What is a Stroke?

A stroke is the result of the loss of blood flow, and consequently oxygen, to part of the brain. Decreased blood flow to parts of the brain can be caused by a blockage, often from blood clots (ischemic stroke), or the rupture of a brain blood vessel and subsequent hemorrhaging (hemorrhagic stroke). Strokes are one of the leading causes of death and disability around the world.

Ischemic and hemorrhagic strokes are severe and life-threatening. Other types of strokes, including transient ischemic attacks (“mini strokes” that resolve within minutes to hours) and silent strokes (strokes that do not cause overt stroke symptoms) are also considered medical emergencies and should receive urgent medical attention.

Nutrients

• Olive oil and olive extracts: Compounds derived from olives, including olive oil, have been found to promote good metabolic health, have antioxidant activity, and have been shown to protect neurons from damage during periods of ischemia.
• Omega-3 fatty acids: Omega-3 polyunsaturated fatty acids, notably eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exhibit a host of protective benefits that may lower stroke risk. They have anti-inflammatory properties, help protect against oxidative stress, and promote neuron regeneration and revascularization after stroke.
• Flavonoids: Flavonoids are compounds in fruits, vegetables, grains, and tea. Diets rich in flavonoids may reduce the risk for stroke. Dietary intake of flavanone, a flavonoid found in citrus fruits, has been found to exhibit an inverse relationship with stroke risk.
• Folic acid and B vitamins: Folic acid and other B vitamins reduce levels of homocysteine, an amino acid that promotes inflammation and atherosclerosis. Studies suggest folic acid and vitamin B6 supplementation reduce the risk for stroke.
• Nattokinase: Extracted from fermented soybeans, studies suggest nattokinase exhibits lipid-lowering, antihypertensive, antiplatelet, and anticoagulant activity.

Medical Treatment

Emergency treatment for ischemic stroke may involve:

• Intravenous thrombolysis (breaking down the clot) with alteplase, a tissue plasminogen activator (tPa)
• Mechanical thrombectomy (removal of the clot)
• Blood pressure management
• Antiplatelet therapy (aspirin)
• Cholesterol management (statins)

Emergency treatment for hemorrhagic stroke may involve:

• Reversal of oral anticoagulant therapy (eg, delivery of high-dose intravenous vitamin K in warfarin users)
• Management of intracranial pressure
• Blood pressure management

Stroke is a leading cause of disability and the second leading cause of death worldwide.² Globally, more than 13 million people experience a stroke each year, and almost 6 million die as a result.³ Around the world, about one of every four people will experience a stroke from 25 years of age onward.⁴ Although older adults are most commonly affected by stroke, the incidence of stroke is growing rapidly among young people.⁵

A stroke occurs when part of the brain is deprived of blood and oxygen, which can cause cells to die.⁶ This can occur either when a clot blocks blood flow to the brain, known as an ischemic stroke, or when a blood vessel in or around the brain ruptures, known as a hemorrhagic stroke.⁶ Ischemic strokes are much more common than hemorrhagic strokes. The American Stroke Association (ASA) estimates that 87% of strokes that occur in the United States are ischemic strokes.⁷

When a stroke occurs, time is of the essence. Treatment of stroke within 4.5 hours is associated with the greatest likelihood of survival and reduced risk for disability.^8,9 However, one-third to one-half of stroke patients do not call 911 before going to the hospital.^10,11 According to a 2021 report from the American Heart Association (AHA), 64% of stroke deaths occur outside of an acute care hospital setting.¹² Early recognition of the symptoms of stroke can mean the difference between life and death.

The ASA estimates that up to 80% of strokes are preventable.⁶ Elevated blood pressure is the primary stroke risk factor, and almost two-thirds of people who experience a stroke have high blood pressure.¹³ Blood pressure control is a crucial aspect of cardiovascular health, and maintaining good cardiovascular health can reduce stroke risk by up to 70%.¹²

General strategies to improve cardiovascular health can also help reduce the risk of stroke. These include consuming a healthy diet (such as the Mediterranean diet), getting regular physical activity, maintaining a healthy weight, managing other health conditions (such as diabetes or high cholesterol), and stopping smoking.^2,12,14-16 Dietary and supplemental nutrients including olive extracts, nattokinase, folic acid, and flavonoids can also support metabolic and vascular health and reduce the risk for stroke.

For people with atrial fibrillation (A-fib), certain medications (eg, anticoagulant therapy) may be required to reduce the risk of stroke.¹⁷ A-fib is a condition that causes the heart to beat irregularly, which increases the risk of ischemic stroke up to 5-fold. It is estimated that one of every seven strokes are linked to A-fib.¹⁸

This protocol will review the different types of strokes and their causes, as well as the risk factors, signs, and symptoms of stroke. Stroke treatment will be discussed, and strategies to mitigate stroke risk through dietary and lifestyle changes, as well as targeted nutrient supplementation, will also be reviewed.

There are two main types of strokes: ischemic and hemorrhagic.^6,19 Strokes are differentiated by type based on clinical presentation and symptoms, as well as brain imaging.¹⁹

Figure 1. Arteries in the Head and Neck²⁰

The brain is an energy-intensive organ, using an estimated 20% of the body’s total oxygen while at rest.²¹ Oxygen is delivered to the brain via two sets of arteries: the left and right carotid arteries, and the left and right vertebral arteries (Figure 1).²² The carotid arteries extend along the front of the neck, whereas the vertebral arteries run more internally along the spinal cord.²² These four arteries supply all of the blood and oxygen to the head and brain, including through a network of smaller vessels that branch off from these four. When blood flow to the brain from any of these vessels is interrupted, it can lead to the death of brain cells and irreversible tissue damage, known as infarction.^19,22

Ischemic Stroke

Most ischemic strokes are caused by the obstruction of blood flow through an artery that supplies blood to the brain. There are two main subtypes of ischemic stroke: thrombotic and embolic.²²

• A thrombotic stroke occurs when a blood clot, orthrombus, blocks an artery supplying blood to the brain.²² When this blockage occurs in the carotid or vertebral arteries, or in another intracranial large vessel, it is known aslarge vessel thrombosis or large vessel occlusion.²³ Strokes can also result from obstructions in the small vessels of the brain, such as those on the surface of the brain.²⁴ Small vessel strokes, also known as lacunar strokes, account for about 25% of all ischemic strokes. Compared with other types of strokes, lacunar strokes have a higher rate of survival and a lower rate of recurrence, and are generally associated with a more favorable prognosis in the early stages after stroke; however, they are still associated with an increased risk for death in the long-term, primarily from cardiovascular events.²⁵



Figure 2. Distinct Regions of the Aorta²⁰
• Embolic strokes occur when a blood clot or fragment of atherosclerotic plaque travels through the bloodstream from another area of the body and becomes lodged in an artery supplying blood to the brain.^7,22 These clots typically originate in the arteries of the heart, chest, or neck.⁷
• Cardioembolic strokes are those caused by clots originating in the heart or aorta.²⁶ Approximately one in four ischemic strokes are cardioembolic strokes.²⁷ The risk of cardioembolic stroke is greater in people with a history of many different kinds of heart disease or injury, including A-fib, valvular heart disease, myocardial infarction (heart attack), and heart failure.^26,27
  
  The aorta is the largest artery in the body, and the aortic arch has been identified as a major source of plaque debris associated with embolic stroke (Figure 2). Up to 21% of people with severe aortic plaque may experience a stroke.²⁸ The relationship between aortic atherosclerosis and the risk for stroke remains unclear due to inconsistencies in studies, but researchers have suggested that plaque buildup in this region may be indicative of more widespread atherosclerotic disease, which increases the risk for stroke.²⁹

Hemorrhagic Stroke

A hemorrhagic stroke occurs when a blood vessel in the brain ruptures and bleeds (hemorrhages). While hemorrhagic strokes are less common than ischemic strokes, some studies have shown they are associated with higher rates of disability and death.^35-38 Hypertension is the most frequent cause of hemorrhagic stroke, as chronic elevated pressure puts a strain on the blood vessels in the brain and causes damage to their structures. This pressure can eventually cause the blood vessel to leak or burst, which results in pooling of blood outside of blood vessels (hematoma). The enlargement of the hematoma, and associated release in pro-inflammatory factors, increases intracranial pressure, disrupts neuron activity, and leads to brain injury.³⁹

Hemorrhagic strokes can also be caused by cerebral amyloid angiopathy, a condition in which proteins build up along the blood vessel wall and increase the risk for bleeding.⁴⁰ Cerebral amyloid angiopathy is most often associated with hemorrhagic stroke in the elderly.⁴¹

Hemorrhagic strokes can be further classified based on location of the bleeding:

• Intracerebral hemorrhages , the most common type of hemorrhagic stroke,⁴² occur when an artery or arteriole within the brain bursts and bleeding occurs directly into the brain.²²
• Subarachnoid hemorrhages occur into the space between the brain and the tissues that cover it.⁴² Subarachnoid hemorrhages are commonly caused by the rupture of an aneurysm,¹⁹ which occurs when the walls of a blood vessel weaken causing bulging or ballooning.⁴³

Up to 90% of strokes are caused by modifiable risk factors.¹⁹ Addressing these risk factors is critical for reducing the risk for stroke.

High Blood Pressure (Hypertension)

High blood pressure, also known as hypertension, is considered the number one risk factor for both ischemic and hemorrhagic stroke.^19,291 Hypertension has been identified in nearly two-thirds of stroke patients, and hypertension is thought to be responsible for over half of strokes globally.^13,44 The risk for stroke increases progressively as blood pressure rises over 115/75 mm Hg.^44,45 In a meta-analysis of 61 studies comprised of almost 1 million people, every 20 mm Hg increase in systolic blood pressure (and 10 mm Hg increase in diastolic blood pressure) over 115/75 mm Hg increased the risk for death from stroke 2-fold in those aged 40‒69 years.⁴⁶ Research provides strong evidence that antihypertensive therapy reduces the risk for stroke.^13,44

Smoking

The chemicals in cigarette smoke, including nicotine and carbon monoxide, can cause damage to the heart and blood vessels, which increases the risk of stroke.²⁹¹ In a meta-analysis of 14 studies including over 300,000 people, the risk for stroke was over 90% higher for people who currently smoked compared to those with no history of smoking.⁴⁷ However, smoking cessation can reduce stroke risk considerably. Exposure to secondhand smoke can also increase stroke risk by 20‒30%.¹²

Diabetes

Obesity, high cholesterol, and high blood pressure are common in diabetics, raising the risk of stroke.²⁹¹ However, diabetes itself also increases the risk for stroke, as high blood sugar levels can damage blood vessels.⁴⁸ According to a pooled analysis of over 775,000 people, diabetes increased the risk for stroke by 83% in men and 128% in women.⁴⁹

Obesity, Poor Diet, and Physical Inactivity

Research indicates obesity is associated with a greater than 50% increase in stroke risk in younger adults, but this may have to do with the co-occurrence of other risk factors, including hypertension and diabetes.⁵⁰ A comparative study of approximately 3,300 adults examining the link between stroke and metabolic syndrome, which is characterized by hypertension, elevated blood glucose levels, dyslipidemia, and excess fat around the waistline, found that metabolic syndrome was associated with a 50% increase in the risk for stroke.^51,52 Interestingly, an “obesity paradox” exists, in which the likelihood of better outcomes after stroke increases with body mass index (BMI), highlighting the complex interaction between weight and risk for and from stroke.⁵³

Analyses of data from a very large global study of overall disease burden found that unhealthy behaviors such as physical inactivity and poor diet account for nearly half of stroke risk.¹² In a paper published in 2009 on an observational trial in nearly 3,300 adults, regular moderate- to high-intensity physical activity was associated with a 35% reduction in the risk for ischemic stroke.⁵⁴ A poor diet, characterized by low fruit and vegetable intake and high sodium content, has also been linked to increased risk for stroke, and diets rich in whole foods (eg, the Mediterranean diet) may be associated with decreased stroke risk.¹²

High Cholesterol (Dyslipidemia)

Abnormally high levels of cholesterol and other lipids (fats) in the blood are a key factor in the formation of atherosclerotic plaque in artery linings, including in the brain. This change in the structure and function of arteries is itself a significant contributor to hypertension, cerebrovascular disease, and stroke.⁵⁵ However, while elevated total cholesterol levels are associated with an increased risk for ischemic stroke, they are associated with a lower risk of hemorrhagic stroke.^56,57 Stroke risk may also be associated with specific types of cholesterol in the blood.⁵⁷ Although results have been somewhat inconsistent, research suggests high-density lipoprotein cholesterol (HDL-C) may be protective against stroke, whereas elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with increased risk for stroke.^12,56,57

Sickle Cell Disease

Sickle cell disease, also known as sickle cell anemia, can increase the risk for stroke.⁵⁵ Studies have found that about one in nine people with sickle cell disease experience a stroke by 20 years of age, and one in four will have a stroke by 45 years of age.⁵⁸

Sleep Apnea

Sleep apnea is characterized by episodic lapses in breathing during sleep, and is associated with an increased risk for stroke.⁵⁷ Several studies found the risk for stroke is approximately 2- to 3-fold higher in people with sleep apnea.^12,57 This relationship is especially pronounced for men with severe obstructive sleep apnea.⁵⁹

High Homocysteine

Elevated levels of the amino acid homocysteine (hyperhomocysteinemia) can be caused by genetic mutations that affect methionine metabolism as well as nutritional deficiencies and are associated with a 2- to 3-fold increased risk for stroke.⁵⁷ Some data from clinical trials suggest intake of B vitamins, which help lower homocysteine levels, may help decrease the risk for stroke, but there is limited evidence that homocysteine-lowering therapy reduces stroke risk in people with established atherosclerotic disease.^57,60

A variety of non-modifiable factors have been identified that increase the risk for stroke.⁵⁶

• Age. Although a stroke can happen at any age, the risk for stroke significantly increases with age. Older age is the most significant risk factor for stroke, and the incidence of stroke doubles every decade after age 55.⁵⁶
• Medical history.
• A previous history of stroke or TIA substantially increases the risk for further stroke. People who have had one or more previous TIAs are nearly 10 times more likely to experience a stroke than their counterparts without a history of stroke or TIA.
• People who previously experienced a heart attack are at increased risk for stroke, as both are frequently caused by a buildup of plaque within the blood vessels.⁶¹
• Atrial fibrillation, or A-fib, is a heart condition characterized by arrythmia, which causes blood to move improperly through the heart and increases the likelihood of blood clot formation. People with A-fib have a 3- to 5-fold greater risk for stroke, and nearly one in four strokes after age 40 are caused by A-fib.⁶²


• Sex. Risk for stroke is generally higher among females than males, which may be related to the risks associated with pregnancy and hormonal birth control use.⁵⁶ Women are also more likely to die from stroke.⁶¹
• Race or ethnicity. African-Americans in the United States are more likely to experience a stroke compared with Caucasians.⁶¹ This may be due to differences in the prevalence of other risk factors, including hypertension, diabetes, and obesity.^56,61
• Genetics and family history. Research has identified a number of genetic alterations associated with an increased risk of stroke.⁵⁶ These may be independent mutations or they may be associated with other disorders that affect blood flow and clotting.^56,61 People with a family member who has had a stroke, particularly if the stroke occurred at a young age (<65 years), are at increased risk for having a stroke.⁶¹

Blood Pressure Control

There is a clear, demonstrated benefit on stroke risk reduction associated with blood pressure-lowering therapy.⁶³ In a review of over 40 studies, use of low-dose diuretics as antihypertensive therapy was associated with a nearly 30% reduced risk for stroke compared with placebo. Other antihypertensive medications were similarly effective.⁶⁴ Multiple analyses of clinical trials and studies have found that 10 to 12 mm Hg reductions in systolic blood pressure and 5 to 6 mm Hg reductions in diastolic blood pressure are associated with an up to 41% reduced risk for stroke.^45,65,66 Antihypertensive therapy can also reduce the risk for another stroke after one has already occurred, lowering risk for a disabling or deadly second stroke by nearly 30%.⁶⁷

Ideal blood pressure targets and intensity of treatment should be determined on an individual basis. A thorough discussion of blood pressure control strategies can be found in the “High Blood Pressure (Hypertension)” protocol.

Smoking Cessation

Quitting smoking reduces the risk of a stroke, and in those who have already had a stroke, it reduces the risk of another stroke. Smoking doubles the risk of dying in those who have a stroke. Importantly, the contribution of smoking to stroke risk is dose-dependent: the more one smokes, the greater the risk. Compared with a non-smoker, a one pack-per-day smoker is six times more likely to have a stroke. One reason is that smoking makes the blood more susceptible to clotting, increasing the likelihood of ischemic stroke. Smoking also causes blood vessels to narrow, which can raise blood pressure, and reduces the oxygen-carrying capacity of red blood cells.⁶⁸

In a study of almost 3.8 million adults in Korea, smoking cessation reduced the risk for stroke by about 30%. This benefit was evident even after accounting for age, sex, BMI, alcohol consumption, income, and exercise. The weight gain that often occurs after quitting smoking did not interfere with the cardiovascular benefit of smoking cessation in this study.⁶⁹ Compared with non-smokers or people who quit smoking more than 10 years prior, current smoking status increases stroke risk about 2- to 4-fold.⁷⁰ In a study of over 3,000 Chinese adults who experienced stroke, the risk for recurrent stroke was 93% higher for current smokers compared with non-smokers, but the recurrence risk was only 31% higher in those who quit smoking after their stroke, and 16% higher in former smokers.⁷¹

Reducing exposure to secondhand smoke may also help reduce the risk for stroke. A meta-analysis of 14 studies involving over 303,000 people found that exposure to secondhand smoke, or passive smoking, was associated with a 45% increased risk for stroke.⁴⁷

Studies on the effects of “vaping,” or the use of electronic cigarettes (e-cigarettes), are in the early stages, but suggest vaping is not a safe alternative to smoking cessation. One study found that compared with the use of combustible cigarettes alone, the combined use of combustible and e-cigarettes increased the likelihood of cardiovascular disease, including stroke, by 36%.⁷² A meta-analysis of six studies found no difference in the odds of developing cardiovascular problems, including stroke, among people who switched from smoking to vaping.⁷³

Glycemic Control and Diabetes Management

High blood glucose levels, also known as hyperglycemia, damages the blood vessels and leads to vascular inflammation, endothelial dysfunction, increased arterial stiffness, and atherosclerotic plaque buildup, all of which increase the risk for stroke.^74,75 In a meta-analysis of 64 studies, the relative risk of stroke in diabetic women was 2.28-fold greater than for non-diabetics, whereas in men the relative risk was 1.83-fold greater. Comparing diabetic women to diabetic men, women’s risk of stroke was 27% greater.⁴⁹ In a Swedish observational study involving over 400,000 people with type 2 diabetes, the risk for stroke increased with worsening glycemic control. In this study, the risk for stroke was 27% higher in diabetic individuals with glycated hemoglobin (HbA1c) levels of 7.1–8% than in healthy controls, and at an HbA1c level > 10.1%, stroke risk was 114% higher. For every 3.0% increase in HbA1c, a 71% increase in stroke risk was observed.⁷⁶

In an observational study that followed 14,856 diabetic participants for four years, those receiving metformin (Glucophage, a blood glucose-lowering drug) were about half as likely to experience a stroke than those not receiving metformin, suggesting this drug may have protective effects against stroke in diabetic patients. Effective glycemic control can also improve outcomes in people with diabetes who have had a stroke.⁷⁷ A study demonstrated that higher levels of HbA1c were associated with lower cognitive scores over time in patients who had experienced a lacunar stroke.⁷⁸ Similarly, hyperglycemia at the time of stroke was found to be associated with continued infarction growth, even after successful thrombectomy, in people who had large vessel ischemic stroke.⁷⁹

Managing blood glucose levels may be even more important in stroke patients using antiplatelet therapy who carry excess body weight. In one study in over 3,000 subjects who had experienced a minor stroke or TIA, the combination of overweight/obesity and poor glycemic control reduced the efficacy of aspirin-clopidogrel treatment. This effect was not observed in subjects with either poor glycemic control or overweight/obesity alone.⁸⁰

For a comprehensive discussion of glycemic control strategies, please see the “Diabetes and Glucose Control” protocol.

Weight Management

Obesity is a risk factor for stroke. Population studies suggest that obesity increases the risk for ischemic stroke by 50‒100% compared to patients with normal weight.⁸¹ The AHA and ASA noted that epidemiological evidence suggests stroke risk increases almost linearly above a BMI of 20 kg/m², such that each 1 kg/m² increase above 20 kg/m² corresponds with a 5% increase in risk of stroke.⁸² The increase in stroke risk associated with obesity may be related to the increased frequency of cardiometabolic comorbidities typically linked to obesity, such as hypertension and diabetes, as well as poor diet and low physical activity.^50,56,83 Losing even small amounts of weight (5‒10 lbs.), eating a healthier diet, and increasing physical activity can have profound effects on metabolic health, which could result in reduced stroke risk.²⁹¹

The AHA/ASA recommend weight loss for primary stroke prevention in people with a BMI over 30 kg/m². These organizations also recommend weight loss among individuals with a BMI of 25–29 kg/m² to reduce blood pressure, which may in turn reduce stroke risk. Importantly, the AHA/ASA noted that stroke risk is more closely related to abdominal obesity than general obesity (which is reflected in BMI).⁸² Thus, it can be concluded that while generally maintaining a healthy weight is important, focusing on healthy body composition to avoid abdominal obesity may be particularly pertinent for reducing stroke risk.

For a comprehensive discussion of weight management strategies, please see Life Extension’s “Weight Management” protocol.

Healthy Diet

The ASA recommends a heart-healthy diet to reduce stroke risk. High-fat diets can increase cholesterol levels and high sodium intake is associated with elevated blood pressure, both of which increase the risk for stroke.²⁹¹ Diets rich in fruits, vegetables, nuts, and olive oil, on the other hand, reduce the risk for stroke.¹² Examples include the Mediterranean and DASH (Dietary Approaches to Stop Hypertension) diets, both of which focus on intake of fruits, vegetables, and whole grains, as well as lean sources of protein, such as fish, poultry, and low-fat dairy in moderation.⁸⁴

In a meta-analysis of data from over 680,000 people in Mediterranean and non-Mediterranean populations, greater adherence to a Mediterranean diet was associated with significant reductions in the risk for both ischemic and hemorrhagic stroke.⁸⁵ Adherence to the Mediterranean diet is associated with improved endothelial function and blood flow, which are critical for good vascular health.⁸⁶ Overall, scientific research has found that high adherence to the Mediterranean diet can decrease the risk for stroke by 10‒36%.⁸⁷

A review of 30 clinical trials involving over 5,500 people revealed that compared with a control diet, adherence to the DASH diet was associated with significant reductions in both systolic (mean, 3.2 mm Hg) and diastolic (mean, 2.5 mm Hg) blood pressure.⁸⁸ Studies involving a total of over 548,000 individuals found that higher levels of adherence to a DASH diet was associated with an approximately 12% reduction in stroke risk over up to 24 years of follow-up, with the greatest benefits observed among Asian populations.⁸⁹

A modified version of the Mediterranean and DASH diets, known as the MIND (Mediterranean-Dash Intervention for Neurodegenerative Delay) diet, was developed by faculty at Rush University Hospital in Chicago.⁹⁰ It also emphasizes fresh produce, whole grains, lean meats, and olive oil, and discourages excess salt consumption. Additionally, it encourages only berries as a fruit; restricts potatoes and dairy; limits fish to one serving per week; and allows eggs. Red meat, processed meats, fried fast foods, sweets and pastries, butter, stick margarine, and whole-fat cheese are all discouraged.⁹¹ A study in 106 patients with a history of stroke found that a higher rate of adherence to the MIND diet was associated with slower rates of cognitive decline compared with the lowest levels.⁹²

Exercise

Physical inactivity is a clear risk factor for stroke, while physical activity is known to improve vascular function and protect against stroke risk factors including hypertension, obesity, and type 2 diabetes. Because of the long duration that would be needed for randomized controlled trials to definitively prove that exercise prevents a first stroke, epidemiologic and observational trials provide most of the evidence for the role of physical activity in stroke prevention.⁹³

In an observational study in nearly 3,300 adults, moderate- to high-intensity physical exercise was associated with a 35% reduction in stroke risk.⁵⁴ In a study of over 70,000 Chinese adults with a history of ischemic stroke, TIA, ischemic heart disease, or hypertension, cardiovascular deaths were less frequent among individuals who were more physically active.⁹⁴ In a meta-analysis of 26 studies, being physically active, as assessed using metabolic equivalent (MET) minutes and taking into account all types of physical exertion throughout the day, was associated with lower ischemic stroke risk. In the study, even those with a low physical activity level, reaching 600–3,999 metabolic equivalent (MET) minutes per week, had a 16% lower ischemic stroke risk than physically inactive individuals. A moderately physically active lifestyle (4,000–7,999 MET min/week) was associated with a 19% lower risk and a highly physically active lifestyle (8,000 MET minutes/week or more) was associated with a 26% lower risk.⁹⁵ Regular physical activity promotes not only weight loss but also good metabolic health, both of which help reduce the risk for stroke.²⁹²

Adults should strive to move more and sit less during the day; even small amounts of physical activity can result in considerable health benefits. For even more health benefits, adults should try to do at least 150‒300 minutes per week of moderate-intensity physical activity or 75‒150 minutes of vigorous-intensity aerobic activity. These activities should be spread throughout the week, and additional physical activity can result in more health benefits.

Lack of physical activity is common among stroke survivors, and exercise and structured physical activity play an essential role in recovery and rehabilitation from stroke. Both aerobic and strength training exercise are indicated for stroke recovery. The AHA and ASA have endorsed exercise training for stroke survivors to improve functional capacity and the ability to perform regular daily activities, as well as quality of life.⁹⁶ Post-stroke rehabilitative exercise can also aid in improving cognitive ability, psychosocial aspects of recovery, balance, and mobility.⁹⁷ The promotion of physical activity in stroke survivors should emphasize a reduction in sedentary behavior; muscle-strengthening; and low- to moderate-intensity aerobic exercise. Stretching and flexibility training are also indicated.^96,97

Management of Atrial Fibrillation

Atrial fibrillation (A-fib) is a condition characterized by an abnormal heart rhythm that can lead to clot formation and stroke. Studies have found that 20‒30% of ischemic stroke patients have A-fib. Unfortunately, many of these patients are not diagnosed with A-fib until after a stroke has already occurred.⁹⁸ At that point, proactive management of stroke risk is still needed as more than one in five people with A-fib who experience a stroke will have another stroke within five years.⁹⁹ Assessment of stroke and bleeding risk using validated tools (CHA₂DS₂-VASc score and HAS-BLED score, respectively) are needed to assess the proper course of treatment.⁹⁸ A meta-analysis of 29 randomized controlled trials determined that the use of warfarin or antiplatelet agents was associated with a 64% or 22% reduction, respectively, in total stroke risk in individuals with A-fib.¹⁰⁰ Warfarin or other vitamin K antagonists have long been standard therapy for A-fib, though newer direct oral anticoagulants (DOACs) are rapidly becoming first-line therapy.⁹⁸ According to the results of an analysis of 35 studies involving over 2 million A-fib patients, bleeding side effects occur less frequently with DOAC use compared with warfarin use.¹⁰¹ A study involving over 56,000 patients with A-fib found that use of a DOAC was associated with a 33% lower risk for major bleeding events, as well as a 36% lower risk for ischemic stroke or systemic embolism compared with warfarin.¹⁰²

Avoid Excessive Alcohol Consumption

The effects of alcohol on stroke risk and other cardiovascular diseases is complex. Heavy alcohol consumption (≥14 drinks/week) is associated with a number of factors that may promote the occurrence of stroke, including inflammation, oxidative stress, increased lipid levels, and elevated blood pressure.¹⁰³ Additionally, both heavy and moderate alcohol consumption (7‒13 drinks/week) have been identified as significant risk factors for hypertension.¹⁰⁴ However, while heavy alcohol intake and binge drinking have a negative effect on stroke risk, low-to-moderate alcohol consumption may be protective against stroke.¹⁰³ Avoiding excessive amounts of alcohol should be considered a component of stroke prevention interventions. The effects of moderate alcohol intake are unclear, but low alcohol consumption potentially provides beneficial effects.

Lipid-lowering Therapy

Use of a statin to lower cholesterol levels may reduce the risk for recurrent stroke, as well as cardiovascular events. Some, but not all, studies of acute statin administration for ischemic stroke have shown improved outcomes and good safety.^105-110 As of this writing it is reasonable to begin statin medication as soon after acute ischemic stroke as is deemed safe and to avoid discontinuing statins after acute ischemic stroke.^110-113

In addition to the interventions described in this protocol, readers may also want to review the Life Extension protocols on Blood Clot Prevention, Cardiovascular Disease, High Blood Pressure, and Arrhythmias.

Magnesium

Magnesium is a mainly intracellular ion that is crucial for cellular energy production and function. Along with other ions, it helps control nerve and muscle cell activation, and is needed for vascular and neuronal health. Low magnesium levels are common in older people due to lower intake, reduced absorption, and increased excretion in urine. Numerous studies have linked poor magnesium status with a wide range of chronic and age-related disorders, including cardiovascular disease, metabolic syndrome, high blood pressure, and stroke.¹¹⁴

A meta-analysis of 15 observational studies with a combined total of 692,998 participants found people with the highest magnesium intake had a 12% lower risk of ischemic stroke than those with the lowest intake. It was estimated that for every 100 mg of additional magnesium intake a day, the risk for both ischemic stroke and total stroke was reduced by 2%. Magnesium intake was not associated with risk of hemorrhagic stroke in eight studies analyzed.¹¹⁵ Nevertheless, a study that included 79,429 participants found those with higher predicted serum magnesium levels based on genetic profiles had a lower risk of hemorrhagic stroke.¹¹⁶ In other studies, low magnesium status was correlated with increased risk of cerebral hemorrhage following intravenous thrombolytic therapy and post-stroke cognitive impairment in ischemic stroke patients.^117,118

A randomized controlled trial included 291 ischemic or hemorrhagic stroke patients who were given either regular sodium-based salt, a potassium-enriched salt, or a magnesium- and potassium-enriched salt to use at mealtimes over the subsequent six months. The intent was to increase magnesium and potassium intake to Daily Recommended Intake levels and reverse possible deficiencies. Compared with those given regular sodium-based salt, those given the magnesium/potassium salt were more than twice as likely to have good neurological performance and improved functional outcome at the end of six months.¹¹⁹

Magnesium may also have a role in acute treatment of some types of stroke. A controlled trial in 36 acute ischemic stroke patients with A-fib being treated with the antiarrhythmic drug amiodarone (Cordarone) found intravenous magnesium sulfate infusions every 24 hours for five days resulted in lower levels of inflammatory markers (eg, C-reactive protein, interleukin-8 [IL-8]), improved levels of immunological and neurological indicators, and reduced disability, indicating a possible attenuation of known adverse side effects of amiodarone.¹²⁰ In general, however, intravenous magnesium sulfate has not been found to significantly improve outcomes in patients who have experienced ischemic stroke.^121,122

It has been proposed that magnesium administration directly into the cerebrospinal fluid may be effective for quickly delivering magnesium to the affected tissues in acute stroke patients, allowing for synergistic approaches with other therapeutic methods such as hypothermia or intravenous magnesium supplementation.¹²³ In a randomized controlled trial in 37 patients with severe subarachnoid hemorrhage, magnesium sulfate infusions (2.5 mg/mL at 20 mL per hour) into the cerebrospinal fluid continuously for 14 days after the hemorrhage delayed cerebral ischemia and resulted in improved clinical outcomes and fewer complications. In addition, intravenous hydrogen therapy was found to enhance the benefits of magnesium in this trial.¹²⁴

Olive Oil and Olive Extracts

The olive (Olea europaea) is a staple in the diet of many Mediterranean cultures, and olive oil is a primary source of added fat in the Mediterranean diet.¹²⁵ Olive oil consumption has demonstrated beneficial effects on blood pressure control.¹²⁶ The benefits of olive oil are attributable in part to its fat content, which primarily consists of healthy monounsaturated fat.¹²⁶ A 2011 study examining the incidence of stroke among 7,625 older subjects during a median of 5.25 years of monitoring found that people with the highest levels of olive oil use had a 41% lower risk for stroke compared with those who never used olive oil.¹²⁷ In a meta-analysis of cohort studies examining the association between olive oil intake and stroke risk, each 25 gram increase in olive oil consumption per day was associated with a 24% reduction in the risk of stroke.¹²⁸

Olive extracts may also play a role in stroke prevention. In a 2008 study involving 40 borderline hypertensive monozygotic twins, supplementing food with 1,000 mg olive leaf extract daily for eight weeks was associated with significant reductions in blood pressure.¹²⁹ In a gerbil model of ischemic stroke, pretreatment with 100 mg/kg olive leaf extract resulted in reduced damage to the hippocampal region of the brain up to 24 hours after ischemia, potentially due to its antioxidant activity.¹³⁰

In addition to healthy fats, several compounds in olive oil have been investigated for their neuro- and cardioprotective activity. Hydroxytyrosol, a phenol found in olive oil, exhibits antioxidant activity and acts as a metal chelator.¹³¹ In mouse models of ischemic stroke, mice fed a hydroxytyrosol-enriched diet had better grip strength, improved short-term memory, enhanced expression of neural growth factors, and increased presence of anti-inflammatory immune cells in the affected area of the brain compared with control mice, but effects on cerebral blood flow have been inconsistent.^132,133 Oleuropein, which is also found in olive oil, has both antioxidant and anti-inflammatory activity.¹³¹ In rodent models of ischemic stroke, oleuropein treatment has been found to be protective against neuronal cell death and was associated with significant improvements in cognitive function after stroke.^134-136

Maslinic acid, an olive constituent, may also play a neuroprotective role subsequent to stroke. In a mouse model of ischemic stroke, administration of maslinic acid (up to 10 mg/kg per day) for seven days after cerebral ischemia was associated with the development of new synaptic connections and regeneration of neurons in the brain.¹³⁷

Omega-3 Fatty Acids

The AHA recommends a diet that emphasizes a variety of fish, especially those that are high in omega-3 fatty acids, for heart health and stroke risk reduction.¹³⁸ Omega-3 polyunsaturated fatty acids, notably eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), exhibit a host of protective benefits that could be expected to lower risk of stroke, including anti-inflammatory and cholesterol-balancing properties. They also help protect against oxidative stress and promote neuron regeneration and revascularization after stroke.¹³⁹ Epidemiologic studies have found that lower blood levels of omega-3 fatty acids (a lower “Omega-3 Index”) are associated with increased risk for stroke and other neurological conditions, when compared to an optimal Omega-3 Index. Similarly, a review of clinical trials found EPA and DHA supplementation is more effective in those with low omega-3 status, and the use of blood tests to target supplementation decisions may lead to greater stroke prevention.¹⁴⁰ A meta-analysis of 10 studies involving over 20,000 people aged 35 to 79 years found that higher levels of circulating DHA were associated with a 22% reduction in stroke risk. Each 1% higher increment of DHA was associated with an 11% reduced risk of stroke. These results applied to protection from ischemic stroke only; no association was found with hemorrhagic stroke risk.¹⁴¹ A randomized controlled trial of 4 grams of isolated EPA per day in high-risk patients taking statins, followed for 4.9 years, found a 37% reduction in incidence of stroke.¹⁴²

Maintaining a healthy omega-6/omega-3 ratio after stroke may also be associated with improved outcomes. In a study of 25 older stroke survivors, a higher omega-6/omega-3 ratio was associated with greater physical dysfunction as well as insulin resistance compared with an optimal ratio.¹⁴³

A prospective observational study of nearly 80,000 women in the United States found those who consumed fish, which is high in omega-3 fatty acids, two to four times per week had a 48% lower risk of thrombotic stroke, and those who ate fish five or more times per week had a 70% lower risk of thrombotic stroke, while hemorrhagic stroke risk was unchanged.¹⁴⁴ Another study in over 43,500 U.S. men found that even once monthly fish consumption was associated with a 44% reduction in risk of ischemic stroke.¹⁴⁵ A meta-analysis of 17 cohort studies involving over 672,000 people found that higher fish consumption was associated with a 13% reduction in stroke risk and 19% reduction in risk for ischemic stroke. However, while higher omega-3 fatty acid intake was associated with a 21% reduction in risk for stroke in women, in this meta-analysis, no association between omega-3 intake and stroke risk was observed in men.¹⁴⁶

Some studies of omega-3 fatty acid supplementation have reported protective effects against cardiovascular disease, but several that have included stroke as one component of multi-outcome endpoints have reported no effect, even among high-risk individuals.^147-150 High-quality randomized controlled trials examining the effect of omega-3 supplementation on stroke risk as a primary outcome are urgently needed.¹⁴⁸ Tools such as the Omega-3 Index that measure blood levels of omega-3 fatty acids can help guide supplementation and dietary modification; individuals with sub-optimal Omega-3 Index scores can modify their supplementation and dietary regimens appropriately. Life Extension encourages most people to achieve an Omega-3 Index score of 8% or greater.

Flavonoids

Flavonoids, naturally occurring substances found in fruits, vegetables, grains, tea, and wine, have antioxidant and anti-inflammatory properties.¹⁵¹ A 2016 meta-analysis of 11 studies involving over 356,000 individuals found that, compared with the lowest dietary intake of flavonoids, those with the highest intake had a stroke risk reduction of 11%. Additionally, for every 100 mg increase in dietary flavonoid intake, there was a 9% decrease in relative risk for stroke.¹⁵² The AHA recommends a diet rich in flavonoid-dense foods, including fruits, vegetables, and whole grains—foods that also characterize the Mediterranean and DASH dietary patterns.¹³⁸

Flavanones, a type of flavonoid found in citrus fruits, may be of particular interest in stroke prevention as a study of over 69,000 women found that the highest levels of flavanone consumption were associated with a 19% lower risk for ischemic stroke.¹⁵³ Another study in over 20,000 U.S. adults found that, over 6.5 years, flavanone and citrus fruit/juice intake were inversely correlated with incidence of stroke, an association not observed for other flavonoids.¹⁵⁴

Folic Acid and B Vitamins

Homocysteine is an amino acid made in the body from a common dietary amino acid, methionine. High levels of homocysteine damage the endothelial lining of blood vessels, and are associated with a two- to three-fold increased risk of cardiovascular disease, including stroke.¹⁵⁵ Supplementation with B vitamins, including folic acid (vitamin B9), reduces the amount of homocysteine in the blood and helps protect against stroke.^57,60 Meta-analyses of multiple clinical trials and studies concluded that folic acid supplementation was associated with a 10‒15% reduced risk for stroke compared with not receiving folic acid supplementation.^156-159 One meta-analysis that included data from eight randomized controlled trials with a combined total of 8,513 participants found B vitamin supplementation (B6, B9, and B12) lowered stroke risk by 13%. In seven of eight trials, the dose of folic acid was 2 mg per day, whereas one trial supplemented with 2.5 mg per day. In all eight trials, B6 was 25 mg per day and B12 was 0.5 mg per day.¹⁵⁹ Findings from another meta-analysis suggested daily doses of folic acid under 2 mg may be more effective than higher doses.¹⁵⁷

Supplementation with other B vitamins may also be protective against stroke. Results from a 2015 analysis of 17 trials involving over 86,000 patients found folic acid plus vitamin B6 provides better protection against stroke than folic acid alone.¹⁶⁰ Additionally, research suggests B vitamin supplementation after stroke reduces the risk for recurrent stroke by nearly one-third.¹⁶¹

Nattokinase

Nattokinase is an enzyme extracted from fermented soybeans. Research generally supports nattokinase supplementation as safe and promising for cardiovascular disease risk reduction¹⁶² and functional protection after stroke.^163,164 In preclinical and clinical studies, nattokinase has been shown to break down the protein fibrinogen, which contributes to blood viscosity and clotting. It has also demonstrated lipid- and blood pressure-lowering activity, as well as neuroprotective effects.¹⁶³ In a randomized controlled trial published in 2008, individuals who received 2,000 fibrinolytic units (FU) of nattokinase per day for eight weeks experienced reductions in systolic and diastolic blood pressure of about 5.5 mm Hg and 3 mm Hg, respectively.¹⁶⁵ In an open-label trial in 45 subjects, supplementation with 4,000 FU of nattokinase daily for two months resulted in decreased levels of blood clotting factors, including fibrinogen, factor VII, and factor VIII.¹⁶⁶

Safety note: Cerebral hemorrhaging was reported in a patient concomitantly using aspirin and nattokinase for secondary stroke prevention.¹⁶⁷ Therefore, a risk assessment by a healthcare provider is warranted before individuals taking an antithrombotic agent initiate nattokinase supplementation.

Garlic

Components of garlic have many properties associated with heart health and exhibit a variety of antioxidant and anti-inflammatory effects that protect against atherosclerosis and hypertension.¹⁶⁸ According to the results of meta-analyses of studies of garlic supplementation, use of garlic supplements was associated with an average 5.1 mm Hg reduction and 2.5 mm Hg reduction in systolic and diastolic blood pressure, respectively, and may help support reduction in cholesterol levels.^169,170

In a study of 125 Chinese individuals with a history of stroke, greater daily garlic intake was associated with improved measures of endothelial function and blood flow, suggesting regular garlic consumption after stroke may help protect against future atherosclerotic events.¹⁷¹ In a 2015 study in a rat model of ischemic stroke, rats injected with 50 mg/kg allicin, a bioactive garlic constituent, every three hours had reduced infarct size, brain edema, and neural cell death.¹⁷²

Vitamin D

Vitamin D plays a role in lipid metabolism and development of atherosclerosis.¹⁷³ Supplementation may help lower blood pressure in those with vitamin D deficiency, and in the elderly.¹⁷⁴ A 2018 analysis of 19 studies from multiple populations found that lower vitamin D status was associated with an over 2-fold increased risk for ischemic stroke, though no association was found for hemorrhagic stroke.¹⁷⁵ A 2019 population-based study involving over 9,300 individuals found that, while no association with low vitamin D status was observed, severe vitamin D deficiency was associated with a 25% increased risk for stroke.¹⁷⁶ Additionally, a study of 982 Chinese ischemic stroke patients found that vitamin D deficiency is common in individuals recovering from ischemic stroke, particularly women and those with more severe stroke.¹⁷⁷ However, not all data indicates a role for vitamin D as a meta-analysis of randomized controlled trials that included over 83,000 individuals did not find a cardiovascular benefit for vitamin D supplementation.¹⁷⁸

In a study of 240 patients with ischemic stroke almost 63% had severe vitamin D deficiency, and the incidence of death after stroke was over 2.5 times higher among individuals with severe vitamin D deficiency compared to those without severe deficiency.¹⁷⁹ A randomized controlled trial of 53 ischemic stroke patients with low vitamin D levels (<75 nmol/L) found that compared with conventional care alone, intramuscular injection of vitamin D3 (600,000 IU) followed by daily calcium (1 gram) and once-monthly vitamin D3 (60,000 IU) supplementation for six months was associated with a 90% higher likelihood of a positive outcome.¹⁸⁰ These results suggest post-stroke vitamin D supplementation may be beneficial for some individuals, although more research is needed.^177,179,180

L-carnitine

L-carnitine is an essential cofactor in the metabolism of lipids into cellular energy.¹⁸¹ In a rat model of ischemic stroke, L-carnitine demonstrated a neuroprotective effect against tissue damage caused by oxygen deprivation.¹⁸² In another rat model of ischemic stroke, pretreatment with acetyl-L-carnitine was associated with a decrease in infarct size and prevention of ischemic damage in neural cells.¹⁸³

A 2019 prospective randomized controlled trial in 100 patients with middle cerebral artery ischemic stroke examined the use of 1 gram per day of oral L-carnitine supplementation in combination with fat emulsion therapy, a key component of nutritional support following stroke that requires large amounts of energy to metabolize. When used in conjunction with standard ischemic stroke treatment, L-carnitine plus fat emulsion therapy resulted in significant reductions in S100B, a biomarker of cellular damage and brain cell damage in particular, suggesting carnitine could be neuroprotective in humans.¹⁸⁴

N-acetylcysteine

N-acetylcysteine (NAC) is an amino acid derivative with potent antioxidant activity.¹⁸⁵ In a randomized controlled trial involving 68 ischemic stroke patients, oral NAC supplementation, at a dose of 4 grams over 48 hours initiated within 24 hours of stroke, was associated with a significantly lower rate of cognitive deficit at 90 days after stroke.¹⁸⁶ Additionally, in a randomized controlled trial in 123 patients with intracranial hemorrhagic stroke, medical researchers examined the effects of daily intravenous injections of 1,000 mg NAC twice daily and 800 mcg selenium twice daily on outcomes after stroke compared with placebo injections. After two weeks, NAC/selenium treatment was associated with a significant reduction in hematoma size, and length of intensive care unit stay was reduced from an average 12.7 days to 6.5 days.¹⁸⁷

However, in a single-blinded placebo-controlled trial involving 62 ischemic stroke patients, intravenous NAC infusions of 100 mg/kg upon admission followed by 10 mg/kg/hour for 10 hours was not associated with any measured benefits in clinical and laboratory profiles compared with standard therapy.¹⁸⁸ Further research is needed to understand the effects of NAC treatment on stroke outcomes.

Saffron Extract

Saffron (Crocus sativus) is a culinary and medicinal herb that is rich in carotenoid pigments, including crocin and crocetin, that confer a distinctive yellow color and antioxidant properties. Saffron extracts have demonstrated antioxidant, anti-inflammatory, neuroprotective, and antihypertensive effects.^189,190 Findings from multiple animal studies suggest saffron and its active constituents may protect against brain injury due to ischemic and hemorrhagic stroke.^191-194

In a randomized controlled trial in 40 acute ischemic stroke patients, those who received 400 mg of saffron extract daily (200 mg twice/day) along with routine stroke care had reduced severity of stroke symptoms after four days compared with those who received routine care alone.¹⁹⁵ In another controlled trial, 19 acute ischemic stroke patients received routine stroke care plus 200 mg saffron extract per day and 20 received routine care alone for three months. During the first four days of the trial, stroke severity was decreased and levels of brain-derived neurotrophic factor (BDNF, a protein that encourages brain cell growth and repair) were increased in the saffron treated-group relative to the routine care group; furthermore, at the end of three months, those who received saffron had lower disability scores and higher functional independence.¹⁹⁶

French Maritime Pine Bark Extract (Pycnogenol)

French maritime pine bark extract (Pycnogenol) is a polyphenolic compound with strong free radical-scavenging effects. Multiple clinical trials have demonstrated its beneficial effects on cardiovascular, metabolic, and brain health.^197,198 In animal research, Pycnogenol has been shown to exhibit anti-inflammatory properties, protect brain tissue from damage caused by ischemia, and attenuate oxidative stress following the return of blood flow (reperfusion) after ischemia.^199,200

In a randomized controlled trial, 184 participants were randomly assigned to receive either standard care (including diet and lifestyle instructions to control cardiovascular risk factors); standard care plus 100 mg aspirin per day; or standard care plus 100 mg aspirin, 150 mg Pycnogenol, and 450 mg gotu kola (Centella asiatica) extract per day for three years. At the end of the trial, those in the aspirin/Pycnogenol/gotu kola group had less progression of atherosclerosis and fewer cardiac events (stroke and heart attack) than the other two groups.²⁰¹

Lutein and Other Carotenoids

Lutein, a prominent carotenoid found in green leafy vegetables, egg yolks, and some fruits, has potent antioxidant effects. Lutein has often been examined for its role in visual health, but preclinical evidence also suggests lutein and related carotenoids, such as astaxanthin, may reduce brain damage related to stroke.^202-205 A review of 24 meta-analyses found increased green leafy vegetable intake is correlated with lower risks of stroke, heart disease, and mortality.²⁰⁶ One meta-analysis that included data from 67 studies found higher intake and higher blood levels of lutein were both associated with better cardiovascular and metabolic health parameters, including lower risk of stroke, compared to those with lower levels or intake of lutein.²⁰⁷ Furthermore, a systematic research review found high dietary intake of several carotenoids, including lutein, zeaxanthin, astaxanthin, lycopene, α-carotene, and β-carotene, were associated with reduced risk of stroke.²⁰⁸ Clinical trials are needed to verify these observations.

Protein Supplementation

Early clinical data indicate protein supplementation may be beneficial for improving outcomes in patients with a history of stroke who were in an exercise training program. In a pilot study, 20 people with long-term impairments after a stroke underwent eight weeks of cycling ergometric training. The participants received either 20 grams of a protein-rich supplement or a calorie-matched carbohydrate-rich supplement. The protein-supplemented group reached greater aerobic capacity, functional improvements, and total lean mass versus fat mass.²⁰⁹ Additional studies are needed to confirm the benefit of protein supplementation on functional outcomes in patients with stroke.

A rapid response is critical when a stroke occurs to minimize the resulting damage. The current medical standard for ischemic stroke therapy emphasizes treatment within 4.5 hours of stroke for the greatest likelihood of survival and reduced risk for disability.^8,9,210,211

Data from the AHA revealed 64% of stroke-related deaths occur outside of acute hospital care, and many people who do not make it to a hospital in time suffer irreparable damage to the brain.^9,12 If possible, it is best for stroke victims to be treated at a care center or hospital unit that specializes in treatment of stroke. A 2020 meta-analysis of 29 trials including almost 6,000 stroke victims found that those treated at a stroke unit, as opposed to an alternative—usually a general care ward—had a 23‒25% lower risk for death or poor outcomes after one year.²¹²

Long-term care following stroke includes both secondary stroke prevention and management of medical complications associated with stroke (see “Outcomes and Complications of Stroke”).^213,214

Evaluation and Initial Assessment

When a person is admitted to the hospital for stroke, clinicians will work quickly to stabilize the patient and evaluate their stroke. Initial evaluation of stroke involves¹¹³:

• Assessment of respiration and vital signs. The healthcare team will work to ensure the airway is open and breathing and circulation are stable. Hypoventilation (shallow or slow breathing) can lead to elevated levels of carbon dioxide in the blood, which can lead to dilation of blood vessels and increased intracranial pressure. Supplemental oxygen or ventilation may be needed for patients with poor respiration.¹¹³
• History and physical. A history will be obtained and a physical exam performed to determine what symptoms are occurring and when they started. These will also be used to determine a potential differential diagnosis.¹¹³
• Neurologic evaluation. A comprehensive neurologic evaluation will be performed to confirm the results of the history and physical and assess severity of the stroke.^112,215
• Laboratory evaluations. Other tests, including an electrocardiogram and assessment of oxygen saturation, blood clotting factors, and blood sugar levels, will be performed.¹¹² Electrocardiography is especially important to determine if underlying cardiac abnormalities may have caused a stroke.¹¹³
• Imaging. Brain, head, and neck imaging will be used to evaluate the type of stroke and location of the obstruction. For most patients, a non-contrast computed tomography (CT) scan or magnetic resonance imaging (MRI) can successfully distinguish between an ischemic and hemorrhagic stroke. For people who present greater than 4.5 hours after the onset of symptoms or who wake up with symptoms and are unable to estimate when a stroke may have occurred, additional imaging may be required.¹¹²

Management of Ischemic Stroke

For ischemic stroke victims who arrive for treatment within 3 to 4.5 hours of the onset of stroke, current treatment guidelines recommend the immediate use of alteplase (Activase) or tissue plasminogen activator (tPa), commonly referred to as intravenous thrombolysis (IVT).^9,112 IVT uses enzymes that break up and dissolve blood clots in order to reestablish blood flow. The use of IVT is associated with better outcomes for ischemic stroke patients, including reduced risk for death, disability, and need for long-term care.^8,9 A meta-analysis of three clinical trials found IVT may also improve outcomes if used within nine hours of stroke for those who wake up with stroke symptoms.²¹¹

For patients with obstructions in large arteries who arrive for emergency treatment within 24 hours, mechanical thrombectomy may also be used.^112,113,216 In a mechanical thrombectomy, a specialized device is threaded through the blood vessels to the site of the stroke-causing clot, which then removes as much of the clot as possible.²¹⁶ Eligibility for mechanical thrombectomy is based on a number of factors, including size and accessibility of the blood clot.^112,216 Mechanical thrombectomy is not used as frequently as IVT, as only about 10% of patients are eligible, and most hospitals outside of stroke centers do not have the specialized equipment or expertise to perform this procedure.²¹⁷

Current treatment guidelines from the AHA/ASA recommend that, for those eligible for mechanical thrombectomy, IVT may still have benefits if administered within the appropriate time frame.¹¹² IVT may resolve the blood clot quickly in the time it takes to prepare patients for mechanical thrombectomy, or may help dissolve enough of the clot such that it is easier to remove mechanically. A review of studies involving the timing of mechanical thrombectomy demonstrated that outcomes are most promising when treatment is initiated early, and delays are associated with increasing likelihood for disability and death.²¹⁸ Additionally, older age (≥80 years) has been identified as a predictor of poor outcomes after mechanical thrombectomy.¹²

Treatment of very high blood pressure is also often a component of ischemic stroke management.^3,19 Interestingly, low blood pressure after stroke has also been linked to worse outcomes, possibly due to decreased blood flow within the brain. Some evidence suggests there is a U-shaped relationship between blood pressure and stroke outcomes: people with both very low and very high blood pressure are at increased risk for death and disability after stroke.²¹⁹

In patients who are eligible for IVT or mechanical thrombectomy, blood pressure treatment is often used to maintain a systolic blood pressure <185 mm Hg and a diastolic blood pressure <110 mm Hg.¹¹² In patients with excessively high blood pressure (≥220/120 mm Hg) who do not receive IVT or mechanical thrombectomy, it is unclear if antihypertensive treatment provides any clinical benefit, but lowering blood pressure by 15% during the first 24 hours after a stroke is considered a reasonable goal.²¹⁵

Because ischemic strokes are inherently caused by the aggregation of platelets, antiplatelet therapy is a key component of acute ischemic stroke management. Aspirin is most often used, which should be started within 24 to 48 hours after the onset of stroke. However, it is not a substitute for acute treatment with IVT or mechanical thrombectomy.²¹⁵ A 2014 meta-analysis of eight clinical trials composed of over 41,000 patients found that initiation of aspirin within 48 hours of ischemic stroke onset reduced the risk for death or disability by 5%.²²⁰ A 2016 meta-analysis of 12 trials involving almost 16,000 patients studied the use of aspirin to reduce the risk for a second stroke after TIA or ischemic stroke. The analysis found that, in the first six weeks after trial randomization, aspirin reduced the risk of recurrent ischemic stroke by 58% and the risk for a fatal or disabling stroke by 71%. Some additional benefit was noted in the period of 6‒12 weeks, but none after 12 weeks. The greatest benefits were observed in people who experienced a TIA or minor stroke (a stroke with mild but persisting symptoms).²²¹ Early short-term dual antiplatelet therapy with aspirin and clopidogrel (Plavix) is indicated to reduce the risk in select TIA or minor stroke patients.⁶⁰

Management of Hemorrhagic Stroke

Hemorrhagic stroke is inherently different than ischemic stroke and requires a different approach to treatment. Whereas the goal of ischemic stroke treatment is to disrupt the blockage of the affected blood vessel, emergency treatment of hemorrhagic stroke is focused on controlling bleeding and pressure in the brain. Hemorrhagic stroke cannot be distinguished from ischemic stroke based on clinical presentation alone, and neuroimaging with MRI or CT scan is thus required as an initial step in management.²²²

Use of oral anticoagulants or antiplatelet therapy is associated with increased risk for hemorrhagic stroke. These agents work to prevent blood clots, which can also increase the risk for bleeding. Up to one in five people who experience intracranial hemorrhaging are taking an oral anticoagulant.²¹³ Prompt discontinuation of antiplatelet and anticoagulant therapy should be undertaken immediately. For people taking the anticoagulant warfarin or another vitamin K antagonist, intravenous vitamin K, intravenous protamine sulfate, and other clotting factors are used to reverse the effects of treatment.²²³ Non-vitamin K oral anticoagulants, also known as direct oral anticoagulants (DOACs), are associated with reduced risk for hemorrhagic stroke compared with warfarin.^213,223 However, increased risk of bleeding may still occur with these medications, but newer agents to reverse their anticoagulant effects, with varying effectiveness, are available.^223,224

As with ischemic stroke patients, blood pressure management is an important aspect of hemorrhagic stroke treatment. This may be achieved using beta-blockers (labetalol or esmolol [Brevibloc]), an angiotensin-converting enzyme (ACE) inhibitor (enalapril [Vasotec]), calcium channel blocker (nicardipine [Cardene]), or vasodilator (hydralazine).⁴¹ In the 2010 INTERACT study, early and intensive antihypertensive treatment significantly reduced the growth of brain hematomas during intracerebral hemorrhage over the course of 72 hours.²²⁵ Reduction of systolic blood pressure to 140 mm Hg is generally considered safe and is recommended to improve functional outcomes. For patients with a systolic blood pressure over 220 mm Hg, more aggressive antihypertensive treatment is needed.^213,223

Managing intracranial pressure is another vital consideration in management of acute stroke. For patients requiring intervention to reduce this pressure, a number of strategies can be used, including elevating the head to a 30-degree angle, administration of oxygen, mild sedation, and osmotic therapy (mannitol, hypertonic saline), which can help reduce and redistribute fluid buildup around the hematoma.^223,226 Under some conditions, ventricular catheterization may be used to monitor intracranial blood pressure, which can also be used to drain fluid buildup or deliver medication if needed.²²⁶

Management of Post-stroke Complications

Venous thromboembolism (VTE). Prevention of future DVT and VTE is complicated in stroke, as the risks for both clotting and bleeding are high. Over one in 10 patients experience DVT or VTE after stroke, including 13% of hemorrhagic stroke victims, so blood clot prevention measures are needed.^226,227 Mechanical therapy with an intermittent pneumatic compression device, compression socks, and/or a venous foot pump are recommended as soon as patients are discharged. Low-dose heparin may be initiated if the risk for bleeding in ischemic stroke victims is low, or once bleeding has stopped following hemorrhagic stroke.^227,228 Patients who are considered at high risk for DVT and VTE may require both pharmaceutical and mechanical DVT prophylaxis.²²⁸

If DVT or pulmonary embolism occurs, more aggressive treatment may be needed. Because a second incidence of pulmonary embolism is fatal in up to 88% of cases, oral or intravenous anticoagulant therapy is likely needed if a DVT or pulmonary embolism occurs.²¹³

Dysphagia and pneumonia. Dysphagia is among the most common complications after stroke, occurring in an estimated one-third to three-quarters of stroke victims, depending on diagnostic method. If swallowing difficulties prevent eating, a feeding tube may be needed to support proper nutrition and hydration until symptoms improve.²¹⁴

Aspiration due to dysphagia can increase the likelihood of developing pneumonia. In fact, the risk for pneumonia is over three times higher in stroke victims with dysphagia compared to those without dysphagia.^214,229 Pneumonia is a common complication after both hemorrhagic and ischemic stroke, occurring in an estimated 4‒10% of patients.^213,214 Formal screening for dysphagia can reduce the risk for pneumonia by an estimated 90%.²³⁰ Speech therapy may also help improve control of swallowing muscles.

Fever. Fever is common after stroke, particularly among hemorrhagic stroke patients.^226,231 Approximately half of patients experience a fever after stroke, and one study found that over 90% of hemorrhagic stroke victims with intracerebral hemorrhage experienced a fever (≥99.5°F) for at least a portion of the 72 hours following hemorrhage.^231,232 The presence and duration of fever are associated with worse outcomes following stroke, including poor functional outcomes.²³² The majority of post-stroke fevers are thought to be infectious in nature, caused by pneumonia or other bacterial and viral infection. Potential noninfectious causes of fever include widespread tissue death and lysis of blood cells following hemorrhage.²³² Treatment of fever may include pharmacological treatment, as well as external cooling systems or intravenous cold saline infusions.^226,232 Hypothermia treatment (see “Novel and Emerging Strategies” section) may also reduce fever, but is still considered investigational at this time.²²⁶

Seizure. Seizures, while relatively uncommon after stroke, may represent an important complication after hemorrhagic stroke in particular. Depending on the location of the hemorrhage, up to one in six people will experience a seizure within a week after hemorrhagic stroke.²²⁶ Anti-seizure treatment is used if seizures occur but is not recommended preventively.^213,226

The damage to the brain caused by a stroke can lead to long-term neurological complications including impaired cognitive function,²³³ memory loss and dementia, communication challenges, and reduced problem-solving abilities.²³⁴ Impaired motor control, including problems with balance, muscle weakness, and even paralysis, are also possible.²³⁵ Although some impairment may persist long-term, rehabilitation can help improve outcomes and independence after stroke.²³⁶

According to the ASA, about 40% of stroke patients will experience moderate-to-severe impairments and one in 10 stroke survivors will require long-term supportive care. However, about 25% of patients will recover with only minor impairment, and about 10% of stroke survivors will experience complete recovery.²³⁷ Most recovery occurs within the first 3‒6 months after stroke, but some patients may continue to experience some cognitive and physical recovery up to 18 months post-stroke.²³⁸

Stroke outcomes and long-term effects depend largely on the brain region affected and extent of brain damage. For example, dementia is frequently observed in people who experience strokes in the left hemisphere of the brain, whereas loss of problem-solving abilities are more common in people who have right-brain strokes.²³⁴ Because the left hemisphere controls the right side of the body, people who have left-brain strokes are more likely to experience impaired motor function on the right side of their body, and vice versa.²³⁵

Other complications of stroke that may require additional treatment include^113,214:

• Dysphagia (difficulty swallowing)
• Deep vein thrombosis and pulmonary embolism
• Pneumonia
• Urinary tract infections and incontinence
• Seizures
• Myocardial infarction and other cardiac injury
• Gastrointestinal bleeding
• Sleep-disordered breathing
• Depression
• Fatigue
• Brain edema (swelling)

Paralysis or Impaired Motor Function

After stroke, some people may experience problems controlling their movements or may even experience paralysis. In a study of over 1,200 people recovering from stroke, over 77% experienced upper limb weakness.²³⁹ This loss of muscle control can make it difficult to walk or maintain balance and can cause problems with normal body functions. Most recovery of motor function occurs within the first three months after stroke.²⁴⁰ Additionally, the majority of people who survive stroke experience difficulty swallowing, a condition known as dysphagia.²⁴¹ Dysphagia can make it difficult to eat or drink and may lead to nutritional deficiencies and illness, including pneumonia.

Sensory Disturbances

Stroke victims may experience pain immediately after stroke or within the following weeks to months. In some people, chronic pain may occur as a result of impaired motor function, which can cause stiffness in the joints. Other sensory issues may emerge, including numbness, tingling, or loss of sensation.²³⁵ Loss of sensation, combined with impaired motor function and reduced cognitive awareness, can lead to incontinence after stroke.^235,242 About half of stroke survivors experience urinary incontinence, and approximately one-third have loss of bowel control.^243,244 These symptoms may improve over time, with just 15% of people experiencing continued urinary incontinence one year post-stroke.^242,243

Speech Problems

Up to one in three people who have a stroke will experience problems using or understanding language, a phenomenon known as aphasia.²⁴⁵ Aphasia can result from stroke-induced damage to regions of the brain that are responsible for speech and language processing.²⁴⁶ Aphasia can affect a person’s ability to write and speak.²³⁵

Cognitive Impairment or Memory Dysfunction

Cognitive impairment occurs within one year in roughly 30% of those who have experienced a first stroke.²⁴⁷ This may affect many mental functions, both simple and complex, including the ability to learn new things or plan ahead, and may impair a person’s attention span, short-term memory, or ability to comprehend others.^235,239 Post-stroke cognitive impairment is different from cognitive decline seen in Alzheimer disease in that it is a more abrupt change in cognitive function.²⁴⁸ In addition to cognitive changes, about one in three patients who experience a large stroke have impaired consciousness at the time of stroke, which, in some cases, persists long-term.^249,250 More severe impairment of consciousness has been correlated with poorer functional outcomes for stroke patients.²⁵⁰

In some people, most commonly those who have left-hemisphere strokes, reduced blood flow to the brain can result in vascular dementia.²⁵¹ Compared with the general population, the risk for all-cause dementia is 69% higher for people with a history of stroke.²⁵² The incidence of vascular dementia varies considerably based on the severity of stroke, with an estimated 5% of people experiencing dementia one year after TIA compared with 34% at one year after severe stroke. Secondary stroke prevention measures are considered a cornerstone of vascular dementia prevention as well.²⁵³

Emotional Disturbances

Many people who have a stroke experience emotional distress, including anxiety, fear, frustration, anger, sadness, and grief.²³⁵ An analysis of 44 studies involving over 5,700 stroke patients found that approximately one-fifth to one-quarter of stroke survivors experience anxiety, which persists up to six months or longer post-stroke.²⁵⁴ The ASA estimates up to 55% of people will experience depression at some point after stroke.²⁵⁵ Post-stroke emotional disturbances can be treated with a variety of interventions, including medication and counseling. Addressing mental and emotional well-being is a key part of recovery after stroke, as anxiety, apathy, and depression have been linked to poor function and outcomes after stroke.^256,257

Uric Acid Therapy

Restoration of blood flow following stroke, known as reperfusion, can lead to the generation of oxidative stress in brain tissue.²⁵⁸ Oxidative stress can cause damage to DNA, cells, and tissues.²⁵⁹ Uric acid can neutralize reactive oxygen species (ROS) and has been examined in clinical trials of ischemic stroke.^260-262 In a placebo-controlled trial with 411 participants, 1,000 mg intravenous uric acid therapy administered during IVT infusion doubled the likelihood of having an excellent outcome in women compared with IVT plus placebo. An excellent outcome was defined as no post-stroke symptoms, mild symptoms without disability, or no worsening of an existing slight disability. In contrast, uric acid administration in men had no effect on outcome.²⁶¹ A second analysis of the trial noted that uric acid therapy was associated with reduced infarct growth and improved outcome in a subgroup of patients with the highest blood glucose levels during acute stroke.²⁶² In a randomized controlled trial evaluating 45 people with ischemic stroke who received both IVT and mechanical thrombectomy, 1,000 mg intravenous uric acid improved functional outcome and reduced mortality compared with placebo. No serious safety concerns regarding uric acid therapy were observed in this study.²⁶⁰

Therapeutic Hypothermia

Therapeutic hypothermia has been investigated as a neuroprotective strategy in several conditions, including cardiac arrest^263,264 and traumatic brain injury.^265,266 This treatment modality involves lowering the body temperature to below normal, typically 89.6°F to 95°F, and is believed to be a powerful neuroprotectant. It has been proposed that this cooling interrupts a range of cellular signaling cascades that result from ischemia and promote edema, inflammation, cell death, and a breakdown of the blood‒brain barrier. Therapeutic hypothermia may more comprehensively address the ischemic cascade that occurs after stroke than other therapies, which typically only address one aspect.²⁶⁷

It is currently difficult to adequately gauge the benefits and effects of therapeutic hypothermia in ischemic stroke. As of the time of this writing studies have often been small, lacked a control group, and used differing cooling methodologies. Perhaps most challenging for the study of therapeutic hypothermia in stroke is that core body temperature is not necessarily indicative of brain temperature, and there is no reliable way to measure brain temperature.²⁶⁷

Taken as a whole, the body of research points to functional improvement with the application of therapeutic hypothermia in ischemic stroke, but with an increased risk of complications.²⁶⁸ These include cardiovascular complications such as heart attack and arrhythmias; increased risk of infection including pneumonia and urinary tract infection, due to immune suppression; abnormal (insufficient) blood clotting; electrolyte imbalances; and insulin resistance.^267,269,270 However, as of mid-2021, existing evidence has not demonstrated robust clinically significant effects related to size of infarct, or mortality. More randomized controlled trials with larger sample sizes are needed to determine if and how therapeutic hypothermia fits into the landscape of treatments for ischemic stroke.²⁶⁷

The effects of therapeutic hypothermia in hemorrhagic stroke have been similarly sporadically studied. In a meta-analysis of nine studies, while some results were mixed, researchers found a 60% lower risk of poor outcomes in hypothermia groups. There was also an almost 40% reduction in occurrence of delayed cerebral ischemia, or the delayed development of new neurological symptoms, in patients who received therapeutic hypothermia. No significant differences in adverse outcomes between hypothermia and usual care were found. Although more research is needed, preliminary results suggest therapeutic hypothermia may improve outcomes after hemorrhagic stroke.²⁷¹

Intravenous Vinpocetine

Vinpocetine is a synthetic derivative of the chemical apovincamine, which is an extract from the leaves of the lesser periwinkle plant. Vinpocetine has been explored widely in a variety of diseases, from cerebrovascular and cognitive disorders to kidney injury and eye conditions. It is associated with a variety of potentially neuroprotective activities, including vasodilation, inhibition of inflammation, and antioxidant properties. Vinpocetine also inhibits sodium channels in the brain, which may prevent excitotoxicity and damage to brain tissue.²⁷² Studies in animal models of ischemic stroke have found that vinpocetine is able to block several aspects of pro-inflammatory signaling within the brain, both within and between neurons.^273-276

In a randomized controlled trial involving 60 people with ischemic stroke, individuals who received standard care plus vinpocetine (30 mg intravenously daily for 14 days) experienced smaller growth of secondary lesions and an attenuated inflammatory response compared with those who received standard care alone. They also had improved clinical outcomes in the weeks after stroke, up to three months later.²⁷⁷ Another small trial involving 30 stroke patients found limited evidence of improvement on a standardized clinical status scale three months post-stroke among patients who received intravenous vinpocetine compared with those who received standard of care. However, there was no statistically significant difference in risk of poor outcomes overall at three months.²⁷⁸

Another clinical trial examined the effects of a single vinpocetine infusion (20 mg intravenously in 500 mL of saline for 60 minutes) followed by three months of oral vinpocetine supplementation (10 mg, three times daily) on outcomes in patients with chronic effects from an ischemic stroke. Those given placebo experienced significant reductions in the digit span backwards test (which measures the ability to repeat a string of numbers backwards), while no worsening in test results was noted in those given vinpocetine. Also, researchers observed no significant changes in any other neuropsychological tests performed and no notable side effects with treatment.²⁷⁹

Additional small clinical trials found that intravenous vinpocetine increased cerebral blood flow in stroke patients, but these studies did not assess functional outcomes.^280,281

Nerinetide

Nerinetide is a peptide molecule that interrupts signaling pathways in the brain that can lead to neurotoxic tissue damage, potentially via inhibition of intracellular nitric oxide production. Although nerinetide has exhibited neuroprotective activity in animal models of ischemic stroke, results from the 2020 ESCAPE-NA1 randomized controlled trial did not show significant improvement in outcomes in patients after ischemic stroke.²⁸² However, it was later noted that, among participants who did not receive IVT with alteplase, those treated with nerinetide had significantly better outcomes compared with placebo.²⁸³ More research is needed to understand the relationship between nerinetide and alteplase, but these preliminary results suggest nerinetide may play a protective role in ischemic stroke for patients who are not candidates for alteplase. No significant differences in occurrence of adverse events were associated with nerinetide use compared with placebo.²⁸²

Intravenous Fisetin

Fisetin, a flavonoid with neuroprotective and anti-inflammatory properties, has inhibited inflammation and prevented tissue injury in several animal models of ischemic stroke, including mice,²⁸⁴ rats,²⁸⁵ and rabbits.²⁸⁶ In a randomized controlled trial that included 192 people with ischemic stroke, the addition of fisetin to standard IVT reduced serum levels of inflammatory markers, including C-reactive protein, and dramatically improved treatment outcomes compared with IVT alone. This was observed in patients for whom treatment was started within three hours after the onset of symptoms as well as in patients whose treatment was delayed (3–5 hours after the onset of symptoms). These findings suggest fisetin may prolong the therapeutic window for IVT in ischemic stroke patients from three hours to five hours.²⁸⁷

Hydrogen Gas Inhalation

Hydrogen therapy may have a role as an adjunct therapy to prevent brain injury due to ischemic stroke and reperfusion,²⁸⁸ which is marked by extreme oxidative stress and is a major contributor to neuronal damage after ischemic stroke. Hydrogen has several beneficial effects, including antioxidative, anti-inflammatory, and antiapoptotic effects.^288,289 Hydrogen can be administered as an inhaled gas with a concentration of 2–4%, orally in enriched water, or intravenously in enriched saline.²⁸⁸ In acute circumstances, inhalation appears to be the most efficient means of administration.²⁹⁰ Animal research also suggests hydrogen therapy may reduce hemorrhagic stroke-related brain damage and mortality; in an animal model of hemorrhagic stroke hydrogen therapy reduced brain edema and improved nerve function for 72 hours.²⁸⁸

The effect of hydrogen gas inhalation on brain tissue damage and functional outcome was examined in a randomized controlled trial including 50 patients with acute ischemic stroke of mild-to-moderate severity. Half of the participants received standard care plus hydrogen therapy (3% hydrogen gas inhalation for one hour twice daily for seven days) and half received standard care alone. Those who received hydrogen therapy had greater brain tissue recovery, as visualized by MRI, after seven days; after 14 days, the hydrogen-treated group had almost complete resolution of changes at the site of the ischemia, while the control group showed persistent ischemic damage. In addition, those who received hydrogen had better functional recovery during the 14 days of monitoring.²⁹⁰