated with good functional outcome, despite an increased risk of symptomatic hemorrhagic transformation (HT).⁵³  While these findings support the use of statin in acute ischemic stroke, the findings were mostly from observational studies at risk of bias.⁵³ 

Despite widespread interest and the large number of published studies, no neuroprotective agents have passed clinical trials with the same observable effect seen in animal models.

Endovascular thrombectomy for large vessel ischemic stroke substantially reduces disability.

Intravenous tPA is the most effective treatment of acute ischemic stroke. However, the most significant concern about the use of tPA is an increased risk of hemorrhage. Many studies have shown thrombolysis is independently associated with HT.⁵⁴  HT is a spectrum of ischemia-related brain hemorrhage and is a frequent spontaneous complication of ischemic stroke, especially after thrombolytic therapy.⁵⁵  HT can be divided into hemorrhagic infarction (HI) and parenchymal hematoma (PH).⁵⁶  HI is a heterogeneous hyperdensity occupying a portion of an ischemic infarct zone on computed tomography (CT) images, whereas PH refers to a more homogeneous, dense hematoma with mass effect. The incidence of spontaneous HT ranges from 13% to 43% in CT studies, whereas the incidence of symptomatic HT is from 0.6% to 7% in the placebo group and from 6.4% to 20% in the thrombolysed group.^57,58  The incidence depends upon many factors such as age, blood glucose level, thrombolytic agent used, route of administration, and time window for the initiation of therapy.^59,60  Symptomatic HT implies a clear causal relationship between clinical deterioration and HT. The rate of occurrence of HI is higher than that of PH; in a large group of consecutive patients with acute ischemic stroke, the incidence of HI was about 9%, whereas that of PH was about 3%.⁵⁴  The risk of HT increases remarkably when massive cerebral infarction is present.^61,62  Massive cerebral infarction is often accompanied by substantial brain edema, which results in compression of the peripheral vasculature. The increased vascular permeability because of prolonged ischemia and hypoxia caused by vascular compression greatly increases the likelihood of HT after release of the edema. HT often occurs in the gray matter, especially in the cerebral cortex, because of its abundant collateral vessels. Gray matter infarction is often due to a large artery occlusion and can lead to massive edema, causing ischemic injury by compressing the surrounding blood vessels. Most instances of white matter infarction are of lacunar type and are caused by the terminal vascular occlusion.

Atrial fibrillation and cerebral embolism are associated with an increased risk of HT.^63–65  Hyperglycemia has a major role in post-ischemic HT. In a transient MCA occlusion rat model, acute hyperglycemia consistently resulted in HT.⁶⁶  Clinical trials also showed a close association between HT and high blood glucose.^67,68  Hyperglycemia during acute ischemic stroke predisposes to PH, which in turn determines a non-favorable outcome at 3 months.⁶⁷  Other clinical studies indicate that lower low-density lipoprotein cholesterol and lower total cholesterol are associated with all the types of HT and symptomatic HT, respectively.^69–71  High-density lipoprotein cholesterol, cholesterol, and triglycerides are not linked to the HT risk.⁶⁹ 

Mild TBI usually requires no treatment other than rest and analgesics to treat a headache. However, a person with a mild TBI needs to be monitored closely at home for any persisting, worsening, or new symptoms.

Immediate emergency care for moderate to severe traumatic brain injuries, as classified on the Glasgow Coma Scale,⁷²  focuses on ensuring the person has an adequate oxygen and blood supply, maintaining blood pressure, and preventing any further injury to the head or neck. Additional treatments in the emergency room or intensive care unit of a hospital are directed at minimizing secondary damage due to inflammation, bleeding, or reduced oxygen supply to the brain. Medications to limit secondary damage to the brain immediately after an injury may include:

• Diuretics: diuretics given intravenously to people with TBI help to reduce pressure inside the brain.

• Anti-seizure drugs: an anti-seizure drug may be given during the first week to avoid any additional brain damage that might be caused by a seizure. Additional anti-seizure drug treatments are only used if seizures occur.

• Coma-inducing drugs: sometimes drugs are used to induce temporary comas because a comatose brain needs less oxygen to function. This is especially beneficial if blood vessels compressed by increased pressure in the brain are unable to deliver the normal amount of nutrients and oxygen to brain cells.

• Emergency surgery may be required to minimize additional damage to brain tissues. This could involve:

• Controlling bleeding: if there is bleeding in the skull cavity, this may be surgically removed or drained. Bleeding vessels or tissue may need to be repaired. Bleeding outside or within the brain can result in a hematoma that puts pressure on the brain and damages brain tissue.

• Repairing skull fractures: in an open head injury, skull fractures may need to be repaired and damaged tissue removed.

• Creating a window in the skull: surgery may be used to relieve pressure inside the skull by draining accumulated cerebral spinal fluid or creating a window in the skull to provide more space for swollen tissues.⁷³ 

The overall goal of all surgical treatment is to prevent secondary injury by helping to maintain blood flow and oxygen to the brain and minimizing swelling and pressure.

Most people who have had a significant brain injury will require rehabilitation. The aim is to improve their ability to perform daily activities. Therapy usually begins in the hospital and continues at an inpatient rehabilitation unit, a residential treatment facility, or through outpatient services. The type and duration of rehabilitation varies by individual, depending on the severity of the brain injury and which part of the brain is injured.^73,74 

The incidence of stroke is increasing in both high-income and lower-to-middle-income countries. Relevant to this is the increasing number of people, including young children, who are overweight or obese. There is also an increasing prevalence of hypertension, which is a major risk factor for stroke. A strong association has been shown between TIA or TBI and subsequent stroke. The risk for stroke is related, among other factors, to age, gender, and race. Existing comorbidities, such as hypertension, diabetes mellitus, atrial fibrillation, coronary artery disease, and obesity, significantly increase stroke risk. Treatment using intravenous tPA or intra-arterial tPA thrombolysis has proven to be efficacious in improving outcome after ischemic stroke. Other treatments that have been shown to provide benefit include aspirin and statins. HT is a frequent spontaneous complication of ischemic stroke, especially after thrombolytic therapy. The risk of HT increases considerably when massive cerebral infarction is present. Atrial fibrillation and cerebral embolism are associated with an increased risk of HT. Hyperglycemia has a major role in post-ischemic HT. Lower levels of low-density lipoprotein cholesterol and lower total cholesterol are associated with all the types of HT and symptomatic HT, respectively.