Cerebral Vascular Disease

Thrombotic (Ischemic) Stroke, Hemorrhagic Stroke, and Cerebral Aneurysm

A cerebral vascular event (stroke) is defined as a sudden neurological deficit in the brain caused by either ischemia (a lack of blood supply to the brain) or a hemorrhage: 80% of all strokes occur due to arterial blockage (ischemia), and 20% occur due to bleeding (hemorrhage). Hemorrhagic strokes are classified as either occurring within the brain tissue (intracerebral or intraparenchymal) or around the brain tissue (subarachnoid).

Incidence and Epidemiology
Stroke is the leading cause of disability in the United States and the third leading cause of death. While it was originally estimated that annual stroke incidents were approximately 550,000 cases, a study in 1998, through more rigorous counting in all racial and ethnic groups, increased the yearly estimate to 731,000 cases (Broderick et al. 1998). This study showed that African Americans have a higher stroke incidence and stroke mortality than other racial groups.

Women have lower stroke rates than men at all age ranges except 75 years and older, when stroke rates are at their highest. It is of concern that the overall declining rate of stroke-related deaths slowed over the past several decades and leveled off in the 1990s (Gillum 1999).

Individual approaches for the management of ischemic and hemorrhagic stroke are discussed under Thrombotic Stroke and Hemorrhagic Stroke in this protocol. Also, the terms thrombotic and ischemic stroke will be used interchangably.

Prognosis and Recovery
In spite of conventional advancement in acute stroke care, the majority of stroke survivors remain permanently partially disabled with neurological symptoms and limitations. While most patients develop some improvement, it is rarely complete. The more severe the initial stroke, the greater the chance of long-term disability. Recovery also varies depending on the size and location of the infarction or hemorrhage. Small infarctions, especially multiple small stroke sites, may result in little disability, whereas large infarctions may cause severe permanent disability.

It is interesting that other related conditions such as high blood pressure do not appear to affect recovery. However, younger patients have a better prognosis than older patients. Overall there is marked variability in recovery, making early disability predictions difficult. In general, recovery is greatest in the first 3 months and rarely occurs beyond 1 year after the stroke. This makes it essential that speech therapy, physical therapy, and occupational therapy be instituted as soon as possible after the stroke occurs and continued three to five times weekly throughout the first year of recovery. All too often, rehabilitative therapy is too infrequent and is stopped prematurely preventing optimal recovery.

Recovery from strokes is relatively poorly understood. While infarcted brain tissue is not able to repair itself, recovery has been theorized to occur by recruiting neighboring neurons (nerve cells) to serve new or additional functions. It is fascinating that electrical brain mapping in monkeys has demonstrated that the cerebral cortex can be functionally reorganized during recovery after an infarction (Nudo et al. 1996). In fact, MRIs in humans have shown increased activity in both hemispheres as patients improve after a stroke. This suggests recruitment of neighboring neurons as well as the corresponding larger regions of the cortex (Cramer et al. 1997).

If you or someone with you is possibly having a stroke, respond immediately! The time it takes to receive treatment is as important to stroke victims as it is for those who are having a heart attack. Not recognizing the symptoms of a stroke, or believing that stroke is untreatable, causes many people to fail to respond to the warning symptoms of stroke and to not seek immediate medical attention.

Regardless of whether the stroke is thrombotic (caused by a clot) or hemorrhagic, management at the onset is considered an acute medical emergency. Stroke patients receiving medical care within 6 hours of the onset of symptoms have a 32% greater chance for a reduced hospital stay (13 days versus 19 days) than those treated after this period (Davalos et al. 1995). Amazingly, 42% of stroke patients wait as long as 24 hours before presenting for medical treatment. That is 21 hours too late! The delay in presenting at the emergency room results in a missed opportunity to effectively treat, and possibly reverse, the damage caused by thrombotic stroke. According to one study, "patients with milder symptoms, for whom treatment might be more effective, were less likely to arrive in time for therapy" (Alberts et al. 1990).

From a preventive medicine and patient education perspective, it is therefore crucial that healthcare providers educate at-risk patients and their families about stroke-related symptoms and encourage them to call 911 if stroke symptoms occur. It is equally crucial that optimal emergency room intervention and treatment occur as soon as the patient arrives in the hospital emergency room.

From the time the patient arrives at the emergency room (ER) triage desk, a computerized tomography (CT) scan should be authorized as soon as possible (within 5 minutes). Multiple timely interventions are crucial in the acute emergency room. These vary based on a range of findings including the patient's temperature, oxygen saturation, blood pressure, glucose levels, complete blood count, electrocardiogram, airway and pulse, medical history, and hydration status. Inclusion and exclusion criteria are reviewed for the consideration of intravenous (IV) thrombolytic therapy if a thrombotic CT scan pattern is identified. The CT scan is further reviewed distinguishing a thrombotic stroke from an intracranial or a subarachnoid hemorrhage. A neurosurgeon will be consulted if an aneurysm or blood pooling is present due to an intracranial hemorrhage. Surgery may be necessary for the evacuation of a hematoma (blood pooling from a hemorrhage). In the intensive care department, blood perfusion (hemodynamics) is continually monitored and assessed. Secondary stroke prevention is initiated based on National Institutes of Health (NIH) guidelines. The treatment of stroke patients in dedicated stroke units has been shown to reduce morbidity, mortality, and disability as well as other post stroke complications (Indredavik et al. 1999).

Stroke-Related Symptoms
The sudden onset of neurological signs and symptoms developing over a few minutes or few hours are indicative of a stroke event. Most of these strokes will be ischemic, involving a thrombus (clot), rather than hemorrhagic. However, any of the following symptoms can result from a clot or bleed, depending upon the arteries in the brain involved in the stroke and their location.

According to the National Stroke Association (1999), strokes more often occur abruptly, with the following symptoms which often develop suddenly:

• Difficulty standing or walking, dizziness, loss of balance, loss of coordination
• Numbness in the face, arm or leg weakness, particularly on one side of the body
• Confusion, difficulty speaking or understanding
• Vision difficulty in one or both eyes
• Severe headaches that have no known cause
• Other important, but less common stroke symptoms include:
• Nausea, fever, and vomiting that is different from a viral illness in the speed of onset (begins in minutes or hours instead of over several days)

Normal Functional Areas of Brain
The brain has two sides: a right hemisphere that controls the left side of the body and a left hemisphere that controls the right side of the body. Each hemisphere has four lobes and a cerebellum that control our daily functions. Depending on what part of the brain has been affected, stroke victims experience a variety of neurological deficits. Rehabilitation is crucial to the stroke patient's recovery. Physical therapists and speech therapists help patients "relearn" their lost functions and devise ways to cope with the loss of those they cannot regain. (Anatomical Chart Company 2002®, Lippincott Williams & Wilkins)

A brief loss of consciousness or a period when there is a reduced level of consciousness (sudden fainting, increased confusion, convulsion, or coma)

Any of these signs may be only temporary and may last only a few minutes.

Hemorrhagic Stroke Symptoms
When a bleed occurs, causing a stroke, the symptoms are less abrupt over one or several hours. The most commonly associated symptoms include headaches, vomiting, and altered states of consciousness.

Cerebral Embolism Symptoms
Symptoms vary further depending upon the nature of the developing stroke. If the stroke is caused by a thrombus (clot) suddenly passing into arteries in the brain (cerebral embolism), the symptoms are of rapid onset, often intensifying over a few seconds, causing headaches on the affected side, seizures, or both. There is often a preexisting heart disease, such as mitral stenosis or atrial fibrillation, endocarditis (an inflamed heart), or a mitral valve prolapse, in which stagnant blood has had the chance to clot and then pass from the heart suddenly into arteries of the brain, blocking blood flow to the brain.

Cerebral Thrombotic Stroke Symptoms
When a cerebral artery becomes blocked from the progressive worsening of a localized clot or a hardened artery in the brain, the symptoms develop over minutes or hours and sometimes over days or weeks. Common causes include gradual hardening and narrowing of cerebral arteries (atherosclerosis) often associated with hypertension, diabetes, coronary artery disease, peripheral vascular disease, or head trauma.

Transient Ischemic Attacks
Often patients can experience temporary symptoms that are associated with a lack of adequate blood supply to the brain. These episodes are known as transient ischemic attacks (TIAs). When TIA-related symptoms occur, they occur suddenly and last from 5 minutes to several hours and then resolve completely. These symptoms are often due to reduced circulation and blood supply from the two main arteries leading into the brain--the carotid arteries located in the neck supply the brain from the front, and the vertebrobasilar arteries supply the brain from the back, passing through holes in the vertebrae of the cervical spine.

The peak age of onset for TIAs is 60-70 years of age. It is interesting that a third of the time, TIAs will lead to a subsequent stroke; a third of the TIAs continue and do not lead to a stroke; and a third of the time TIAs spontaneously remit and no longer occur.

It is commonly agreed that TIAs are due to microembolization (small clots moving into the brain), excessive platelet aggregation, or from ulcerations in the walls of atheromatous hardened arteries. Other causes include transient episodes of low blood pressure due to dehydration or adrenal insufficiency, mechanical kinking of arteries in the head and neck during head rotation, cervical spine bone spurs compressing the vertebrobasilar artery, or heart arrhythmias.

TIA symptoms are artery-location dependent. Here is a list of the arteries and brain regions that may be temporarily restricted in blood supply and the associated symptoms that develop.

Thrombotic Stroke

Ischemic, Thrombotic, Embolic, and Transient Ischemic Attack
In this section, we will discuss methods of preventing primary and secondary thrombotic (ischemic) strokes, along with approaches to restoring function to brain cells that are damaged by a thrombotic stroke (i.e., inducing or accelerating rehabilitation, or both). Because some people may refer to this protocol if they have symptoms of an acute stroke, we will begin with the initial steps involved in diagnosis and immediate treatment.

Aggressive Stroke Therapy
Healthcare providers still do not treat stroke as aggressively as they do heart attack. Many therapies that are proven to work are not made available to the acute stroke patient presenting in the emergency room.

Further contributing to stroke deaths is the belief by many healthcare providers that stroke is untreatable, leading to an attitude of "watchful waiting" with an onset of a stroke instead of being focused on treating the stroke as a medical emergency. The National Stroke Association has described this opinion as being an outdated attitude that serves as the largest obstacle to effective prevention and emergency treatment of strokes.

The use of CT and Doppler ultrasonography has made radical changes in early diagnosis of ischemic and hemorrhagic strokes (Wintermark et al. 2002). These advances have resulted in declines in stroke mortality. In the 1980s, the development of magnetic resonance imaging (MRI) further improved evaluation of persons with cerebrovascular disease (Hesselink 1986; Welch et al. 2000).

Tissue Plasminogen Activator
The FDA approved the use of a tissue plasminogen activator (t-PA) in June 1996 to treat strokes. t-PA had already been approved to dissolve clots that occur in the coronary arteries (which cause an acute heart attack), but the FDA has delayed approving t-PA to treat ischemic stroke for many years. Millions of cases of death and permanent paralysis occurred because of the FDA's delay in approving t-PA in treating stroke caused by abnormal blood clotting in the brain's arteries. Physicians affiliated with the Life Extension Foundation were using t-PA in emergency rooms to treat ischemic stroke years before the FDA gave its official seal of approval.

t-PA (sold under the brand name Activase) should be administered immediately (or within 3 hours) after a stroke to dissolve the clot that is preventing blood from reaching a portion of the brain. t-PA is a natural clot-dissolving substance produced by the body and can literally "blow open" the blood clot in the brain that is causing the acute ischemic brain damage characteristic of a stroke. However, it is crucial that the attending physician review all of the inclusion and exclusion criteria associated with the use of t-PA in advance of its administration. Examples of exclusion criteria making t-PA absolutely contraindicated include an intracranial mass or hemorrhage; very low or high glucose; a previous stroke or head trauma within the last 3 months; current use of anticoagulant drugs; a seizure at the onset of the stroke; major surgery within the last 2 weeks; low platelets; gastrointestinal hemorrhage within the last 3 weeks; blood pressure greater than 185/110; or a previously known cerebral aneurysm (Adams et al. 1996).

One study has shown that 30% more stroke victims were able to regain full use of their faculties after receiving t-PA. In this study 45% of the stroke victims had a good result, defined as "complete regression or slight neurological sequelae." The subgroups with poor prognosis outcomes in three parameters showed a good outcome in 30% of those patients with each of these characteristics (Trouillas et al. 1998). Even today, patients may encounter extreme resistance from emergency room physicians who are reluctant to administer it (Alberts 1998), even if a patient's life is at stake. In some cases, surgery may be required to remove any blockage of blood vessels going to the brain because it is important to get the blood circulating to the brain.

While t-PA can dissolve the blood clot that causes a blood vessel blockage, there are other complications that occur during ischemic stroke that have to be addressed if permanent brain damage is to be prevented. Any interruption in blood flow causes an oxygen imbalance that results in massive free-radical damage. It is critically important to have antioxidants in your bloodstream when t-PA is administered to reduce the free-radical damage that will occur when blood flow is restored (Ozmen et al. 1999).

Heparin
Heparin is a natural polysaccharide normally found in mast cells. Heparin increases the activity of antithrombin III, preventing the conversion of fibrinogen to fibrin. Heparin must be administered parenterally (by IV) because it is not absorbed in the GI tract. Because of this, heparin may be used in acute care situations, but not usually in stroke prevention.

Silent Strokes
Debilitating strokes depicted on television shows or in movies have severe symptoms. Most strokes, however, are not as dramatic. Often the symptoms are minor and transient and may be ignored or dismissed as unimportant. Over time these silent strokes lead to memory loss and other neurological problems. According to one study, by the time people reach their 70s, one in three has a silent stroke every year (Leary 2001).

Of particular concern to stroke victims is that silent strokes occur frequently, causing neurological damage days or weeks after the initial crisis. A 2001 study found that one fourth of stroke survivors had at least one silent stroke during the 2 years following their initial stroke (Corea et al. 2001).

The Underlying Causes
We usually consider a heart attack a life-or-death health event. Strokes have been given less attention, but the realization that stroke is an acute event has now led to stroke being referred to as a brain attack. Thrombotic strokes are a major cause of brain attacks and are caused in part by atherosclerosis, hypertension, and procedures that cause abnormal arterial blood clot formation (thrombosis), such as atrial fibrillation and heart valve replacement.

As with almost all cardiovascular disease, strokes are generally the result of several underlying diseases which result in stopping or reducing the flow of blood to the brain.

The majority of strokes occur when a blood clot blocks the flow of oxygenated blood to a portion of the brain. This type of stroke, caused by a blood clot blocking or "plugging" a blood vessel, is called ischemic stroke. An ischemic stroke can be caused by a blood clot that forms inside the artery of the brain (a thrombotic stroke) or by a clot that forms somewhere else in the body and travels to the brain (an embolic stroke). In healthy individuals, blood clotting is beneficial. When you are bleeding from a wound, blood clots work to stop the bleeding. In the case of ischemic stroke, abnormal blood clotting blocks large as well as small arteries in the brain, cutting off blood flow and resulting in a clinical diagnosis of ischemic, thrombotic, or embolic stroke.

Ischemic strokes account for 80% of all strokes and occur as either an embolic or thrombotic stroke. Thrombotic strokes represent 52% of all ischemic strokes. Thrombotic strokes are caused by unhealthy blood vessels becoming clogged with a buildup of fatty deposits, calcium, and blood-clotting factors such as fibrinogen and cholesterol. We generally refer to this as atherosclerotic disease. Simplistically, what happens with a thrombotic stroke is that our bodies regard these buildups as multiple, infinitesimal, repeated injuries to the blood vessel wall. Our own bodies react to these injuries, just as they would if we were bleeding from a small wound, and they respond by forming blood clots. Unfortunately, in the case of thrombotic strokes, these blood clots get caught on the plaque on the vessel walls and reduce or stop blood flow to the brain. That is when we experience a brain attack.

Two types of thrombosis can cause a stroke: large vessel thrombosis and small vessel disease. Thrombotic stroke occurs most often in the large arteries, magnifying the impact and devastation of disease. Most large vessel thrombosis is caused by a combination of long-term atherosclerosis followed by rapid blood clot formation. Many thrombotic stroke patients have coronary artery disease, and heart attacks are a frequent cause of death in patients who have suffered this type of brain attack.

The second type of thrombotic stroke is small vessel disease which occurs when blood flow is blocked to a very small arterial vessel. Little is known about the specific causes of small vessel disease, but it is often closely linked to hypertension and is an indicator of atherosclerotic disease.

In an embolic stroke, a blood clot forms somewhere in the body (usually the heart) and travels through the bloodstream to the brain. Once in the brain, the clot eventually travels to a blood vessel small enough to block its passage. The clot lodges there, blocking the blood vessel and causing a stroke.

Risk Factors
The risk factors for thrombotic stroke are the presence of hypertension, atherosclerosis, high LDL-cholesterol, excessive blood-clotting factors (such as fibrin and fibrinogen), heart valve defects, diabetes, and aging. High serum levels of homocysteine, fibrinogen, or C-reactive protein may be the strongest predictive risk factors.

A 30-year study of male twins showed that elevated blood pressure in midlife predisposed men to an increase in stroke later in life. Men with even mildly elevated blood pressure 25 years before showed smaller brain volumes and more strokes compared to their twin brothers who did not have the elevation in blood pressure (DeCarli et al. 1999). This study in the journal Stroke emphasized the importance of aggressively treating elevated blood pressure even if it is not grossly abnormal (refer to the Cardiovascular Disease protocol for information about blood pressure control therapies and diets).

Uncontrollable Risk Factors
Increasing age. The chance of having a stroke more than doubles for each decade of life after age 55. While strokes are common among the elderly, substantial numbers of people less than 65 also have strokes.

Gender. Overall, men have about a 19% greater chance of a stroke than women. Among people under age 65, the risk for men is even greater when compared to that of women.

Family history. The chance of a stroke is greater in people who have a family history of strokes.

Race. African Americans have a much higher risk of death and disability from a stroke than Caucasians, in part because African Americans have a greater incidence of high blood pressure.

Diabetes mellitus. Diabetes is an independent risk factor for stroke and is strongly correlated with high blood pressure. While diabetes is treatable, having it still increases a person's risk of a stroke. People with diabetes often also have high cholesterol and are overweight, increasing their risk even more.

Controllable Risk Factors
High blood pressure. High blood pressure is the most prominent risk factor for stroke. In fact, stroke risk varies directly with blood pressure. More widespread treatment of high blood pressure is a key reason for the decline in the death rates for strokes.

High blood levels of homocysteine, C-reactive protein, or fibrinogen. The safe ranges of these blood indicators will be described later in this protocol, along with steps that can be taken if excess levels of these stroke risk factors are detected.

Heart disease. A diseased heart increases the risk of a stroke. In fact, people with heart problems have more than twice the risk of a stroke as those with a heart that works normally. Atrial fibrillation (the rapid, uncoordinated beating of the heart's upper chambers), in particular, raises the risk for stroke. Heart attack is also the major cause of death among survivors of a stroke.

High cholesterol. High cholesterol can directly and indirectly increase stroke risk by clogging blood vessels and putting people at greater risk of coronary heart disease, another important stroke risk factor.

Sleep disordered breathing. Sleep apnea is a major cardiovascular and stroke risk factor, increasing blood pressure rates, which may cause stroke or heart attack. Studies also indicate that people with sleep apnea develop dangerously low levels of oxygen in the blood while carbon dioxide levels rise, possibly causing blood clots or even strokes to occur. Diagnosing sleep apnea early may be an important stroke prevention tool.

Prior stroke. The risk of a stroke for someone who has already had one is several times that of a person who has not.

Carotid artery disease. The carotid arteries in your neck supply blood to your brain. A carotid artery damaged by atherosclerosis (a fatty buildup of plaque in the artery wall) may become blocked by a blood clot which may result in a stroke. If you have a diseased carotid artery, your healthcare provider may hear an abnormal sound in your neck (called a bruit) when listening with a stethoscope.

Transient ischemic attacks (TIAs). TIAs are mini-strokes that produce stroke-like symptoms, but no lasting damage. They are strong predictors of a stroke. A person who has had one or more TIAs is almost 10 times more likely to have a stroke than someone of the same age and sex who has not.

TIAs are extremely important stroke warning signs. Do not ignore them!

High red blood cell count. A moderate or marked increase in red blood cell count is a risk factor for stroke. The reason is that more red blood cells thicken the blood and make clots more likely.

Lifestyle Factors
Cigarette smoking. Studies have shown cigarette smoking, including secondhand cigarette smoke, to be an important risk factor for stroke. The nicotine and carbon monoxide in cigarette smoke damage the cardiovascular system in many ways. The use of oral contraceptives combined with cigarette smoking also greatly increases stroke risk.

Excessive alcohol intake. Excessive drinking (an average of more than one drink a day for women and more than two drinks per day for men) and binge drinking can raise blood pressure; contribute to obesity, high triglycerides, cancer, and other diseases; and cause heart failure, leading to stroke.

Weight. Excess weight puts a strain on the entire circulatory system. It also makes people more likely to have other stroke risk factors such as high cholesterol, high blood pressure, and diabetes.

Other potential risk factors
Geographic location. Stroke is more common in the southeastern United States than in other areas. These are the so-called stroke belt states. The age-adjusted death rates from a stroke are much higher in these states than in the rest of the country.

Season and climate. Stroke deaths occur more often during periods of extremely hot or cold temperatures.

Socioeconomic factors. There is some evidence that people of lower income and educational levels have a higher risk for stroke.

Certain kinds of drug abuse. IV drug abuse carries a high risk of stroke from cerebral embolisms. Cocaine use has been closely related to strokes, heart attacks, and a variety of other cardiovascular complications. Some of them have been fatal even in first-time cocaine users.

Recognizing stroke symptoms and realizing that the symptoms require immediate emergency treatment can save your life!

Prevention
There are conventional drugs that can be prescribed to reduce the risk of a second stroke:

• Appropriate treatment of hypertension (high blood pressure) clearly reduces the risk of stroke. Refer to the Hypertension section of the Cardiovascular Disease protocol for information about controlling blood pressure that your physician may be overlooking.
• Low-dose aspirin is considered first-line therapy for the stroke prevention in those with high risk.
• Anticoagulant drugs such as Coumadin (warfarin) interfere with the initiation of the coagulation cascade and significantly reduce the risk that a blood clot will form. Coumadin is so side-effect prone that it is reserved for extremely high-risk individuals such as those with mechanical aortic valve replacements.
• Antiplatelet drugs such as Ticlid (ticlopidine) or Trental (pentoxifylline) inhibit platelet aggregation, thereby reducing the risk of a new blood clot forming in the brain.

The use of anticoagulant drugs involves frequent blood testing and adjusting of dose because the anticoagulating response to these drugs varies between individuals. These drugs do not do anything to the clots that may already have been formed. The side effects of anticoagulant drugs mandate careful monitoring, and some people avoid these drugs because of the risk of serious side effects.

A more benign approach is to combine aspirin with nutrients like ginkgo biloba, melatonin, fish oil, garlic, and green tea extract that are relatively free of side effects. A discussion of the pros and cons of Coumadin versus aspirin therapy can be found in the Thrombosis Prevention protocol. Those at very high risk for developing a blood clot often have to take Coumadin.

Low-Dose Aspirin
Low-dose aspirin is the antiplatelet agent of choice for stroke prevention. Doses of 160-325 mg daily administered within 48 hours of stroke onset have been shown to significantly reduce the risk of recurrent stroke during the first 2 weeks and possibly improve outcome at 6 months (CASTCG 1997; IST 1997). The Second European Stroke Prevention Study reported risk reductions for aspirin treatment, when compared with a placebo, to be as high as 27.6% (Sivenius et al. 1999).

Aspirin has shown such a potent effect in preventing strokes that the use of anticoagulants such as heparin to treat ischemic strokes decreased from 1985-1990, whereas the use of aspirin increased by more than 50% as reported in the Minnesota Stroke Survey, reported in the Journal of Stroke and Cerebral Diseases (McGovern et al. 1996).

An article in the journal Thrombosis Research described a study on patients who had survived a stroke or TIA. The research showed that the use of a low-dose aspirin (50 mg) reduced the incidence of stroke by 18-28% when study participants consumed aspirin over a period of time (Investigators 1998).

One of the main side effects of aspirin is unwanted bleeding. Tinnitus can also occur at high doses (Day et al. 1989). Aspirin is contraindicated for those at high risk of hemorrhagic stroke. Many health-oriented people are taking aspirin in combination with natural platelet aggregation inhibitors including vitamins C and E, bromelain, garlic, ginkgo biloba, curcumin, St. John's wort, green tea, policosanol, vinpocetine (periwinkle), and fish oils. It is important to monitor template bleeding time to ensure stable blood thinning effects are consistent while avoiding fluctuations in platelet aggregation that may increase the risk of hemorrhagic stroke. The template bleeding time test is described later in this protocol.

Aspirin is considered by many to be a miracle drug and may have many undiscovered health benefits. Aspirin inhibits prosta n glandin E2 and C-reactive protein, both of which have been linked to many chronic inflammatory conditions (Ikonomidis et al. 1999).

Warfarin
Warfarin (Coumadin) is the most commonly prescribed drug for thrombosis prophylaxis (prevention) in very high-risk individuals. Its uses include prophylaxis for myocardial infarction, stroke, arterial thromboembolism, and deep venous thrombosis. Warfarin is also used in patients with prosthetic (artificial) heart valves.

Warfarin was originally isolated from sweet clover in 1939. It is the active ingredient in commercial rat poison and insecticide. Warfarin interferes with the synthesis of vitamin K which forms several essential coagulation factors. Warfarin prolongs prothrombin time (PT) and thromboplastin time (APTT). Prothrombin time is used to guide treatment. The International Normalization Ratio (INR) is becoming the new standard to monitor anticoagulation treatment.

Side-Effects and Contraindications for Warfarin
Bleeding is the primary adverse effect of warfarin therapy and is related to the intensity of anticoagulation, length of therapy, the patient's underlying clinical state, and the use of other drugs that may affect blood coagulation or interfere with warfarin's metabolism.

• Minor bleeding complications include bleeding from mucous membranes, subconjunctival hemorrhage (bleeding under the mucous membranes covering the eyes and inner eyelids), hematuria (blood in the urine), epistaxis (nosebleed), and ecchymoses (purple patches on the skin).
• Major bleeding complications include bleeding from the gastrointestinal tract, intracranial bleeding, and retroperitoneal bleeding. Massive hemorrhage usually involves the gastrointestinal tract, but may involve the spinal cord or cerebral, pericardial, pulmonary, adrenal, or hepatic sites.

Warfarin (Coumadin) has an extremely long list of contraindications and drug interactions (see below). Of particular concern is its use in elderly patients because they are more susceptible to the effects of anticoagulants and have an increased possibility of hemorrhage.

• Warfarin is contraindicated in alcoholism, aneurysm, breast-feeding, the elderly, endocarditis, hemophilia, hemorrhage, hepatic disease, hypertension, intramuscular injections, leukemia, lumbar puncture, peptic ulcer disease, pericardial effusion, polycythemia vera, pregnancy, protein C deficiency, protein S deficiency, psychosis, surgery, vasculitis, vitamin C deficiency, and vitamin K deficiency.
• Warfarin interacts with a large number of common drugs, including acetaminophen, aspirin, barbiturates, some antibiotics, estrogens, ethanol, heparin, influenza virus vaccine, lovastatin, NSAIDs, oral contraceptives, thrombolytic agents, and thyroid hormones. Your physician must be informed of all prescription and over-the-counter medications you are taking before beginning warfarin therapy.
• Adverse side effects to warfarin include agranulocytosis, alopecia (hair loss), anorexia, bone loss, bleeding, chondrodysplasia punctata, cleft palate, diarrhea, exfoliative dermatitis, fetal abortion, intracranial hemorrhage, intraocular hemorrhage, leukopenia, nausea/vomiting, pruritus (itching), purple-toe syndrome, skin necrosis, and urticaria.
• Warfarin may interact with natural platelet aggregation inhibitors including those mentioned earlier for aspirin. It is important to monitor template bleeding times to ensure stable blood thinning effects are consistent with supplementation to avoid fluctuations in platelet aggregation.

Combining Coumadin with Antiplatelet Therapies
A patient taking Coumadin has to be concerned that any food, drug, nutrient, or other substance that he puts into his body may not only increase the bleeding time, but also affect Coumadin metabolism, which may either increase or decrease the effect of Coumadin on the INR. The inherent variability that occurs in each individual taking Coumadin makes it difficult to provide general guidance. For instance, the underlying medical condition determines the degree of desired anticoagulation. No studies have correlated optimal anticoagulant doses of Coumadin (as measured by the INR blood test) with optimal doses of multiple antiplatelet agents (as measured by the template bleeding time [TBT]). The TBT is done in a physician's office. A template device nicks the skin and the number of minutes it takes for blood flow to stop is assessed by a nurse or lab technician. The normal template bleeding time is up to 9 minutes. A bleeding time (BT) of 4-5 minutes might indicate increased thrombotic risk, while a bleeding time over 9 minutes may indicate an increased hemorrhagic risk. However, what is really important in this setting is the patient.

As it relates to antiplatelet agents such as fish oil and garlic, a BT of 4-5 minutes could suggest a benefit of taking higher amounts of these agents, whereas a BT over 9 minutes in a patient already on an antiplatelet agent might indicate that antiplatelet agent doses are having a biological effect and further dose increases should be avoided. The problem patients face today is that there are no standards that document the ideal balance between Coumadin and antiplatelet agents such as fish oil, garlic, vitamin E, and so forth. Too much Coumadin or antiplatelet agents can cause hemorrhage, whereas too little Coumadin or antiplatelet agents can cause thrombosis. In this context, as with many medical issues, balance is the key concept. The approach that a meticulous physician uses to achieve this balance is called titration. There is an art to titrating doses to a point where the happy medium is reached.

In an ideal setting, a physician would carefully monitor the INR and the template bleeding time to precisely measure the optimal level of anticoagulant and antiplatelet agents, respectively, in an individual patient. For instance, a patient with a heart valve replacement may have a desired INR range of 2.5-3.0, while an optimal template bleeding time may be between 7-9 minutes. If these tests were routinely conducted, a more scientific determination of the ideal intake of Coumadin, fish oil, garlic, vitamin E, and other supplements could be made.

An example of why prothrombin time (the result is presented as an INR) and template bleeding time testing are so important can be seen in a scenario of a patient taking Coumadin for one medical problem while at the same time using nutrients such as coenzyme Q10 (CoQ10) and fish oil for other medical conditions. A person who has congestive heart failure (a common complication with valve replacement) may require supplemental CoQ10 to improve cardiac function, for example, cardiac output. CoQ10 enhances the energy-producing organelles called mitochondria to more effectively produce energy within heart muscle (Rosenfeldt et al. 2002). Coumadin is being utilized to prevent a clot from forming on the donated heart valve which could break off, enter the blood circulation, and lead to a cerebral vascular accident (CVA)--what is commonly called a stroke.

In this same patient, CoQ10 is being used to optimize heart muscle performance to improve the heart's function as a pump. CoQ10 is also helping this patient by preventing oxidation of LDL cholesterol which is felt to be part of the pathogenesis of vascular disease. In the context of this patient, the valve replacement surgery inflicts massive trauma on the body that can result in a chronic systemic inflammatory syndrome. High-dose fish oil and gamma-linolenic acid (GLA) can help suppress pro - inflammatory cytokines that are the underlying causes of so much degenerative disease. If periodic TBT tests are performed and Coumadin dosing is being properly titrated via the INR, then one can optimally adjust the antiplatelet agent (fish and borage oil) dose to guard against excess bleeding. The TBT test combined with the INR test would theoretically enable patients to take supplements they may need to sustain life (CoQ10), optimize the use of Coumadin, and reduce the risk of hemorrhage. The end result is therapy with an improved therapeutic index for the patient. This is an example of how listening to the biology of vital processes can enhance the quality and quantity of life.

Ticlopidine
Ticlopidine (Ticlid) inhibits platelet aggregation by interfering with the binding of fibrinogen to the platelet membrane. Ticlopidine is a prescription drug that may be of value as an alternative to aspirin. Ticlopidine is often considered in patients that have a high risk of thrombotic stroke and are intolerant of aspirin.

• Ticlopidine is contraindicated in blood disorders such as hemorrhage, coagulopathy, intercranial hemorrhage, neutropenia, and thrombocytopenia. It is not used before surgery. Ticlopidine is also contraindicated in hepatic (liver) disease and hypercholesterolemia.
• Ticlopidine has drug reactions with antacids, anticoagulants, aspirin, cimetidine, cyclosporine, digoxin, theophylline and thrombolytic agents.
• Ticlopidine has a large number of side effects, including agranulocytosis, anemia, arthropathy, cholestasis, diarrhea, dyspepsia, elevated hepatic enzymes, hemolysis, hepatitis, hypercholesterolemia, hyponatremia, interstitial pneumonitis, jaundice, nausea or vomiting, nephrotic syndrome, neutropenia, pancytopenia, peripheral neuropathy, pruritus, purpura, serum sickness, throm-bocytopenia, thrombotic thrombocytopenic purpura (TTP), and urticaria vasculitis.

An analysis of 18 trials documented a 23% reduction in stroke risk with antiplatelet agents. The drug ticlopidine was found to be the most effective antiplatelet agent, but its adverse side effects frequently restrict its long-term use (Albers 1995).

A review of clinical trials compared aspirin and ticlopidine. Ticlopidine was found to be modestly but significantly more effective than aspirin in preventing serious vascular events in patients at high risk, but there is uncertainty about the size of the additional benefit. Ticlopidine was associated with less gastrointestinal hemorrhage and other upper gastrointestinal upset than aspirin, but commonly had side effects of skin rash and diarrhea. Ticlopidine was also associated with developing side effects of neutropenia and thrombotic thrombocytopenic purpura (Hankey et al. 2000).

Cholesterol-Lowering Drugs
Studies have found that statin drugs (HMG-CoA reductase inhibitors) may be of benefit in reducing the incidence of ischemic stroke for patients with established coronary artery disease (Furberg 1999; Vaughan et al. 1999; Vaughan et al. 2001a; 2001b). Unfortunately, these trials have shown a reduction in risk of stroke only in patients enrolled in studies for coronary artery disease. Studies have not been done for primary stroke prevention or in patients without coronary artery disease. In patients with previous myocardial in-farction and cholesterol levels lower than 240 mg/dL, pravastatin reduced the risk of stroke by 31%, compared with placebo (Sacks et al. 1996). The beneficial effects of statin drugs in stroke prevention may be due to several mechanisms, including:

• Lowering LDL cholesterol levels
• Anti-inflammatory and antithrombotic actions of statins that occur within the blood and in plaque
• Protecting against cerebral ischemia through beneficial modulation of the brain endothelial nitric oxide system. Statins both up-regulate endothelial nitric oxide synthase (eNOS) and inhibit inducible nitric oxide synthase (iNOS), effects that may protect the nervous system.

A study examined the protective effects of Mevacor ( mevastatin lovastatin ) in male mice. Mevastatin (2 mg/kg or 20 mg/kg a day) was administered to male mice for 7, 14, or 28 days before inducing a middle cerebral artery occlusion. Lo Me vastatin increased levels of endothelial nitric oxide synthase mRNA and protein, reduced infarct size, and improved neurological deficits in a dose- and time-dependent manner. The greatest protection was seen with 14- and 28-day high-dose treatment (26% and 37% infarct reduction, respectively). Cholesterol levels were reduced after only 28 days of treatment and did not correlate with infarct reduction. Baseline absolute cerebral blood flow was 30% higher after 14-day high-dose treatment (Amin-Hanjani et al. 2001).

Mevacor ( lo me vastatin) and other statin drugs used to lower cholesterol are available by prescription.

Novel Factors that Contribute to Primary or Secondary Stroke Homocysteine
Homocysteine, an intermediate molecule formed from methionine, has been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke. Elevated homocysteine levels are found in 20-40% of patients with heart disease. Elevated homocysteine is present in as many as 50% of patients with stroke. Measuring and reducing homocysteine levels is an important preventive highly recommended by the Life Extension Foundation since as early as 1981 (more than a decade before it was recognized by conventional medicine) (Selhub et al. 1998; Boden-Albala et al. 2000; Hankey et al. 2001).

The exact mechanism by which homocysteine promotes arteriosclerosis is currently being investigated. Several mechanisms have been proposed (Sarkar et al. 1999):

• Homocysteine accumulates in endothelial cells causing endothelial dysfunction and injury, followed by platelet activation and thrombus formation.
• Homocysteine stimulates the proliferation of smooth muscle cells which line arteries, a central component in atherogenesis.
• Homocysteine induces endothelial cell injury due to the generation of hydrogen peroxide which damages endothelial cells, exposing the underlying cell matrix and smooth muscle cells. This, in turn, promotes the activation of platelets and leukocytes to repair the injury (the blood clotting system).
• Homocysteine increases nitric oxide production by activating transcription factor NF.
• Homocysteine leads to an overproduction of oxidative radicals (reactive oxygen species) that cause lipid peroxidation and oxidation of LDL cholesterol. These oxidized lipids form dense particles which are consumed by macrophages that create foam cells that accumulate in plaques on the endothelial cells lining arteries.
• Homocysteine also interferes with DNA repair which makes the blood vessels less pliable and more susceptible to plaque buildup.

Dr. Kilmer McCully (1996) reported that homocysteine plays a key role in every pathophysiological process that leads to arteriosclerotic plaque. Some consider homocysteine to be much worse than cholesterol.

Homocysteine, although toxic itself, is normally metabolized into other nutrients that are beneficial to the body, including cysteine, taurine, and glutathione. Several natural supplements (including vitamin B6, vitamin B12, folic acid, zinc, and methyl donors such as trimethylglycine, SAMe, and choline) are needed for homocysteine metabolism.

While it does make sense to take supplements that contain these important nutrients, one should not automatically assume that their homocysteine levels are fine without a specific laboratory test. For more information about homocysteine, see the Homocysteine and Hypertension section s of the Cardiovascular Disease protocol and the Hypertension protocol .

Fibrinogen
Fibrinogen is a blood protein that forms fibrin in a reaction that initiates the formation of blood clots. The entire mechanism is called coagulation (the process of changing from a liquid into a solid). If fibrinogen levels are too high, blood clots can form. If fibrinogen levels are too low, the blood will be too thin and a hemorrhage can result (see the Hemorrhagic Stroke section for more information).

An article in the New England Journal of Medicine showed that those with high levels of fibrinogen were more than twice as likely to die of a heart attack. Large studies have confirmed that fibrinogen is a risk factor of equal or higher value than total cholesterol (Wilhelmsen et al. 1984; Rosengren et al. 1996; Beamer et al. 1998; Ma et al. 1999).

Fibrinogen can be increased by several factors:

• Smoking increases fibrinogen (Wilhelmsen et al. 1984; Lip 1995).
• Homocysteine can make fibrinogen more dangerous by inhibiting the production of plasminogen activators (substances that break down fibrin).
• Infections and exposure to cold have been shown to increase fibrinogen levels, which may explain why cardiovascular mortality is increased during the winter months (Khaw 1997; Zhu et al. 2001).
• Psychological and mental stress can increase fibrinogen levels (Lip 1995).
• There appears to be a hormonal influence on fibrinogen. Increased fibrinogen levels and elevated platelet aggreg r ation (with an increased risk of thrombosis) have been found in individuals that use oral contraceptives (Lip 1995).

A study of 34 patients with thrombotic stroke and 58 matched controls found that stroke victims had a significantly higher level of fibrinogen. The researchers also found a correlation between fibrinogen levels and white blood cell aggreg r ation. The authors proposed that enhanced white blood cell adhesion and aggreg r ation with the subsequent release of free radicals may be one of the mechanisms of fibrinogen in the development of stroke (Belch 1998).

The Life Extension Foundation long ago recognized the importance of monitoring fibrinogen levels both as a preventive measure in otherwise healthy individuals and for those at risk of stroke. Elevated fibrinogen levels, particularly in a non-smoker, deserve particular attention. The optimal level of fibrinogen is under 300 mg/dL, compared with the standard reference range of up to 460 mg/dL used by conventional medicine.

Lipoprotein (a)
Lipoproteins are small molecules that carry lipids (fats, including cholesterol and triglycerides) in the blood. Lipoprotein (a) is an altered form of LDL that contains the apolipoprotein, B-100, linked with apolipoprotein (a), which is structurally similar to plasminogen (a key protein in fibrinogen). Because of this similarity, lipoprotein (a) is considered to be very "sticky" and has been found to be a key component in blood clots (Rath et al. 1989; Beisiegel et al. 1990; Rath et al. 1990a; 1990b).

The lipoprotein (a) theory of heart disease was a central part of Linus Pauling's work. Drs. Pauling and Rath proposed that lipoprotein (a) acts as a surrogate (substitute) for vitamin C. They hypothesized that a deficiency of vitamin C resulted in the increased production of lipoprotein (a) which both hardened the arteries and caused blood clots. Pauling recommended the use of high doses of pure vitamin C and lysine to suppress lipoprotein (a) levels.

Insulin Resistance, Syndrome X
Syndrome X is a cluster of symptoms (high triglycerides, reduced HDL, increased blood pressure, central obesity, and elevated LDL) characterized by insulin resistance. The insulin does not have as strong an effect on lowering blood glucose. The pancreas responds by producing more insulin to stabilize blood glucose levels, but at a significant cost in terms of increased risk of cardiovascular disease. Syndrome X is considered to be a precursor of diabetes mellitus, a known risk factor for stroke. The question about whether Syndrome X is an independent risk factor for stroke has been the subject of several research studies. While some have found a moderate increase in stroke risk, others have found no significant relationship (Shinozaki et al 1996; Pyorala et al. 2000; Adachi et al. 2001).

Syndrome X is associated with carbohydrate metabolism problems and can be managed with dietary changes that focus on reducing total and simple carbohydrates (e.g., sugar, sweets, bread, pasta, and other "junk foods") and increasing protein and beneficial fats. Syndrome X is discussed in more detail in the protocol, Diabetes Type II and the Syndrome X Connection.

Inflammation
Chronic inflammation is associated with a variety of systemic diseases, including increased fibrinogen levels. C-reactive protein (CRP) is an early marker for systemic inflammation that rises before the erythrocyte sedimentation rate (ESR), the marker of inflammation used in conventional medicine. C-reactive protein appears to bind with LDL cholesterol, increasing its stickiness and vascular adherence. C-reactive protein is considered to be a highly sensitive risk factor for cardiovascular disease.

An article in the journal Stroke described a study of 193 patients in whom serum CRP was measured within 24 hours after an ischemic stroke, within 48-72 hours, and at discharge. CRP levels at admission and discharge were found to be predictors of new vascular events or death at 1 year. The CRP level at hospital discharge was the strongest indicator, with a hazards ratio of 7.42 (95% confidence interval) (Di Napoli et al. 2001).

An article in the journal Circulation described the Women's Health Study in which CRP was measured in 122 healthy participants and in 244 age- and smoking-matched controls. Higher CRP levels were found in women who developed cardiovascular events. Those with the highest levels had a fivefold increased risk of any vascular event and a sevenfold increased risk of myocardial infarction (MI) or stroke. The authors concluded that CRP was a strong independent risk factor for cardiovascular disease (Ridker et al. 1998).

An article in the journal Stroke described a study in which CRP levels were measured in patients diagnosed with ischemic stroke. Survival in those with higher CRP levels (the average was 10.1 mg/L) was significantly worse than those with lower levels. Higher CRP levels were found to be an independent predictor of mortality together with age and stroke severity (Muir et al. 1999).

Chronic inflammation is a component of most chronic diseases, including arthritis. Several herbs that have multiple beneficial effects are anti-inflammatory. These include aspirin (derived from the bark of the white willow tree), turmeric (the yellow spice which contains curcumin), and the essential fatty acids found in fish, flax, perilla, and borage oils.

Several studies have examined the relationship between CRP levels and the risk of future strokes or myocardial infarction. One article related plasma CRP levels to incidence of first ischemic stroke or TIA in the Framingham Study original cohort. CRP levels were measured in the previously frozen plasma samples of 591 men and 871 women free of stroke/TIA during their 1980-1982 clinic examinations, when their mean age was 69.7 years. During 12-14 years of follow-up, 196 ischemic strokes and TIAs occurred. Independent of age, men in the highest CRP quartile had two times the risk of ischemic stroke/TIA (RR = 2.0), and women had almost 3 times the risk (RR = 2.7) compared with those in the lowest quartile (Rost et al. 2001).

The following tables show the relative risk of a future myocardial infarction (MI) or stroke in both men and women. A lower relative risk is desirable and is correlated with lower values of CRP. Men have a much lower CRP level corresponding to the same relative risk as women. For a relative risk of 1.0, men would have to achieve CRP levels less than 0.55. Women needed to achieve CRP levels less than 1.50. The difference reflects the higher incidence of myocardial infarction and stroke in men.

Of particular interest is that the standard reference range for CRP levels is less than 4.9 mg/L. This would correspond to a very high relative risk of future stroke or MI for both men and women, especially for men. The optimal range that knowledgeable researchers and the Life Extension Foundation recommend is for CRP levels to be less than 1.3 mg/L and preferably less than 0.5 mg/L.

The Life Extension Foundation, recognizing the central role inflammation plays in disease, highly recommends that C -reactive protein RP levels be measured. High sensitivity testing for CRP can assess the risk of cardiovascular and peripheral vascular disease. The optimal range for both men and women is as low as possible. To learn more about how to suppress the underlying inflammatory factors that may be contributing to these excess levels of C -reactive protein RP , refer to the Inflammation: Chronic protocol.

Hormonal Deficiency
Hormones play a central role in regulating the body's metabolism, including neurological function and repair. DHEA and pregnenolone help coordinate brain cell activity and protect neurons from damage. Aging causes a severe deficiency in pregnenolone and DHEA production.

Conventional medicine has focused on the role of estrogen and stroke risk. At present, a controversy exists over the increased risk of stroke associated with hormone replacement therapy and oral contraceptive use. Much of the information was based on early studies with high-dose preparations, particularly with oral contraceptives containing more than 50 mcg of estradiol (Goldstein et al. 2001).

It is clear that hormones play a role in neurological function and repair. The Life Extension Foundation highly recommends that its members make health decisions based on specific laboratory tests, particularly with regard to hormone replacement therapy. Natural hormone replacement therapy can be based on the results of these laboratory tests. For more information, see the Male and Female Hormone Modulation protocols.

Nitric Oxide Synthesis
Nitric oxide is a soluble free gas naturally produced in the body (from the amino acid arginine) by endothelial cells, macrophages, and specific neurons in the brain. Nitric oxide plays several key roles in the body, including:

• Nitric oxide relaxes vascular smooth muscle, which causes vasodilation.
• Nitric oxide reduces platelet aggreg r ation and adhesion.
• Nitric oxide produced by macrophages is cytotoxic to certain microbes and tumor cells.

Nitric oxide is synthesized from the amino acid arginine by the enzyme nitric oxide synthase. The reaction requires several nutritional cofactors, including:

• NADPH (nicotinamide adenine dinucleotide phosphate, a form of niacin)
• Thiol (a sulfhydryl group, composed of sulfur and hydrogen)
• Tetrahydrobiopterin (a chemical derived from folate)
• FAD (flavin adenine dinucleotide, a chemical derived from riboflavin)
• FMN (flavin mononucleotide, also derived from riboflavin)

Thus, nitric oxide synthesis requires vitamin B2 (riboflavin), vitamin B3 (niacin), and folate (Ganong 1995).

Nitric oxide has been identified as having a key role in blood pressure regulation. Nitric oxide lowers blood pressure by stimulating the release of calcium from vascular smooth muscle cells, thereby causing the blood vessels to relax and dilate. There is now evidence that nitric oxide deficiency can cause hypertension and may also be involved in the pathogenesis of atherosclerosis. Nitric oxide donors (such as nitroglycerine and arginine) lower blood pressure and increase cerebral blood flow in patients with acute ischemic stroke.

Uncontrolled nitric oxide production, however, can lead to massive peripheral vasodilation and shock. Nitric oxide can oxidize sulfhydryl groups on proteins and cause a depletion of cytosolic glutathione. It can also react with hydroxyl radicals to form the strong oxidant, nitrogen dioxide. Nitric oxide has also been implicated in a variety of inflammatory diseases. Inhibitors of nitric oxide production are being tested clinically and may be of use in controlling conditions associated with excess oxidant production, such as in acute ischemic stroke. Interestingly, nitric oxide donors are also being tested for the same conditions due to their vasodilation effects. Nitroglycerine, a well-known drug for angina, is a nitric oxide donor.

Modulating Nitric Oxide
The best naturally occurring source of nitric oxide is the amino acid arginine. A study examined the use of L-arginine to prevent experimental ischemic stroke in rats. L-arginine was administered at the time of ischemia and at 6 and 24 hours later. The areas of neuronal necrosis were reduced by 99%, 96%, and 89%, respectively. The study also examined L-arginine in combination with a calcium antagonist (TMB-8) and found that the combination of TMB-8 and L-arginine is more effective in treating ischemic stroke by simultaneously reducing calcium-activated proteolysis and improving cerebral blood flow than using TMB-8 or L-arginine alone (Hong et al. 2000).

However, to avoid the potentially harmful free-radical damage that can result from excessive nitric oxide, one of the vitamin E fractions, gamma tocopherol, has been found to function as the best antioxidant for nitric oxide. Therefore, for best stroke, heart disease, and hypertension protection, consider arginine, 2700 mg 3 times per a day with plenty of B complex as cofactors and 400 IU of gamma tocopherol for optimal protection.

Certain precautions must be exercised when supplementing with arginine:

• Diabetics and borderline diabetics should use arginine with care because it may worsen diabetes.
• Children, teenagers, and pregnant or lactating women should not use arginine (or growth hormone stimulators) except under the care of a knowledgeable physician.
• Arginine sometimes reactivates latent herpes virus infections. Those with ocular or brain herpes should avoid it. Persons with herpes benefit from lysine which competes with arginine in amino acid metabolism. If you have herpes and use arginine at all, use lysine at a separate time of day on an empty stomach to avoid lysine depletion and herpes exacerbations.
• Arginine should be used with care in those with psychosis because they may experience a worsening of symptoms.
• Arginine should always be taken with antioxidants.

Nitroglycerin (glyceryl trinitrate) is a drug commonly used to treat angina. Nitroglycerin is a nitric oxide donor (Ikeda et al. 1997; Castillo et al. 2000).

A double-blind, randomized, controlled trial examined the effects of the nitric oxide donor glyceryl trinitrate (Nitroglycerin), a known systemic and cerebral vasodilator, on 37 patients with recent (<5 days) ischemic or hemorrhagic stroke. Transdermal glyceryl trinitrate significantly lowered blood pressure by 13.0/5.2 mmHg at day 1 and 9.3/5.0 mmHg at day 8. The lesser reduction at day 8 than day 1 suggests that tolerance to glyceryl trinitrate was developing. The authors concluded that transdermal glyceryl trinitrate lowered blood pressure by 5-8%, a clinically significant and relevant, but not excessive, degree in patients with acute stroke (Bath et al. 2001).

Nitric oxide and its role in blood pressure regulation is the subject of scientific research, both with European drugs (aminoguanidine, discussed in the Innovative Drug Strategies section) and natural supplements (arginine, folic acid, and vitamins B2 and B3).

Nitroglycerine, being a nitric oxide donor, works best with B complex as supporting cofactors along with gamma - tocopherol to quench the excessive and potentially damaging free radical effects of nitric oxide.

Laboratory Tests
For the last 50 years, medical doctors have concentrated on controlling blood pressure as the primary method of preventing stroke. As you can see, there are several other mechanisms involved. Assessing the status of the blood clotting system through laboratory testing is central to assessing the risk of stroke in high-risk individuals. The following tests are typically used:

• Prothrombin time (PT) evaluates the time it takes for a clot to form after thromboplastin and calcium are added to the patient's plasma. Normal values are between 11-13 seconds. Prothrombin time is commonly used to monitor Coumadin therapy.
• The International Normalization Ratio (INR) standardizes prothrombin time to a control batch of thromboplastin (as the sensitivity of commercial thromboplastin reagents is variable) which allows comparisons between different samples and laboratories.

INR = (patient PT/control PT) × ISI
(International Sensitivity Index)

The target INR is 2.5 for those at risk for thromboembolic stroke, with a range of 2-3. A target of 2 with a range of 1.6-2.5 may be used in elderly patients to reduce the risk of hemorrhage. Some authorities, however, disregard age and recommend the higher target of 2.5.

The following may be predictive for the risk of stroke:

• Fibrinogen levels are useful because fibrinogen is converted into fibrin under the influence of thrombin. Fibrinogen is often elevated after acute trauma or illness, inflammation, and as a side effect of birth control pills.
• Triglyceride levels have been found to be a predictor of myocardial infarction, and elevated serum triglycerides have been specifically tied to the occurrence of atherothrombotic stroke and transient ischemic attacks.
• Homocysteine levels have been shown to be a risk factor for cardiovascular disease, including atherosclerosis, heart attack, and stroke.
• C-reactive protein (CRP) is a sensitive marker of inflammation in the body. Inflammation may be a crucial factor in atherosclerosis and is considered to be a strong predictor of myocardial infarction and stroke (Di Napoli et al. 2001; Ridker 2001).

In addition, overall cardiovascular risk should also be assessed with the following laboratory tests:

• Total, HDL, and LDL cholesterol levels have been associated with cardiovascular risk for well over 40 years.

A comprehensive health assessment would also include measurements of the body's hormones, including DHEA, testosterone, estradiol, and progesterone (for women).

It is important to realize that conventional medicine uses blood tests as a diagnostic tool. Standard reference ranges are based on statistics that find the average value for all people taking the test, including both healthy and unhealthy people. The Life Extension Foundation recommends optimal ranges as a standard to measure wellness.

Drug Strategies for Treatment and Possible Rehabilitation
In the 1960s, hypertension was identified as a treatable risk factor for stroke, and the decline in the incidence of and mortality from a stroke started when physicians began implementing aggressive antihypertensive therapies. In the 1970s, aspirin was first demonstrated effective in preventing strokes, although few physicians prescribe aspirin even to this day to reduce the risk of ischemic stroke. Cigarette smoking has been proven conclusively to be a major risk factor for stroke, and smoking cessation produces a significant risk reduction within 2 years.

Researchers now believe there are an immense number of mechanisms at work causing brain cell damage and death following a stroke. Each of these mechanisms represents a potential route for intervention, as well as prevention. Given the multidimensional nature of ischemic brain cell injury, stroke experts predict that no single drug will be able to completely protect the brain during a stroke. More likely, a combination of agents will be necessary for full recovery potential.

Most strokes culminate in a core area of cell death (infarction) in which blood flow is so drastically reduced that the cells usually cannot recover. This threshold seems to occur when cerebral blood flow is 20% of normal or less. Brain cells ultimately die as a result of the actions of calcium-activated proteases (enzymes which digest cell proteins), lipases (enzymes which digest cell membranes), and free radicals formed as a result of the ischemic cascade.

Without neuroprotective agents, nerve and brain cells may be irreversibly damaged within several minutes. This knowledge is leading to unprecedented therapy development. Expanding knowledge regarding the nature of ischemic brain cell injury is leading researchers to focus on the development of calcium antagonists, glutamate antagonists, antioxidants, and other types of neuroprotective agents. The use of the drug Hydergine to treat acute stroke may be the most effective therapy to combine with t-PA to prevent permanent brain damage.

Those who have already suffered neurologic impairment caused by ischemic stroke may also consider the following drugs.

Hydergine
The most potent antioxidant that a hospital pharmacy normally stocks for the treatment of strokes is Hydergine. Insist that the emergency room doctor administer 10 mg of Hydergine sublingually and another 10 mg of Hydergine orally in liquid form. Hydergine is a powerful antioxidant that reduces free-radical damage. Hydergine will increase the amount of oxygen delivered to the brain, enhance the energy metabolism of brain cells, and protect brain cells against both the low- and high-oxygen environments that ischemic stroke victims often encounter (Marc-Vergnes 1974; Saletu et al. 1990).

Hydergine is used in Europe and the rest of the world as a treatment for stroke, but most emergency room physicians in the United States are reluctant to prescribe it because the FDA does not recognize its value in preventing brain cell death. Paralyzed stroke victims consume billions of healthcare dollars every year, and the reason most ischemic stroke victims are permanently paralyzed is that the FDA has stopped patients from being treated with medications to prevent brain cell death. Regrettably, some hospital formularies may not carry Hydergine or its generic equivalent.

Piracetam
Piracetam, a nootropic medication similar to pyroglutamate (an amino acid), would be useful in the treatment of ischemic stroke if it were approved in the United States for acute use. Piracetam appears to protect brain cells from injury and death during a stroke, thereby lessening the potential for permanent neurological damage. The recommended dosage for piracetam is 4800 mg taken orally. Piracetam is not currently available in the United States , but has been successfully used in Europe for 25 years as reported in the Journal of Pharmacopsychiatry (De Reuck et al. 1999). Piracetam may be obtained by prescription through selected compounding pharmacists throughout the United States . Non-FDA approved drugs, available in other countries, can often be legally prescribed in the United States when a licensed physician collaborates with a licensed compounding pharmacist to safely compound a substance for a particular patient (1938 Federal Government Compound Pharmacy Protection Act). Piracetam is also available from several offshore pharmacies.

A Belgian study indicated that piracetam may be very beneficial if administered within 7 hours after the onset of a stroke (De Deyn et al. 1997).

An article in the journal Stroke described a double-blind, placebo-controlled study of piracetam used to improve language recovery in post-stroke aphasia: 24 stroke patients were assigned to receive either placebo or 2400 mg of piracetam twice a day. After 6 weeks, the piracetam group showed improvement in six language functions, compared with only three in the placebo group. The authors concluded that piracetam as an adjunct to speech therapy improves the recovery of several language functions (Kessler et al. 2000).

A review of three studies of piracetam in ischemic stroke, however, did not find sufficient evidence to support routine use. The authors concluded that more clinical trials are needed (Ricci et al. 2000).

Nimodipine
Nimodipine is a European drug especially recommended for head trauma victims. Nimodipine (brand name Nimotop) is a calcium channel blocker specific to the central nervous system. It prevents movement of calcium into the cells of blood vessels, thereby relaxing the vessels and increasing the supply of blood and oxygen. It dramatically improves cerebral blood flow. Nimodipine is an FDA-approved drug used to prevent and treat problems caused by a burst blood vessel around the brain, but it has been ignored by most neurologists treating victims of stroke and other age-related neurological diseases.

An article by Pantoni et al. (2000a) described a 26 week, multinational, double-blind, placebo-controlled study of nimodipine in patients with multi-infarct dementia. This study failed to show a significant effect of nimodipine on cognitive, social, or global assessments. However, a lower incidence of cerebrovascular and cardiac events was observed in the nimodipine-treated patients in comparison with the placebo group. A subgroup analysis found that those patients with subcortical vascular dementia performed better on the majority of neuropsychological tests and functional scales in comparison with patients on placebo (Pantoni et al. 2000b).

Studies on the use of nimodipine on thrombotic and ischemic stroke have shown mixed results (Chua et al. 2001). In one study, low-dose nimodipine therapy was shown over high-dose therapy to positively affect systolic and diastolic blood pressure (Ahmed et al. 2000). However, in a second study, higher dose nimodipine was more effective than lower dose therapy (240 versus 120 mg per a day) in reducing cerebrospinal fluid calcium, thereby improving cerebral blood flow (Bereczki et al. 2000).

There is a delayed response to nimodipine therapy. Nimodipine is recommended for at least 21 days in subarachnoid hemorrhage, and its beneficial effects in migraine prophylaxis usually become apparent after 1 or 2 months of therapy. This delayed benefit may be the reason why nimodipine has not been found to be effective in several clinical studies.

Nimodipine is highly recommended as long-term therapy for thrombotic stroke patients because of its well-known effect on increasing cerebral blood flow and because of its tolerance in most individuals. The most common side effect is hypotension. Rapid elimination rates correspond to a half-life of 1-2 hours which necessitates frequent dosing (e.g., every 4 hours). The recommended dose of nimodipine is 30 mg, three times a day.

Aminoguanidine
Aminoguanidine is being studied for use in stroke because of its action as an inducible nitric oxide synthase inhibitor (Fasbender et al. 2000).

Aminoguanidine is one of the most widely used drugs in Europe . It works by preventing crosslinks caused by glycosylation (a chemical reaction between blood sugar and protein). Animal studies have found that aminoguanidine can prevent diabetic atherosclerotic blood vessel aging and molecular crosslinking in cells throughout the body. Aminoguanidine also prevents destructive crosslinking of collagen and elastin fibers in the brain, which is a primary cause of mental degeneration in the elderly.

An article in Brain Research described a study of aminoguanidine in a rat model of middle cerebral artery occlusion. Daily injections of aminoguanidine (100 mg/kg) began 6 hours after the occlusion. Treatment resulted in a slowing of the growth of ischemic lesions. Interestingly, serial measurements of nitric oxide and nitric oxide synthase activity found no difference between the treatment and placebo groups which suggested that the neuroprotective effects of aminoguanidine may be due to mechanisms other than nitric oxide metabolism (Cash et al. 2001).

An earlier study in the journal Brain Research also used aminoguanidine in a rat model of middle cerebral artery occlusion. The authors found that treatment for a longer period of time (more than 2 days) decreased the volume of ischemic injury. The average reduction was 21% at 3 days and 30% at 4 days (Zhang et al. 1998).

An article in the journal Stroke described a study of aminoguanidine used to treat rats with induced cerebral artery occlusion. Aminoguanidine administered 15 minutes after the onset of ischemia resulted in a significant reduction of infarct volume. Protection was also measured when aminoguanidine was administer e d 1 or 2 hours after the onset of ischemia (Cockroft et al. 1996).

Aminoguanidine and piracetam are European drugs that are not approved for general use in the United States by the FDA. They can, however, be purchased from offshore pharmacies for personal use and may be obtained by physician prescription through compounding pharmacists. The Life Extension Foundation maintains a list of offshore pharmacies that ship European drugs to United States citizens. This list is available by calling the Life Extension Foundation at (800) 226-2370.

Carnosine
Since it is difficult for Americans to obtain aminoguanidine, a nutrient called carnosine should be considered. Carnosine has demonstrated potent anti - glycosylation properties and protects brain cells by additional mechanisms. Carnosine is a peptide made from the amino acids beta-alanine and L-histidine. Several researchers have proposed that carnosine may be of benefit in protecting against stroke. Carnosine acts to regulate the metabolism of zinc and copper, which play a major role in the modulation of central nervous system excitability (Horning et al. 2000; Suslina et al. 2000; Trombley et al. 2000).

In a study in Brain Research Bulletin, rats were subjected to 45 minutes of reduced blood flow (ischemia) to the brain. The result was massive injury that caused 67% of the animals to die. In a group pretreated with carnosine, only 30% died in response to the ischemic injury, and a significant protective effect was shown to in cell membranes and cerebral enzyme levels. The scientists that conducted the study concluded that "carnosine protects against oxidative injury and thereby increases the survival of the animals" (Stvolinsky et al. 2000).

Based on extrapolations from this study and previous reports, the risk of acute death from a stroke in someone taking carnosine every day might be reduced by more than 50% and the chances of significant neuronal impairment that could cause paralysis would also be lowered. The volume of published data on carnosine shows multiple benefits, including antioxidant, anti - glycating, aldehyde quenching, and metal chelating actions.

To derive benefit from carnosine, enough must be consumed to saturate the carnosinase enzyme to make free carnosine available to the body. This dose is typically 1000 mg a day.

Nutrients to Aid in Brain Cell Rehabilitation and to Help Prevent New Strokes
Any disruption of blood flow to the brain causes massive free-radical damage that induces much of the reperfusion injury to brain cells characteristic of strokes. When blood flow is interrupted and subsequently restored (reperfused), tissues release iron, providing a catalyst for the formation of free radicals that often permanently damage brain cells. The Life Extension Foundation has spent millions of dollars conducting research that involves developing methods of protecting the brain cells from injury caused by blood flow disruption. The use of antioxidant nutrients, drugs, and hormones, along with specific calcium-channel blockers and cell membrane-stabilizing agents, provides enormous protection to brain cells.

If you know that an ischemic stroke is occurring, antioxidant vitamins and herbs such as ginkgo biloba would be of benefit. Magnesium in an oral dose of 1500 mg is a safe nutrient to relieve an arterial spasm, a common problem in thrombotic strokes. If you take high-potency antioxidant nutrients at least three times a day, your chances of fully recovering from an ischemic stroke may be significantly improved.

For those who have already incurred brain damage caused by ischemic stroke, a wide range of nutrients may be considered to aid in possible neurological recovery via several different mechanisms. The suggested doses of the nutrients listed below are contained in the summary that appears at the end of this protocol.

One of the most powerful aspects of natural supplements is that they have several different mechanisms by which they exert their beneficial effects. The supplements have been arranged in sections based on their primary action. A few supplements, however, are so important that they are in a section by themselves:

• CDP-Choline (Citicholine) may reduce injury to the CNS and inhibit free-radical production.
• Ginkgo biloba is a powerful antioxidant. It inhibits platelet aggregation, enhances cerebral blood flow, and is well-known for its beneficial effect on memory and cognitive function.
• Essential fatty acids, especially docosahexaenoic acid (DHA), are important in neurological repair because the brain is composed almost entirely of fatty acids. They also have very strong anti-inflammatory properties.
• Antioxidant therapy is important in stroke recovery to reduce the oxidative damage that occurs following cellular injury. Antioxidants, such as vitamin C, vitamin E, and alpha-lipoic acid, have been found to be beneficial in stroke.
• Minerals play in an essential role in neurologic function primarily as neurotransmitters. Calcium, magnesium, potassium, and selenium are important nutrients.
• Hormones such as DHEA have a definite influence on metabolism, including neurological function and repair.
• Nitric oxide metabolism is the focus of scientific investigation for its effect on cerebral blood flow and blood pressure. Arginine facilitates nitric oxide synthesis.
• Vinpocetine enhances cerebral circulation and improves neuronal energy metabolism.
• A healthy diet is an essential part of any wellness plan and many studies have confirmed the beneficial effect of fruits and vegetables on cardiovascular risk.

CDP-Choline
Choline and pantothenic acid (vitamin B5) are used to produce acetylcholine, the major neurotransmitter that transmits nerve impulses between neurons. Choline is also needed for cell membrane integrity and to move fats in and out of cells. Choline is, therefore, essential for proper brain function because the brain is composed of millions of nerve cells and is composed almost entirely of fats.

CDP-choline is a unique form of choline that readily passes through the blood-brain barrier directly into brain tissue. CDP-choline is a rate-limiting intermediate in the biosynthesis of phosphatidylcholine, an important component of the neural cell membrane. CDP-choline (citicholine) may reduce central nervous system ischemic injury by stabilizing cell membranes and reducing free radical generation.

CDP-choline has been found to be of value in studies on animals and humans. It is approved in Europe and Japan for use in stroke, head trauma, and other neurological disorders (D'Orlando et al. 1995).

Animal Studies of CDP-Choline:

• CDP-choline alone and in combination with urokinase resulted in a significant decrease in neuronal damage in a study on rats with focal ischemia induced by occlusion of the middle cerebral artery (Shuaib et al. 2000).
• CDP-choline was shown to significantly attenuate blood-brain barrier (BBB) dysfunction after transient forebrain ischemia was induced in gerbils. CDP-choline substantially attenuated edema at 3 days and reduced neuronal death after 6-day reperfusion (Rao et al. 1999).
• In a study of rats with induced carotid artery embolisms, CDP-choline was shown to reduce the median infarct size from 37% in the control group to 22% at a dose of 250 mg/kg and 11% at a dose of 500 mg/kg. CDP-choline was also studied in combination with recombinant tissue plasminogen activator (rt-PA). The infarct size was 24% with rtPA 5 mg/kg; 11% with rt-PA and 250 mg/kg CDP-choline; and 19% with rt-PA and 500 mg/kg CDP-choline (Andersen et al. 1999).
• A study examined the effects of CDP-choline with medial cerebral artery occlusion induced in spontaneous hypertensive rats. CDP-choline significantly improved behavioral dysfunction (Arnowski et al. 1996).
• A study of CDP-choline used to treat ischemia induced in rats demonstrated that CDP-choline significantly reduced infarct volume with a trend towards reducing brain edema and mortality (Schabitz et al. 1996).

Human Studies of CDP-Choline
Four studies of intravenously administered CDP-choline have been conducted outside the United States :

• A multicenter, double-blind, placebo-controlled study of CDP-choline (1000 mg per a day intravenously for 14 days) was conducted on patients with acute, moderate to severe cerebral infarction: 133 patients received CDP-choline treatment and 139 received placebo. The group treated with CDP-choline showed significant improvements in level of consciousness compared with the placebo-treated group, and CDP-choline was an entirely safe treatment (Tazaki et al. 1988).
• A double-blind, placebo-controlled study of CDP-choline (750 mg a day intravenously for 10 days) used within 48 hours of stroke onset showed a significant improvement on a quantified neurological assessment scale rating motor strength, muscular force, sensation, higher cortical function, and ambulation at 90 days. Patients treated with CDP-choline were significantly more likely to be ambulatory compared with placebo-treated patients at 90 days (Goyas et al. 1980).
• A second double-blind, placebo-controlled trial of intravenous CDP-choline (250 mg 3 times a day for 10 days) in stroke patients treated within 48 hours of their symptoms found that a significantly higher percentage of patients had a very good to fairly good recovery with CDP-choline versus placebo treatment at 10 days after stroke (Boudouresques et al. 1980).
• A small double-blind, placebo-controlled study examined the effects of CDP-choline (1000 mg a day of IV for 30 days) or placebo in 19 patients with acute stroke treated within 48 hours. In comparison to their baseline assessments, 76% of the CDP-choline-treated patients demonstrated im-provement compared with only 31% of the placebo-treated patients (Corso et al. 1982).

Two trials of orally administered CDP-choline have been conducted in the United States :

• A randomized, double-blind, multicenter trial of CDP-choline was conducted on 259 stroke patients. Both the 500 mg per a day CDP-choline group and the 2000 mg a day CDP-choline (orally) group had a significant improvement in terms of the percent of patients who had a favorable outcome on the Barthel Index at 90 days. There were no drug-related serious adverse events or deaths in this study. This study suggests that oral CDP-choline can be used safely with minimal side effects in acute stroke treatment. CDP-choline appears to improve functional outcome and reduce neurologic deficit with 500 mg of CDP-choline appearing to be the optimal dose (Clark et al. 1997).
• In a follow-up study in the journal Stroke, 394 patients with acute (24 hours) ischemic stroke received either CDP-choline (500 mg orally daily) or placebo for 6 weeks. No difference was found between the placebo and CDP-choline-treated groups. The authors, however, found a significantly higher percentage of patients with mild strokes in the placebo group (34%) than those treated with CDP-choline (22%). The researchers also found a similar discrepancy in the previous study (above) (Clark et al. 1997). Re-analysis of the data found that the 2000-mg dose provided the greatest therapeutic effect (instead of the 500-mg dose.) For this reason, the authors have chosen to use the 2000-mg dose in future trials (Clark et al. 1999).

A key difference was evident between the U.S. and non-U.S. trials. Those conducted in the United States by Clark et al. (1999) used oral doses of CDP-choline (500 and 2000 mg), whereas the non-U.S. trials used IV CDP-choline at various concentrations and dosages (750 mg per a day, 250 mg 3 times per a day, and 1000 mg per a day).

Ginkgo Biloba
Ginkgo biloba is one of the oldest living species of tree, with individual trees living as long as 1000 years. Ginkgo is most commonly recommended to help with memory loss and Alzheimer's disease. It is an antioxidant and inhibitor of platelet aggreg r ation, making a powerful combination for circulatory disorders, such as atherosclerosis.

• Ginkgo appears not only to protect against free radicals and abnormal blood clotting, but also enhances neuronal metabolic rates that are severely impaired as a result of ischemic insult.
• The conclusions of a report of 40 clinical trials stated that "positive results have been reported for ginkgo biloba extracts in the treatment of cerebral insufficiency" (Kleijnen et al. 1992).
• Earlier, double-blind, placebo-controlled trials of ginkgo biloba extract involving 55 patients with acute cerebral ischemia showed a significant improvement in cognitive function based on the Matthews scale (Garg et al. 1995).
• Ginkgo biloba was used with heart patients in a treadmill test in France . The doctors concluded: "In a comparison of the differences before and after treatment, the areas of ischemia decreased by 38%" after its use (Mouren et al. 1994).
• A French study of mice at the Universite de la Mediterranee ( Marseille , France ) in 1998 reported that neuroprotective drugs such as ginkgo biloba extract could prevent ischemia-induced impairment (Pierre et al. 1999).
• A Japanese study found that ginkgo biloba increased cerebral blood flow and reduced infarct volume and ischemic brain damage resulting from middle cerebral artery occlusion induced rats (Zhang et al. 2000).

Essential Fatty Acids
Essential fatty acids are important in both stroke prevention and during the repair of brain tissue damaged by stroke. The brain is almost entirely composed of fatty acids. The Framingham study confirmed that the friendly fats have a beneficial effect on stroke prevention. Essential fatty acids include alpha-linolenic acid ( ALA ) found in perilla and flaxseed oils and docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) found in cold-water fish oil. Fish oils reduce inflammation due to their high content of DHA and EPA. Fish oil acts as platelet aggregation inhibitors as well as triglyceride lowering agents.

Alpha-Linolenic Acid
Alpha-linolenic acid, an omega-3 fatty acid, may be the most efficient fatty acid in the prevention of stroke by helping to prevent abnormal blood clotting (Renaud 2001). Perilla oil and flaxseed oil are rich sources of alpha-linolenic acid.

An article in the journal Vascular Medicine described the Edinburgh Artery Study of over 1100 subjects examined in a random sample survey. Measurements of the fatty acid levels in red cells found that alpha-linolenic acid was significantly lower in those with stroke and lower limb disease (Leng et al. 1999).

These findings were confirmed in another study of 96 men with incidental stroke and 96 matched controls who were enrolled in the Multiple Risk Factor Intervention Trial. Statistical analysis of fatty acid levels found a 28% and 37% decrease in the risk of stroke with alpha-linolenic acid depending on the increase above average levels. Interestingly, an increase in stearic acid (a food additive derived from beef) was associated with a 37% increase in the risk of stroke (Simon et al. 1995).

Docosahexaenoic Acid (from Fish Oil)
Docosahexaenoic acid (DHA) from fish oil has been shown to prevent the development of hypertension in stroke-prone spontaneous hypertensive rats. Measurements also found that dietary DHA resulted in a decrease of arach i a donic acid (a fatty acid from animal meat that increases inflammation), and restored the inferior learning performance observed in the control group (Minami et al. 1997; Kimura 2000).

Another study found that omega-3 oils, such as fish, perilla, and flaxseed oils, prolonged the survival time of stroke-prone spontaneous hypertensive rats by about 10% as compared to the omega-6 safflower oil. They also found that rapeseed (canola) oil shortened the survival time by about 40% (Miyazaki et al. 2000).

An article in JAMA described the Nurses' Health Study which found that dietary intake of fish and omega-3 polyunsaturated fatty acids were associated with a reduced risk of thrombotic infarction, primarily among women who did not regularly take aspirin (Iso et al. 2001).

An article in the journal Stroke described a study of 552 men in the town of Zutphen , The Netherlands between 1960-1970. Fewer strokes occurred among the 301 men who always reported fish consumption than among the men who changed fish consumption habits or did not consume fish at all during the study. The authors concluded that these results suggest that consumption of at least one portion of fish per week may be associated with a reduced stroke incidence (Keli et al. 1994).

Antioxidants

Vitamin C.
Vitamin C may be useful in stroke because of its antioxidant properties (Grzegorczyk et al. 2001).

Although ascorbic acid does not pass the blood-brain barrier, its oxidized form, dehydroascorbic acid (DHAA), does. A study in the Proceedings of the National Academy of Science compared the effects of ascorbic acid and DHAA used to treat mice after induction of cerebral artery occlusion. Both DHAA and ascorbic acid reduced infarct volume when given before the ischemia, but only DHAA had an effect when administered after the ischemia. DHAA (250 mg/kg or 500 mg/kg) administered 3 hours after the ischemia reduced infarct volume by six- to ninefold, to only 5% with the highest DHAA dose (Huang et al. 2001a).

An article in the journal Stroke described a 20-year study in Japan that examined vitamin C levels and the risk of stroke. High serum vitamin C concentration was associated with reduced stroke, cerebral infarction, and hemorrhagic stroke risk (Yokoyama et al. 2000).

Vitamin E
Vitamin E is well-known for its antioxidant, anti-inflammatory, and antiplatelet effects. Vitamin E increases the production of prostaglandin-I2, a platelet aggreg r ation inhibitor and vasodilator. Vitamin E has also been found to increase HDL (the "good" cholesterol).

The Life Extension Foundation recommends the complete spectrum of vitamin E be used including alpha tocopherol, gamma tocopherol, and the tocotrienols. Vitamin E should be used with care (under the advice of a knowledgeable physician) in patients on anticoagulant drugs (Coumadin).

The gamma tocopherol fraction is the most protective antioxidant for patients taking prescription drug nitrates such as nitroglycerine or isosorbide mononitrite or people using the amino acid arginine for its vasodilating effects.

Alpha-Lipoic Acid
Alpha-lipoic acid is a commercially available supplement with a variety of actions that may be beneficial during acute stroke. These actions include inhibiting platelet and leukocyte activation and adhesion, reducing free-radical generation, and increasing cerebral blood flow.

The effects of alpha-lipoic acid were studied on strokes induced in mice. Alpha-lipoic acid (100 mg/kg subcutaneous injection) or placebo was administered 1.5 hours before transient middle cerebral artery occlusion was induced. Infarct volume was significantly reduced, and neurologic function was significantly improved in the alpha-lipoic acid group as compared to placebo (Clark et al. 2001).

Most of the tissue damage that occurs from a stroke is observed during reperfusion, which is primarily attributed to oxidative injury from the production of oxygen free radicals. During the process, antioxidants such as glutathione and alpha-lipoic acid are depleted. Pretreatment with alpha-lipoic acid in rats subjected to reperfusion following cerebral ischemia dramatically reduced the mortality rate from 78% to 26% during 24 hours of reperfusion (Panigrahi et al. 1996).

Another study examined the neuroprotective effects of alpha-lipoic acid using models of focal cerebral ischemia in mice and rats. Alpha-lipoic acid was able to reduce the infarct area only when it was administered subcutaneously 1-2 hours before the occlusion of the middle cerebral artery (Wolz et al. 1996).

Minerals
Calcium, magnesium, and potassium are the most abundant minerals in the body. They play an important role in many of the functions of the body.

Calcium
Calcium is needed for the transmission of signals between neurons. Ionized calcium initiates the formation of blood clots. It stimulates the release of thromboplastin from platelets and is a cofactor in the conversion of prothrombin to thrombin.

An article in the journal Stroke described a study of calculated dietary intakes of calcium, potassium, and magnesium in the Nurses' Health Study cohort. Women in the highest quintile of calcium intake had an adjusted relative risk of ischemic stroke that was 31% lower compared with those in the lowest quintile; for potassium intake the corresponding relative risk was 28% lower. The authors concluded that low calcium intake (and perhaps low potassium intake) may contribute to increased risk of ischemic stroke in middle-aged American women (Iso et al. 1999).

Magnesium
Magnesium regulates the absorption of calcium and complements its actions. Magnesium is a natural medicine calcium channel blocker which inhibits calcium ions into cells and can reduce stroke risk. Calcium functions to contract muscles, while magnesium relaxes them. Taking too much magnesium will loosen the stools, causing diarrhea. Magnesium also functions to decrease coagulation, while calcium is involved in increasing coagulation. It is important to maintain a proper ratio between calcium and magnesium.

The use of magnesium in acute stroke cases is at present controversial. Several studies report positive effects, while others do not. There are several reasons for this. The time-to-treatment variable is important because the damage from a stroke happens quickly. Studies in rats show that magnesium is extremely effective if used within 2 hours, but the effectiveness rapidly decreases. A 6-hour window of opportunity is recommended (Yang et al. 2000).

An interesting article in the journal Alcohol proposed that intravenous magnesium may be particularly useful in alcohol-induced hemorrhagic strokes , which are preceded by a rapid fall in intracellular free magnesium ions. They also propose that women are more prone to this fall in magnesium due to the hormonal effects on free magnesium. In support of this hypothesis, they state that premenstrual tension headaches and alcohol-induced headaches (e.g., hangovers) can be ameliorated with intravenous injections of magnesium sulfate (Altura et al. 1999; Babu et al. 1999).

A randomized, placebo-controlled, double-blind study examined the effects of magnesium sulfate given intravenously during the first 24 hours following a stroke. Intravenous magnesium was shown to have a significant positive effect (Lampl et al. 2001).

Potassium
Potassium is also used by the body for conducting impulses between neurons. Potassium works with sodium to maintain muscle tone, blood pressure, and water balance. Studies have shown that a low potassium diet is related to a higher incidence of stroke (Bazzano et al. 2001). In a study reported in Circulation, diets rich in potassium, magnesium, and cereal fiber reduced the risk of stroke, particularly among hypertensive men. The authors concluded that potassium supplements may also be beneficial, but because of potential risks, use of potassium should be carefully monitored (Ascherio et al. 1998).

Selenium
Selenium is a trace mineral that is involved in the synthesis of glutathione peroxidase, a key detoxification enzyme. A study examined the association between serum selenium concentration and 5-year risk of cardiovascular disease in 1110 men aged 55-74 years in two rural areas of Finland . In the total cohort, all-cause and cardiovascular deaths were associated significantly with serum selenium of less than 45 mcg/L, with an adjusted relative risk of 1.4 and 1.6, respectively. Among men free of stroke at the outset, low serum selenium was associated significantly with stroke mortality, an adjusted relative risk of 3.7 (Virtamo et al. 1985).

Homocysteine-Lowering Supplements
Elevated levels of serum homocysteine strongly predict stroke risk. Homocysteine detoxification requires several nutrients, including vitamin B6, vitamin B12 (cobalamin), and folic acid. Although these three vitamins are currently well publicized, other nutritional factors are also involved in detoxifying homocysteine. Methyl donors, such as trimethylglycine (TMG) and SAMe, are also needed.

B Vitamins and Trimethylglycine (TMG)
Currently, several studies are underway to evaluate the effectiveness of lowering homocysteine with vitamins. The Vitamins in Stroke Prevention (VISP) study is evaluating vitamin B6, B12, and folic acid in patients at least 35 years old that had a nondisabling ischemic stroke within 120 days and high plasma homocysteine (Spence et al. 2001).

The Life Extension Foundation recommends that people measure their homocysteine levels. Homocysteine is of particular concern for those at risk of stroke and victims of stroke. Supplementation with vitamin B6, vitamin B12, folic acid, and trimethylglycine are essential for stroke risk reduction in those whose homocysteine levels are above 7.2 (micromol/L) of blood. The methylating effects of TMG produce SAMe which has been shown to ease depression and remyelinate nerve cells. TMG should be taken with the B vitamin cofactors mentioned above for the full effects to be reached. See the Cardiovascular Disease protocol for more information.

SAMe
S-adenosyl-L-methionine (SAMe) is an amino acid made naturally in the body. It has been shown to be a potent antidepressant in several double-blind studies (Bell et al. 1988; Kagan et al. 1990). SAMe is so effective that it has rapidly become one of the best-selling dietary supplements in the United States . Studies found that SAMe increases glutathione levels and decreases free radical activity. SAMe also inhibits lipid peroxidation. SAMe is a methyl donor that improves brain methylation which may account for its antidepressant properties.

In experiments with rats, SAMe was found to increase cellular energy levels (ATP and cAMP) and suppress the elevation of lactic acid that commonly follows ischemia. The authors concluded that SAMe protected energy failure and accelerated recovery from ischemia and that it is beneficial for treatment of cerebral ischemia in the acute stage (Katayama et al. 1985).

Cholesterol-Lowering Supplements

Policosanol
Policosanol is a natural supplement made from sugarcane. The main ingredient is octacosanol, an alcohol found in the waxy film that plants have over their leaves and fruit.

Octacosanol is a "long chain fatty alcohol" (similar to cholesterol which is also an alcohol). Policosanol is a combination of octacosanol and several other long chain fatty alcohols--hence the name "poli"-cosanol. Keeping octosanol together with other naturally occurring fatty alcohols makes it more stable. There is evidence that octosanol also works better when it is combined with other fatty alcohols. Research has shown that policosanol has the following benefits:

• Lowers cholesterol. Several studies have compared policosanol with pr a o vastatin, lovastatin, and sim-vastatin. Policosanol was found to be more effective than all three at lowering LDL and total cholesterol, increasing HDL cholesterol, and improving the ratios of LDL to HDL and total cholesterol to HDL (Castano et al. 1999; Crespo et al. 1999; Prat et al. 1999).
• Inhibits the oxidation of LDL (Menendez et al. 1999). Oxidized LDL is dangerous. It promotes the destruction of blood vessels by creating a chronic inflammatory response. Oxidized LDL can also provoke metalloproteinase enzymes (Xu et al. 1999). These enzymes promote blood vessel destruction, partly by interfering with HDL's protective effect. Studies show that rats treated with policosanol have fewer foam cells, reflecting less inflammatory response causing less blood vessel destruction (Noa et al. 1996; Lindstedt et al. 1999).
• Reduces the proliferation of cells. Healthy arteries are lined with a smooth layer of cells so that blood can race through with no resistance. One of the features of diseased arteries is that this layer becomes thick and overgrown with cells. As the artery narrows, blood flow slows down or is blocked completely. Policosanol was tested for its ability to stop the proliferation of these cells (Noa et al. 1996). According to the results, policosanol's ability to stop cell overgrowth "is in agreement with the anti - proliferative effects reported for other lipid-lowering drugs, such as most of the statins" (Negre-Aminou et al. 1996).
• Inhibits the formation of clots. Policosanol may work synergistically with aspirin in this respect. In a comparison of aspirin and policosanol, aspirin was better at reducing one type of platelet aggregation (clumping together of blood cells). But policosanol was better at inhibiting another type. Together, policosanol and aspirin worked better than either alone (Arruzazabala et al. 1997; Stusser et al. 1998). A related effect is that significant reductions in the level of thromboxane occur in humans after 2 weeks of policosanol (Carbajal et al. 1998). Thromboxane is a blood vessel-constricting eicosanoid produced by platelets.
  Note: Eicosanoids are powerful chemicals created in cells that can do things such as create fever to kill infections; cause blood vessels in lungs to expand so you can breathe; and reduce inflammation. The body could not function without eicosanoids. Problems arise when eicosanoid reactions are disrupted by drugs, disease, poor diet, and other factors that interfere with their natural balance.
• Decreases thrombus weight. Policosanol was shown to significantly decrease the thrombus weight in venous thrombosis experimentally induced in rats, with the protective effect persisting up to 4 hours after its oral administration (Carbajal et al. 1994).

Garlic
Garlic is a well-known herb that is of great benefit in decreasing the risk of arteriosclerosis. It has been shown to decrease total and LDL-cholesterol; increase HDL-cholesterol; reduce serum triglyceride and fibrinogen concentration; lower arterial blood pressure and promote organ perfusion; enhance fibrinolysis; inhibit platelet aggregation; and lower plasma viscosity.

In a prospective, 4-year clinical trial, standardized garlic caused a 9-18% reduction and 3% regression in plaque volume; a decrease in LDL level by 4%; an increase in HDL concentration by 8%; and lowering in blood pressure by 7%. These effects resulted in a reduction of relative cardiovascular risk for infarction and stroke by more than 50% (Siegel et al. 1999).

Fibrinogen-Lowering Supplements
Low-dose aspirin and certain nutrients can provide partial protection against abnormal blood clots, but if you have high fibrinogen levels, additional measures should be taken to prevent heart attack and stroke. Platelet-aggregation inhibitors reduce the risk of fibrinogen causing an abnormal blood clot. Some effective nonprescription platelet-aggregation inhibitors include low-dose aspirin, green tea, ginkgo biloba, garlic, and vitamin E.

High vitamin A and beta-carotene serum levels have been reported to reduce fibrinogen levels in humans. For example, animals fed a vitamin A-deficient diet have an impaired ability to break down fibrinogen, but when they are injected with vitamin A, they produce tissue plasminogen activators that break down fibrinogen (Kooistra et al. 1991). A study in the October 1997 Diabetes Care Journal indicates that no one antioxidant may be effective and that total antioxidant capacity is important in reducing the risk associated with fibrinogen and cardiovascular disease (Ceriello et al. 1997).

Additionally, both fish and olive oil have been shown to lower fibrinogen in women with elevated fibrinogen levels (Oosthuizen et al. 1994). The minimum daily amount of fish oil required to produce a fibrinogen-lowering effect is 6 grams. In study results reported in the July 1997 issue of the American Journal of Clinical Nutrition, researchers at Louisiana State University (Baton Rouge) indicated, based on two randomized, double-blind, placebo-controlled, parallel studies conducted in human subjects, that increasing the amount of fish oil consumed to 15 grams a day "decreased fibrinogen concentrations" (Hwang et al. 1997).

Elevated homocysteine levels have been shown to block the natural breakdown of fibrinogen by inhibiting the production of tissue plasminogen activators (Midorikawa et al. 2000). Folic acid, trimethylglycine (TMG), and vitamins B12 and B6 significantly reduce elevated homocysteine levels.

The therapeutic benefits of vitamins B6 and B12 were discussed in a 1998 Cardiovascular Reviews and Reports (United States), reinforcing the use of these vitamins as part of an integrated therapy or disease prevention approach. Another study in 1998, based on data from 80 clinical and epidemiological studies that included more than 10,000 patients, suggested that supplementation with B vitamins, in particular with folic acid, is an efficient, safe, and inexpensive means to reduce the elevated homocysteine levels implicated in cardiovascular risk and disease (Refsum et al. 1998).

Since the 1980s, vitamin C has been studied and found beneficial in the reduction of fibrinogen levels. In a report in the journal Atherosclerosis, heart disease patients were given either 1000 or 2000 mg a day of vitamin C to assess its effect on the breakdown of fibrinogen. At 1000 mg a day, there was no detectable change in fibrinolytic activity (fibrinogen breakdown) or cholesterol. At 2000 mg a day of vitamin C, however, there was a 27% decrease in the platelet-aggregation index, a 12% reduction in total cholesterol, and a 45% decrease in fibrinolytic activity (Bordia 1980).

For additional fibrinogen-lowering effect, the proteolytic enzyme bromelain derived from the pineapple plant may also be effective for coagulation inhibition (Lotz-Winter 1990).

For those seeking to lower elevated fibrinogen levels and inhibit coagulation, 2-6 capsules a day of a supplement called Herbal Cardiovascular Formula containing a standardized bromelain concentrate should be considered.

Low-dose niacin was reported effective in reducing plasma fibrinogen in a 1998 American Journal of Cardiology study that "demonstrated that niacin supplementation decreases plasma fibrinogen and low-density lipoprotein cholesterol in subjects with peripheral vascular disease." The researchers reported further that those changes in fibrinogen levels are highly correlated with changes in low-density lipoprotein cholesterol in subjects taking niacin (Philipp et al. 1998).

While niacin is considered relatively safe, like cholesterol-lowering prescription drugs, it can cause liver toxicity when taken in high doses. Monitoring liver enzymes every 6 months is important when taking more than 1000 mg of niacin a day. Those with hepatitis should avoid niacin to avoid complications.

Restoring Youthful Hormone Levels
Maintaining healthy hormone levels may assist in rehabilitating neurological impairment due to stroke. Hormone levels naturally decline with aging. These declines contribute to numerous degenerative illnesses such as cardiovascular disease, immune impairment, cancer cell proliferation, and memory decline. The Life Extension Foundation has long endorsed hormone supplementation to prevent or reverse the signs of aging in both men and women. Several hormones have demonstrated an ability to facilitate brain cell energy, maintain proper levels of acetylcholine, and protect brain cell membrane function. These hormones help restore youthful synchronization of nerve impulses within the brain. Individuals who are experiencing cognitive decline from the effects of a stroke are advised to have their hormone levels checked and to discuss hormone replacement with their physician.

DHEA
Pregnenolone and DHEA improve brain cell activity and enhance memory. (Pregnenolone is converted into DHEA in the body.) DHEA is the most plentiful steroid hormone in the human body, but its exact function is unknown. What is known is that its concentration plummets with age: its daily production drops from 30 mg at age 20 to less than 6 mg at age 80. DHEA is naturally synthesized in abundance in young people from pregnenolone in the brain and the adrenal glands. It is known to affect the excitability of neurons in the hippocampus, the part of the brain responsible for memory.

Current findings suggest that DHEA enhances memory by facilitating the induction of neural plasticity, the condition that permits the neurons (nerve cells of the brain) to change in order to record new memories. Studies have shown that DHEA not only improves memory deficits, but also relieves depression in older people and increases perceived physical and psychological well-being. DHEA has been shown to help preserve youthful neurological function. Together, pregnenolone and DHEA help to maintain the brain cells' ability to store and retrieve information in short-term memory.

A study found that DHEA and 7-oxo-DHEA -acetate , which is formed from DHEA, completely reversed the memory deficit induced by an injection of scopolamine in young mice. Only acetyl- 7-oxo-DHEA -acetate , a precursor to oxo-DHEA was effective, however, in similar tests on older mice (Shi et al. 2000).

An article in the journal Stroke described a study of DHEA-S used to treat rabbits exposed to ischemia induced by temporary occlusion of infrarenal aorta. Treatment with DHEA-S 5 minutes after the ischemia significantly prolonged the duration of ischemia associated with a 50% probability of permanent paraplegia (paralysis of the lower extremities). The beneficial results were still measurable after 4 days. The authors concluded that DHEA-S may have substantial therapeutic benefit for the treatment of ischemic stroke (Lapchak et al. 2000).

DHEA competitively inhibits cortisol. This means as you take DHEA, cortisol lowers. This is often helpful in stroke risk patients who are often under high stress and have high cortisol and low DHEA levels. DHEA is contraindicated in both men and women with certain hormone-related cancers. See the DHEA Replacement protocol for more information.

Pregnenolone
Pregnenolone has been described as "the most potent memory enhancer yet found," according to an article in the Proceedings of the National Academy of Sciences (Flood et al. 1995). Pregnenolone is a hormone formed from cholesterol that is a precursor to all adrenal hormones including progesterone, testosterone, androstenedione, ethiocolanone, estrogen, and DHEA.

Researchers have proposed that pregnenolone may play a role in stroke in regulating the balance between excitation and inhibition in the central nervous system. Pregnenolone enhances N-methyl-D-aspartate (NMDA)-gated currents in spinal cord neurons, while inhibiting receptors for the inhibitory amino acids glycine and gamma-aminobutyric acid, as well as non-NMDA glutamate receptors (Wu et al. 1991).

Melatonin
Melatonin is one of the most potent antioxidants known and readily crosses the blood-brain barrier to provide protection against free radicals generated after cellular injury (such as during a stroke). Melatonin has thousands of published research studies showing its benefits for almost every chronic disease, including cardiovascular disease, age-associated immune impairment, Alzheimer's, and Parkinson's disease. Melatonin induces drowsiness and is commonly used in insomnia.

Consideration should be given to the use of melatonin as part of an integrated treatment for thrombotic stroke. According to a 1998 report, "Melatonin is one of the most powerful scavengers of free radicals. Because it easily penetrates the blood-brain barrier, this antioxidant may, in the future, be used for the treatment of Alzheimer's and Parkinson's diseases, stroke, nitric oxide, neurotoxicity, and hyperbaric oxygen exposure" (Bubenik et al. 1998).

A study conducted at the University of Texas Health Sciences Center (San Antonio, Texas) and reported in the November 1998 Journal of Neuroscience Research indicates that "considering melatonin's relative lack of toxicity and ability to enter the brain, these results along with previous evidence suggest that melatonin, which is a natural substance, may be useful in combating free radical-induced neuronal injury in acute situations such as strokes" (Tan et al. 1998).

In laboratory experiments funded by the Life Extension Foundation, in which severe brain ischemia is artificially induced, the addition of melatonin to a cocktail of antioxidants, calcium-channel antagonists, and cell membrane-stabilizing agents provided significant protection against brain damage.

Testosterone
As men age past year 40, hormonal changes occur that perceptibly inhibit physical, sexual, and cognitive function. The outward appearance of a typical middle-aged male shows increased abdominal fat and shrinkage of muscle mass, a hallmark effect of hormone imbalance. A loss of feeling of well-being, sometimes manifesting as depression, is a common psychological complication of hormone imbalance (Barrett-Conner et al. 1999; Rabkin et al. 1999; Schweiger et al. 1999; Seidman et al. 1999; Winters 1999).

According to Jonathan Wright, M.D., coauthor of the book Maximize Your Vitality & Potency: For Men Over 40, the following effects have been reported in response to low testosterone levels (Wright et al. 1998):

• Loss of ability to concentrate
• Moodiness and emotionality
• Touchiness and irritability
• Great timidity
• Feeling weak
• Inner unrest
• Memory failure
• Reduced intellectual agility
• Passive attitudes
• General tiredness
• Reduced interest in surroundings
• Hypochondria
• Reduced libido, erectile dysfunction, or both

The above feelings can all be clinical symptoms of depression, and testosterone replacement therapy has been shown to alleviate these conditions.

In a study conducted on healthy older men, short-term testosterone administration was shown to enhance cognitive function. Cherrier et al. (2001) described a randomized, double-blind, placebo-controlled study of 25 healthy volunteers aged 50-80 years. Participants received weekly intramuscular injections of either 100 mg testosterone enanthate or placebo (saline) for 6 weeks. Circulating total testosterone was raised an average of 130% from baseline at week 3 and 116% at week 6 in the treatment group. Estradiol increased an average of 77% at week 3 and 73% at week 6 in the treatment group. The treatment group had significant improvements in cognition for spatial memory (recall of a walking route), spatial ability (block construction), and verbal memory (recall of a short story) compared with baseline and the placebo group (Cherrier et al. 200l).

A study of 144 men with acute ischemic stroke and 47 healthy male controls found that both total and low free testosterone were associated with increased stroke severity and decreased 6-month survival. Low total testosterone resulted in significantly larger infarct size. The authors concluded that these results supported the idea that testosterone affects the pathogenesis of ischemic stroke in men (Jeppesen et al. 1996).

Human Growth Hormone
Human growth hormone (HGH) is produced naturally by the pituitary gland and secreted during sleep hours. HGH steadily declines during aging from a high of 300-450 mg/mL as a young adult to as low as 30 mg/mL in the elderly. A minimum of HGH must be present in the body to maintain a healthy immune system and brain functioning. HGH is present in cerebrospinal fluid and is able to cross the blood-brain barrier to reach receptor sites on the hypothalamus, pituitary, and hippocampus. The hippocampus controls a significant amount of cognitive functioning and memory.

Researchers have found low levels of HGH in several neurological disorders including Alzheimer's disease, Parkinson's disease, MS, and stroke. Considerable research has been done on the effects of HGH over the past decade. In studies on middle aged and elderly people, HGH supplementation has increased muscle mass, skin thickness, and bone mass, while decreasing body fat. In patients with senile dementia and Alzheimer's disease, noticeable improvements have been observed with sustained use. Researchers theorize that HGH increases blood flow to the brain, regenerates neuronal dendrites and axons, and helps to rebuild protein that leads to the formation of RNA and DNA (Shippen et al. 1998).

An article in the journal Neurology described a study of the hormonal patterns in eight stroke patients and five matched healthy volunteers. Nocturnal plasma hormone measurements showed low growth hormone levels and elevated prolactin concentrations. Cortisol levels, however, were normal. The authors concluded: "Suprahypothalmic lesions influence hypothalamus function so as to facilitate prolactin secretion and inhibit growth hormone release" (Culebras et al. 1984).

Vinpocetine
Vinpocetine is derived from vincamine, the major indole alkaloid from the periwinkle plant. Vinpocetine has been used for many years in Europe to enhance memory and mental function. Vinpocetine improves blood supply to the brain, increases oxygen and glucose use by the brain, increases the vasodilation response to hypoxia (oxygen deficiency), and reduces abnormal coagulation of the blood.

An article in the European Journal of Neurology described a study of 30 patients diagnosed with acute ischemic stroke. The National Institute of Health Stroke Scale was marginally (but significantly) better in the group treated with vinpocetine at 3 months. No significant adverse effects were seen. The authors concluded that a full-scale trial of vinpocetine was feasible and warranted (Fegin et al. 2001).

Vinpocetine, derived from Vinca minor (lesser periwinkle), has been used as a prescription medication in Europe and Asia for over 20 years. Vinpocetine selectively increases blood flow to the brain and reduces neuronal excitotoxicity, resulting in improved stroke recovery and stroke preventive benefit. Vinpocetine has been shown to increase memory and cognition, improve intellectual performance, and enhance coordination. It has been shown to improve vision, hearing, and tinnit u i s (ringing in the ears) as well (Subhan et al. 1985; Balestreri et al. 1987; Hindmarch et al. 1991).

Theanine
Theanine is an amino acid found in green tea that has a tranquilizing effect on the brain. Theanine increases GABA (gamma-amino butyric acid), an inhibitory neurotransmitter, while caffeine decreases it. Theanine creates a sense of well-being and relaxation without drowsiness.

An article in Neuroscience Letters described a study in which theanine was given to gerbils 30 minutes before an ischemic stroke was induced by bilateral occlusion of the carotid artery. The number of intact neurons in the hippocampus were was assessed 7 days after the ischemic event. Pretreatment with theanine was found to prevent neuronal death in a dose-dependant manner (Kakuda et al. 2000).

Fruits and Vegetables
An article in JAMA evaluated the relationship between fruit and vegetable intake and cardiovascular disease in two prospective cohort studies: the Nurses' Health Study and the Health Professionals' Follow-up Study. After controlling for standard cardiovascular risk factors, those with diets containing over five servings of fruit and vegetables per day had 31% risk reduction compared with the group that consumed the least amount. An increment of one serving per day of fruits or vegetables was associated with a 6% lower risk of ischemic stroke. Cruciferous vegetables, green leafy vegetables, citrus fruit including juice, and citrus fruit juice contributed most to the apparent protective effect of total fruits and vegetables. The authors concluded that these data support a protective relationship between consumption of fruit and vegetables (particularly cruciferous and green leafy vegetables and citrus fruit and juice) and ischemic stroke risk (Joshipura et al. 1999; Suter 1999).

Resveratrol (3,4',5-trihydroxystilbene) is a phyto-estrogen (plant-based estrogen) found in the skins of most grapes. Its neuroprotective effects are attributed to its antioxidant, vasodilating, and antiplatelet aggregating actions. An article in Life Sciences described a study of resveratrol and infarct size. A middle cerebral artery occlusion was induced in rats 15 minutes after pre-treatment with resveratrol. Resveratrol significantly reduced the total infarction volume (Huang et al. 2001b). Supplemental grape seed-skin extract is a good source of resveratrol.

Consulting Your Physician
When over-the-counter supplements such as aspirin, vitamins, herbs, and oils are used as the primary antithrombotic therapy, the risk of undesirable side effects is reduced significantly. Although over-the-counter medications such as aspirin and natural therapies come with a lower risk of hemorrhaging, they should not be substituted for prescription medication if you are at a high risk for thrombosis.

In all circumstances requiring anticoagulation therapy or antithrombotic therapy, your physician should be consulted if you desire to substitute your medication because the risk can be life-threatening and the appropriate therapeutic dosing is crucial. Since medications such as Coumadin and heparin have a very narrow therapeutic range, anyone on these medications should have his or her blood tested frequently for one or more of the following: PT, PTT, INR. Once the effective dose is achieved, blood testing is recommended every 2-4 weeks to monitor the medication blood levels and avoid overdosing which could lead to hemorrhaging. The template bleeding time test should be conducted if over-the-counter drugs or natural supplements that affect the clotting cascade are added to the regimen. Some of these supplements include vitamins C and E, CoQ10, bromelain, ginseng, garlic, ginkgo biloba, curcumin, St. John's wort, green tea, policosanol, vinpocetine (periwinkle), and fish oils. If you are taking any of these supplements, do not vary your dose of Coumadin without rechecking your PTT (and INR) and template bleeding time.

Diagnosis, Treatment, and Prevention Overview
Many people are familiar with the dramatic portrayal of strokes in movies. While strokes are clearly a medical emergency, most strokes are far less dramatic. In fact, the symptoms of most strokes are so mild that they are often dismissed as unimportant. The critical time for strokes is immediately after they occur.

• The symptoms of thrombotic strokes include nausea and dizziness; sudden, severe headaches; weakness, numbness; paralysis, particularly to one side of the body; partial or total loss of sight in one eye.
• Diagnostic procedures for thrombotic strokes include ultrasound, CT scan, and MRI.
• Treatment of thrombotic strokes consists of medication, natural supplements, and surgical interventions, based on the underlying cause. Controlling hypertension is essential prevention in the occurrence of ischemic strokes.
• Silent strokes commonly occur after thrombotic strokes and may cause damage weeks or months after the initial stroke.

Ischemic stroke is a medical emergency. Time to treatment of this brain attack is important, concerning what is done once in the emergency room.

• Tissue plasminogen activator is of great importance immediately after a stroke has occurred to help dissolve blood clots before they thrombose.
• Heparin is sometimes used in critical care settings and should be requested by stroke victims.
• Warfarin is the drug of choice to prevent strokes. Unfortunately, warfarin has a large number of contraindications and drug interactions with many commonly used medications.
• Low-dose aspirin is widely recommended to help thin the blood and prevent strokes. One 81-mg tablet of aspirin a day with a heavy meal is recommended for its anticlotting and anti-inflammatory effects.
• Ticlopidine may be recommended as a substitute for aspirin.
• Mevacor, a statin drug (HMG-reductase inhibitor), is being investigated for use in reducing the risk of stroke, primarily because of its effect on cholesterol.

The following drug strategies should be considered in stroke prevention, treatment, and rehabilitation.

• Hydergine, an antioxidant medication that protects brain cells, may be given in an acute situation. The recommended dosage is 10 mg given sublingually and 10 mg administered orally. Because the FDA has not approved Hydergine for this purpose, the patient or patient's advocate should request that the medication be given.
• Piracetam, a nootropic medication, may be useful in the prevention of thrombotic strokes because it appears to protect brain cells from injury during the stroke event. The recommended dosage for piracetam is 4800 mg a day, administered orally.
• Nimodipine is a prescription medication that dramatically increases cerebral blood flow by acting as a calcium channel blocker. Nimodipine may be of clinical benefit in acute stroke. The recommended dose is 30 mg 3 times a day, although up to 60 mg 4 times a day have been used in studies.
• Aminoguanidine, a medication that prevents glycosylation of proteins and helps prevent mental decline in the elderly, may be useful in preventing thrombotic strokes. The recommended dose is 300 mg once a day with food. This dose should not be exceeded.

An aggressive program for stroke prevention begins by addressing the known risk factors for stroke. The risk factors for ischemic strokes are hypertension, arteriosclerosis, and blood that has a propensity to clot abnormally inside vessels. Blood components that increase the risk of abnormal arterial clotting include elevated levels of LDL cholesterol, homocysteine, C-reactive protein, and/or fibrinogen. Drug and alcohol abuse, age, gender, and race are also factors.

Conventional medicine often recommends several drugs to cover some of these risk factors, including antihypertensives, cholesterol-lowering drugs (statins), and anticoagulants, such as Coumadin and aspirin. Each of these drugs has side effects and may interact with each other, particularly with Coumadin. Bleeding is of primary concern with anticoagulant therapy as it dramatically increases the risk of hemorrhagic stroke.

Natural supplements can be used as an adjunct to conventional drugs. Proper testing is required to monitor the effectiveness of both drug and nutritional supplement programs. Recommended blood tests include total cholesterol, HDL, LDL, triglycerides, glucose, prothrombin time, homocysteine, C-reactive protein, fibrinogen, and template bleeding time. Further, the Life Extension Foundation highly recommends using optimal levels, instead of the standard reference ranges, for these laboratory tests. The primary objective of using the following nutrients is to help restore function to injured brain cells.

• CDP-Choline has been shown to be effective and is currently in clinical trials in the United States for treating strokes. CDP - Choline Caps contain 250 mg of pharma c t eutical grade cytidine-5'-diphosphocholine. One capsule a day is recommended for healthy people over the age of 40. Those with neurological impairment should take two capsules daily under the care of a physician.
• Ginkgo biloba has been shown to be very effective as an antioxidant and in treating cerebral vascular deficiency, including stroke. Super Ginkgo Extract contains 120 mg of standardized ginkgo leaf powder. One capsule daily is recommended. Use ginkgo with caution when taking anticoagulants.
• Essential fatty acids, including alpha-linolenic acid ( ALA ) and docosahexaenoic acid (DHA) from fish oils are recommended. Essential fatty acids are necessary to control inflammation leading to elevated levels of C-reactive protein and to lower fibrinogen levels. Super GLA/DHA provides high potency anti-inflammatory fatty acids. Six 1000-mg capsules a day are recommended. Perilla oil provides high potencies of precursors to EPA and DHA. Six 1000-mg capsules a day are recommended.
• Vitamin C is recommended as a daily supplement for healthy people and may also be of benefit in stroke; 1000-4000 mg of high-quality vitamin C may be taken daily. Vitamin C should be taken with cofactor lysine for maximum benefit.
• Vitamin E is an antioxidant and blood-thinner. The recommended dose for most people is 400-500 IU of alpha tocopherol, 200 mg of gamma tocop o herol, and at least 50 mg of the tocotrienols. Vitamin E should be used with caution with warfarin because it thins the blood.
• Alpha-lipoic acid may also be considered. Super Alpha Lipoic Acid with Biotin contains 250 mg of pharmaceutical-grade alpha-lipoic acid and 3000 mcg of biotin. One to two capsules daily are suggested for healthy people. Up to 4 capsules can be taken for therapeutic effect. Alpha-lipoic acid should be taken with vitamin B12 because it may cause a worsening of symptoms in those with a vitamin B12 deficiency.
• Minerals, including calcium, magnesium, potassium, and selenium should be considered based on the results of serum electrolytes (although serum levels may not represent mineral stores in the body). Thiazide and loop diuretics deplete potassium and coffee increases excretion. Magnesium is needed for the absorption of potassium.
• The Mineral Formula for Men contains four different forms of magnesium, two forms of calcium, potassium, and manganese. One to four capsules daily are recommended as a booster to the minerals contained in the Life Extension Mix.
• The Mineral Formula for Women contains more calcium, which reflects the greater need by women. One to four capsules daily are recommended as a booster to the minerals contained in the Life Extension Mix.
• Calcium and magnesium are available separately in several forms, including calcium citrate with vitamin D3, calcium carbonate powder, calcium/magnesium powder, magnesium, magnesium citrate, and magnesium oxide powder.
• Super Selenium Complex contains three different forms of selenium in capsule form. One capsule per day is recommended. Selenium drops are also available. One to five drops are suggested daily. Lower doses of selenium are recommended when taking Life Extension Mix.
• Vitamin B6, vitamin B12, folic acid, and trimethylglycine should be considered if homocysteine levels are elevated (see the Cardiovascular Disease protocol for more information).
• TMG t T ablets contain 500 mg of trimethylglycine. One to five tablets are recommended daily for healthy people. Up to 12 tablets can be taken daily if high levels of homocysteine persist.
• Vitamin B6 may be taken at doses up to 800 mg daily to reduce homocysteine levels though high doses of 100-250 mg daily are usually adequate.
• Vitamin B12, 300-1500 mcg daily.
• Folic acid, 800 mcg daily.
• Elevated fibrinogen leads to the formation of blood clots. Many of the recommended supplements to control homocysteine and lower cholesterol levels will work synergistically in keeping fibrinogen levels in the normal range. The following supplements may also be considered:
• Green tea extract, 350 mg daily.
• Vitamin A, 20,000 IU in a liquid base.
• Beta carotene, one 25,000-IU softgel daily.
• Bromelain, one 500-mg tablet at the beginning of each meal.
• Niacin, 1500-3000 mg daily. Niacin should be monitored to avoid liver toxicity at doses above 1000 mg daily. Flush-free niacin may be taken to avoid the red face and flushing sensation of regular niacin.
• SAMe may be considered, particularly if there is related depression. SAMe tablets contain 200 or 400 mg of pharmaceutical-grade S-adenosyl-methionine. The recommended total daily dose is 400-1600 mg. SAMe is best taken without food, unless GI upset occurs.
• Policosanol has been shown to have a dramatic effect on lowering cholesterol, reducing platelet aggreg r ation and decreasing the size of experimentally induced thrombus. Policosanol tabs contain 10 mg of policosanol. The ideal cholesterol range is between 180-200 mg/dL. The average person uses 10 mg a day to achieve optimal cholesterol levels. Some people may only need 5 mg a day, while others may require 20 mg a day. Cholesterol levels should be monitored regularly because levels below 150 may be dangerous.
• Garlic extract, 1000-6000 mg daily, may help lower cholesterol levels. (See the Cardiovascular Disease protocol for more information.) Garlic is available in two effective forms. One is the aged garlic extract under the Kyolic brand name. Use the formula that provides 1000 mg of Kyolic odorless garlic in each caplet. Pure-Gar Caps provide a high-allicin garlic that is not odor-free (900 mg garlic powder), and Pure-Gar with EDTA (a chelating agent).
• Melatonin readily crosses the blood-brain barrier and may help protect against further free radical-induced brain cell injury. Melatonin is to be taken before bed as a sleep-enhancer, 300 mcg-10 mg nightly is recommended.
• Hormones play a clear role in neuronal functioning and repair. Blood testing is recommended for all people over 40 to determine hormonal deficiencies.
• Pregnenolone is synthesized from cholesterol. It acts as a memory enhancer and converts to progesterone and DHEA. One 50-mg capsule, 1-4 times daily.
• DHEA improves brain cell activity and suppresses overproduction of the adrenal hormone, cortisol. The usual dose for men is 50 mg daily. For women the usual dose is 15-25 mg early in the day. See the DHEA Replacement protocol for additional information and warnings.
• Testosterone and estrogen replacement are determined by blood testing. These hormones must be prescribed by a physician.
• Arginine, vitamin B2, vitamin B3, and folic acid may be considered as a way to naturally increase nitric oxide synthesis. L-Arginine c C aps contain 900 mg of pure L-Arginine HCl. Arginine should be used with caution in diabetics and those with psychosis.
• Carnosine may be useful in protecting the brain from neurological damage. Super Carnosine contains 500 mg of pure carnosine. One capsule 2-3 times a day is recommended.
• Vinpocetine has been shown to have a positive effect on brain metabolism and to protect against excitotoxicity and may be of benefit in stroke recovery. Take 10 mg 3 times daily. For additional protection against excitotoxicity, consider a sublingual vitamin B12 lozenge called methylcobalamin in the dose of 5-40 mg a day.
• Theanine, an amino acid found in green tea, produces a tranquilizing effect on the brain by increasing production of GABA, an inhibitory neurotransmitter. Theanine may also prevent ischemic damage to neurons. Up to four 100-mg capsules can be taken daily.
• Dietary measures to lower stroke risk include high amounts of fresh fruits and vegetables every day and several servings of fish a week.

To learn about therapies that may protect arteries prior to a thrombotic stroke, or to reduce the risk of further disease or stroke attacks, refer to the protocols on Cardiovascular Disease and Thrombosis Prevention. To learn more about therapies that may restore neurological function following thrombotic stroke, refer to the protocol for Age-Associated Mental Impairment.

Hemorrhagic Stroke

For those who have experienced a hemorrhagic stroke or who have a cerebral vascular disease, such as cerebral aneurysm, it is suggested that nutrients that help build collagen and elastin be taken to help rebuild the endothelial lining of the cardiovascular arterial system. Nutrient supplements have also been reported to help reduce the risk of or damage caused by aneurysm or hemorrhage.

Of all patients diagnosed with an aneurysm or cerebral hemorrhage, 50% have hypertension. Cerebral atherosclerosis is also an underlying risk factor for cerebral vascular disease.

Although hemorrhagic strokes account for only 15% of all strokes, hemorrhagic strokes have a much higher mortality rate. There are two subcategories of hemorrhagic stroke: intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH). Although ICH and SAH are very similar, they generally result from different causes.

Intracerebral Hemorrhage (ICH)
ICH is defined as the rupturing of cranial blood vessels, resulting in the leakage of blood into brain tissues. Symptoms of ICH include:

• Partial or total loss of consciousness
• Vomiting or severe nausea
• Weakness, numbness, or paralysis, especially on one side of the body
• Sudden, severe headache
• Severe vertigo (unable to walk or stand)

If these symptoms occur, it is essential to receive immediate medical attention.

ICH rarely occurs in people under the age of 45; however, the risk for developing ICH doubles every 10 years thereafter. ICH accounts for 11% of stroke deaths. ICH occurs more frequently in men, and African-Americans are more likely to be affected than are Caucasians.

Risk Factors
Risk factors for intracranial hemorrhage include:

• Untreated hypertension, 50%
• Amyloid angiopathy, 17%
• Anticoagulation treatment (Warfarin), 10%
• Brain tumors, 5-10%
• Smoking, 5%
• Drug abuse, especially crack cocaine and amphetamines, 5%. (This is the most common cause of ICH for people in their 20s and 30s.)

The most common risk factor for ICH is chronic hypertension. Hypertension causes arteries and arterioles to become weakened, resulting in leakage. A Chinese study noted that there was considerable increased risk for ICH in hypertensive patients who did not regularly take their medications (Hsiang et al. 1996).

Anticoagulants, such as Coumadin or Heparin, are prescribed for a variety of conditions, including ischemic stroke, myocardial infarction, and deep vein thrombosis. Proper monitoring of these medications is essential because they increase the risk of ICH.

Aspirin has also been shown to increase the risk of ICH in elderly patients (Wong et al. 2000). An article in the journal Stroke identified epistaxis (nosebleed) as a risk factor for ICH in middle-aged and elderly people, both independently and combined with the use of aspirin. The authors proposed that nosebleeds may be a warning sign for increased risk of ICH in people using aspirin (Saloheimo et al. 2001).

Hepatitis C virus infection has been identified as a risk factor for ICH. ICH patients with hepatitis C infections were also found to have lower cholesterol levels, lower platelet counts, and longer prothrombin times than ICH patients without hepatitis C, although most of the values were within normal range (Karibe et al. 2001).

Subarachnoid Hemorrhage (SAH)
A SAH occurs when blood leaks into the membranes that surround the brain. The underlying causes for SAH include ruptured aneurysm (a ballooning of the arterial wall) and vascular malformations. Symptoms of SAH include:

• Sudden onset of severe headache
• Nausea or vomiting
• Stiff neck
• Light intolerance
• Total or partial loss of consciousness

After an aneurysm ruptures, a blood clot forms over the affected area. If the clot is disturbed, rebleeding occurs. Rebleeding is the leading cause of death among SAH patients. It is critical that patients with the symptoms of SAH seek immediate medical attention.

Risk Factors
Risk factors for SAH include hypertension, cigarette smoking, and family history of a primary relative with a SAH (4% risk). Other risk factors include age, gender, race, and alcohol use. The risk of rupture depends on the size of the aneurysm.

The incidence of SAH increases throughout middle age and peaks between the ages of 40 and 60. SAH affects women in 60% of all cases. African Americans have nearly twice the risk as Caucasians. Cigarettes and alcohol abuse have been shown to increase aneurysm rupture. People with a family history of aneurysm-induced SAH are at higher risk because certain types of aneurysms appear to run in families.

Diagnosis
The most common diagnostic procedures for determining the cause of hemorrhagic stroke are CT scan, MRI, and cerebral angiogram. These procedures are used to determine the type of stroke and the specific area of the brain that has been affected. Treatment of the stroke is based on the findings of these procedures.

Additional Risk Factors

Can Cholesterol Levels Be Too Low?
Cholesterol has obtained such a bad reputation, that some people may be inadvertently harming themselves by intentionally keeping their serum cholesterol too low.

At the American Heart Association's Annual Stroke Conference (February 1999), a report was presented showing that people with cholesterol levels under 180 doubled their risk of hemorrhagic stroke compared to those with cholesterol levels of 230. Hemorrhagic stroke occurs when a blood vessel in the brain breaks open and is different from the more common thrombotic stroke caused by an abnormal blood clot. This study also showed that the risk of thrombotic stroke was twice as likely in those with cholesterol levels over 280 compared to those at 230. The report concluded that the optimal cholesterol level for overall stroke prevention was around 200.

An article in the journal Neuroepidemiology found that the proportion of intracerebral hemorrhage (ICH) cases with low cholesterol was significantly greater than in controls. The authors concluded that an increased risk for primary ICH was associated with low cholesterol, a relationship that may apply specifically to hemorrhages from hypertensive vasculopathy (Segal et al. 1999).

Some Foundation members have pushed their cholesterol levels far below 180. In the few reports of hemorrhagic stroke experienced by Foundation members, their cholesterol levels have all been far below 180 mg/dL. The Life Extension Foundation recommends that cholesterol levels be monitored regularly and medication or supplement doses regulated to maintain a range of between 180-200 mg/dL.

Drugs that May Increase Bleeding Risk
Phenylpropanolamine (PPA). PPA is a popular ingredient in dozens of over-the-counter and prescription diet aids and cough and cold remedies. A case-control study found that the use of PPA significantly increased the risk of hemorrhagic stroke in women. The FDA has requested that drug companies stop marketing products containing PPA (Kernan et al. 2000; Mersfelder 2001).

Coumadin. Intracranial hemorrhage is one of the known side effects of Coumadin (warfarin). Coumadin is the drug of choice for thrombosis prophylaxis (prevention). Its uses include prophylaxis for myocardial infarction, stroke, arterial thromboembolism, and deep venous thrombosis. Coumadin is used in patients with prosthetic (artificial) heart valves and is sometimes used in combination with aspirin to thin the blood.

Coumadin interferes with the synthesis of vitamin K which forms several essential coagulation factors. It prolongs prothrombin time (PT) and thromboplastin time (APTT). Prothrombin time is the time measured in seconds for a fibrin clot to form. Thromboplastin time measures in seconds the ability of blood to clot normally. Both tests are closely related and are often ordered together. The universal standard coagulation blood test for Coumadin patients is called the INR or International Normalization Ratio.

Bleeding is the primary side effect of Coumadin therapy. Minor bleeding often occurs in the mucous membranes, particularly around the eyes and nose (causing nosebleeds). Of particular concern is easy bruising and ecchymoses (purple patches on the skin). Another side effect is "purple toe syndrome," referring to drastically reduced blood flow to the feet.

Coumadin (warfarin) has an extremely long list of contraindications and drug interactions (see below page 521 ). Of particular concern is its use in elderly patients because they are more susceptible to the effects of anticoagulants and have an increased possibility of hemorrhage.

• Coumadin is contraindicated in alcoholism, aneurysm, breast-feeding, the elderly, endocarditis, hemophilia, hemorrhage, hepatic disease, hypertension, intramuscular injections, leukemia, lumbar puncture, peptic ulcer disease, pericardial effusion, polycythemia vera, pregnancy, protein C deficiency, protein S deficiency, psychosis, surgery, vasculitis, vitamin C deficiency, and vitamin K deficiency.
• Coumadin interacts with a large number of common drugs, including acetaminophen, aspirin, barbiturates, some antibiotics, estrogens, ethanol, heparin, influenza virus vaccine, lovastatin, NSAIDs, oral contraceptives, thrombolytic agents, and thyroid hormones. Your physician must be informed of all prescription and over-the-counter medications you are taking before beginning Coumadin therapy.
• Adverse side effects to Coumadin include agranulocytosis, alopecia (hair loss), anorexia, bleeding, chondrodysplasia punctata, cleft palate, diarrhea, exfoliative dermatitis, fetal abortion, intracranial hemorrhage, intraocular hemorrhage, leukopenia, nausea/vomiting, pruritus (itching), purple-toe syndrome, skin necrosis, and urticaria.

Those currently on anticoagulant therapy with Coumadin and aspirin should closely monitor their PT and INR and take the clinical symptoms of hemorrhage seriously. Particular attention should be given to nosebleeds. Even minor symptoms of bleeding should be cause for alarm, particularly in the elderly and those on multiple medications.

There are several natural blood-thinners that may be used in conjunction with Coumadin and aspirin. See the Thrombosis Prevention and Thrombotic Stroke protocols for more information.

Conventional Treatments
Treatment of hemorrhagic stroke is based on the underlying cause of the hemorrhage and the extent of damage to the brain: treatment includes medication and surgical intervention. In patients with hypertension-induced ICH, initial treatment involves the use of antihypertensive agents. However, lowering blood pressure in ICH remains controversial. Studies have shown that one third of ICHs expand in the first 24 hours (Brott et al. 1997). Some physicians have therefore concluded that a need to lower blood pressure exists in managing acute ICH. No trial has demonstrated the effectiveness of lowering blood pressure. Furthermore, there is significant concern about reducing cerebral blood perfusion pressures in patients with elevated intracranial pressure.

The American Heart Association guidelines recommend that mean arterial blood pressure be kept lower than 130 mmHg in patients with a history of hypertension (Broderick et al. 1997). If the hemorrhage results from the use of anticoagulants, such as Coumadin or Heparin, these medications are discontinued immediately. Protamine and vitamin K may be given to reduce bleeding in patients with anticoagulant-induced bleeding.

In patients with ruptured aneurysms, surgical intervention is the method of treatment and includes placing a clip across the aneurysm or embolization if the damaged area is difficult to approach. During embolization, a wire-packed catheter is threaded through the blood vessels until it reaches the damaged area; the wires are then detached so that they form coils that attract blood cells to promote clot formation. Patients with ICH may benefit from a surgical evacuation of the hematoma. Surgical intervention is contraindicated in patients who are 75 years old or older, who have significant pre-existing disease, or who arrive at the hospital in very poor condition.

Innovative Drug Strategies

Hydergine
Hydergine, an antioxidant medication that helps to protect brain cells, may be beneficial for the treatment of hemorrhagic shock. In Europe , Hydergine is administered on an acute-care basis for the prevention of brain damage following stroke. The recommended dosage of Hydergine in an acute situation is 10 mg administered sublingually and 10 mg given orally. Because the FDA has not approved Hydergine for use in the treatment of stroke, emergency room physicians may not be willing to administer this medication. Patients or their surrogates can, however, request that this medication be used. Hydergine has been approved in the treatment of other diseases, so it is available through the hospital pharmacy.

Piracetam
Piracetam, a nootropic medication similar to pyroglutamate (an amino acid), may be useful in the treatment of hemorrhagic stroke. Piracetam appears to protect brain cells from injury and death during stroke, thereby lessening the potential for permanent neurological damage. The recommended dosage for piracetam is 4800 mg a day taken orally. A Belgian study indicated that piracetam may be very beneficial if administered within 7 hours after the onset of stroke (De Deyn et al. 1997). Piracetam is not currently available in the United States .

Any disruption of blood flow to the brain causes massive free radical damage that induces much of the reperfusion injury to brain cells characteristic of stroke. When blood flow is interrupted and subsequently restored (reperfused), tissues release iron that provides a catalyst for the formation of free radicals that often permanently damage brain cells. The Life Extension Foundation has spent millions of dollars conducting research that involves developing methods of protecting the brain cells from injury caused by blood flow disruption. The use of antioxidant nutrients, drugs, and hormones, along with specific calcium-channel blockers and cell membrane-stabilizing agents, provide enormous protection to brain cells.

To learn more about therapies that may restore neurological function following hemorrhagic stroke, refer to the Foundation's protocol for Age-Associated Mental Impairment.

Supplements

CDP-Choline
CDP-choline (citicholine) is a unique form of choline that readily passes through the blood-brain barrier directly into the brain. Choline is essential for proper brain and neuron function. It is used to make acetylcholine, one of the major neurotransmitters. Choline also aids the movement of fats in and out of cells. Brain tissue is composed almost entirely of fats.

An article in the journal Stroke described a study of citicholine sodium (cytidine-5'-diphosphocholine) in an experimental model of ICH using Swiss albino mice. Treatment with citi choline significantly improved neurological functional outcome and reduced the volume of ischemic injury surrounding the hematoma (Clark et al. 1998).

CDP-Choline has been approved in Europe and Japan to treat stroke, head injuries, and other neurological impairments. Its effectiveness in treating stroke has not been substantiated in more recent clinical trials, so CDP should be considered an adjuvant therapy at best.

Vitamin C
Vitamin C is well known for its health benefits. Humans, unfortunately, are not able to produce ascorbic acid. We therefore rely upon dietary sources. Pauling earned his second Nobel Prize by proposing that vitamin C deficiency was a major cause of atherosclerosis and cardiovascular disease.

A study in the journal Stroke measured the levels of vitamin C in 13 patients with intracranial hemorrhage and 15 patients with head trauma. Compared with 40 healthy controls, ascorbic acid (vitamin C) levels were significantly lower and inversely correlated with the severity of neurologic impairment (Polidori et al. 2001).

An article in the journal Stroke described a 20-year study in Japan that examined vitamin C levels and the risk of stroke (Yokoyama et al. 2000). High concentrations of vitamin C strongly predicted lower risks of cerebral infarction and hemorrhagic stroke. Those who had a dietary intake of vegetables 6-7 times per week had half the sex- and age-adjusted risks of all stroke and cerebral infarction than those consuming vegetables 0-2 times a week. The authors noted that the effects of vitamin C on stroke could not be explained by the antioxidant theory alone because an inverse association of serum vitamin C concentration was observed not only with cerebral infarction, but also with hemorrhagic stroke. The authors proposed several mechanisms by which vitamin C may protect against stroke:

• Vitamin C levels are inversely correlated with blood pressure. High blood pressure is a well known risk factor for stroke.
• Ascorbic acid promotes endothelial prostacyclin which decreases vascular tone and inhibits platelet aggregation (Srivastava 1985; Toivanen 1987; Lefer 1990).
• Oxidized LDL-induced increases in leukocyte-platelet aggregation may be prevented by ascorbic acid (Lehr et al. 1995).

Those at risk of a stroke or victims recovering from stroke may have increased demands for vitamin C. High amounts of vitamin C should not be acutely administered during the period when one is actually having a stroke. This recommendation is based on Life Extension Foundation-sponsored research indicating that during an acute ischemic event to the brain, too much vitamin C may promote iron-induced oxidative stress. This type of oxidative stress does not occur during periods of normal blood flow when other antioxidants (such as tocopherols) are available to balance the catalyzing effects of vitamin C, and iron is not being abnormally released from the tissues due to re-perfusion injury.

Whenever vitamin C supplements are used, it is important to consume antioxidants such as alpha-lipoic acid, the tocopherols-tocotrienols, and N-acetyl-L-cysteine to protect the vitamin C itself from turning into an oxidizing agent.

Strengthening Cerebral Vasculature
The skin of thick-skinned berries such as cherries and grapes, the seeds of grapes, and the skin, leaf, and flower of the Hawthorne tree are all naturally rich sources of a potent antioxidant called oligomeric proanthocyan a i dins (OPC). These naturally occurring antioxidant flavonoids are tissue specific for strengthening the walls of arteries and thereby reducing the risk of recurring aneurysms and hemorrhagic strokes. In addition to antioxidant protection, OPCs also support collagen and help maintain elastin throughout the entire body. These two critical proteins are major components of all our connective tissues and organs. They are responsible for maintaining structural integrity as well as the elasticity of all the tissues throughout your body. This includes joints, blood vessels, skin, ligaments, tendons, muscles, and even the heart.

By maintaining healthy levels of structural collagen and elastin, our bodies are able to continue to function more efficiently and maintain their youthful strength and flexibility longer. OPCs attach to "reactive sites" on collagen molecules and protect them from free radical attack. This is one of the reasons they are so protective and so valuable for the circulatory system (Laperra et al. 1977; Thebaut et al. 1985; Blazso et al. 1997; Rohdewald 1998; Packer et al. 1999). As noted earlier, oligomeric proanthocyan i a dins are found in grape seeds, Hawthorne tree skin, leaf, and flowers, thick-skinned berries, and the inner rind of citrus fruit.

Conclusion
Hemorrhagic stroke is a medical emergency. The two types of hemorrhages involved are ICH and SAH.

• The primary risk factor for ICH is hypertension, because chronic hypertension weakens blood vessels. Other risk factors include drug and alcohol abuse, anticoagulant medications, age, gender, and race.
• The underlying cause for SAH is cerebral aneurysm (an abnormal dilation of a blood vessel in the brain). Risk factors for SAH include family history of aneurysm, age, gender, and race.

Symptoms for both types of hemorrhagic stroke are similar and include sudden onset of severe headache, loss of consciousness, nausea and vomiting, and partial or total paralysis. Diagnosis of the underlying cause of hemorrhagic stroke is by CT scan, MRI, and angiography. Surgical evacuation of the hematoma may be necessary. For SAH, treatment includes clipping or embolization of the aneurysm.

The medications Hydergine and piracetam may be beneficial to patients with hemorrhagic shock. The FDA has not approved Hydergine for the treatment of stroke, but it should be available through the hospital pharmacy, and patients or their surrogates should request its use. Piracetam may be beneficial in preventing permanent neurological damage following stroke. Piracetam is not currently available in the United States .

There is little research on natural supplements for hemorrhagic stroke. CDP-Choline and vitamin C may be of some benefit in facilitating recovery and preventing future strokes. Supplements like vinpocetine and phosphatidylserine that enhance neuronal energy metabolism could also help in the rehabilitation process. See the section on Cerebral Aneurysm for recommendations on maintaining healthy blood vessels.

1. The symptoms of intracerebral hemorrhage (ICH) include nausea and vomiting; sudden, severe headache; weakness; numbness; paralysis, particularly to one side of the body; and partial or total loss of consciousness. The symptoms of subarachnoid hemorrhage (SAH) include sudden, severe headache; nausea and vomiting; stiff neck; light intolerance; and partial or total loss of consciousness.
2. Diagnostic procedures for hemorrhagic stroke include CT scan, MRI, and cerebral angiogram. Treatment of hemorrhagic stroke consists of medication and surgical interventions, based on the underlying cause of the hemorrhage:
   1. For intracranial hemorrhage resulting from uncontrolled hypertension, the initial treatment is blood pressure control (see the Cardiovascular Disease protocol for more information about natural blood-pressure lowering supplements and the Hypertension protocol ).
   2. Persons taking anticoagulants (Coumadin and aspirin) should exercise extreme care to prevent ICH. If signs of major hemorrhage are present, these medications should be immediately discontinued. For more information about Coumadin and natural blood-thinners, see the Thrombosis Prevention protocol and the Thrombotic Stroke section.
   3. Smoking should be discontinued for those at risk of ICH. The detrimental effects of smoking on the cardiovascular system are well known.
   4. Amyloidosis can be due to several diseases, including multiple myeloma (amyloid light chains) and Alzheimer's disease (beta-amyloid). The Alzheimer's Disease protocol contains information on several natural supplements that reduce beta-amyloid deposition.
3. Hydergine, an antioxidant medication that protects brain cells, may be given in an acute situation. The recommended dosage is 10 mg given sublingually and 10 mg administered orally. Because the FDA has not approved Hydergine for this purpose, the patient or patient's advocate should request that the medication be given.
4. Piracetam, a nootropic medication, may be useful in the prevention of hemorrhagic stroke because it appears to protect brain cells from injury during the stroke event. The recommended dosage for piracetam is 4800 mg a day, administered orally.
5. CDP-choline may be useful in both preventing and reducing the neurological damage following hemorrhagic stroke. CDP-Choline Caps contain 250 mg of cytidine-5'-diphosphocholine. One capsule a day is recommended for healthy people over the age of 40. Those with neurological impairment should take 2 capsules daily.
6. Vitamin C has been shown to both lower the risk of hemorrhagic stroke and reduce the neurological damage following hemorrhagic stroke. An appropriate dosage of vitamin C depends on the dietary intake. A prophylactic dose of 2.5-6 grams daily is recommended. Up to 15 grams a day may be taken therapeutically. Large doses should be consumed with meals. Do not take high doses of vitamin C during an acute stroke.
7. For further protection from free-radical induced brain injury, consider taking 300 mcg-10 mg of melatonin (at night) and 100-200 mg of palm-oil derived tocotrienols (vitamin E) a day.

Cerebral Aneurysm

Cerebral artery aneurysm, one of the cerebral vascular diseases, can be fatal. An aneurysm is a weakened portion of the heart or a blood vessel, usually an artery, that fills up with blood under pressure, causing it to balloon outward. Aneurysm can be caused by a hereditary weakness in the vessel wall, high blood pressure, atherosclerosis, direct injury, infection, and other diseases.

Approximately 30,000 people a year in the United States experience an aneurysm rupture, causing cerebral hemorrhage. It has been estimated that if five people were to experience a cerebral hemorrhage today, in 1 year: only one of those people would be alive and well; one would be disabled; and the other three would be dead.

Cerebral vascular hemorrhage may also produce delayed problems such as hydrocephalus ("fluid on the brain") and narrowing of the blood vessels because of the irritation of the blood on the blood vessels (known as vasospasm). Rebleeding, hydrocephalus, and vasospasm can happen days to weeks after the initial bleed. Aneurysms can and do grow. If they reach a certain size, usually more than 25 mm (1 inch), they may start applying pressure on the surrounding brain tissue and cause additional problems.

Cerebral aneurysm is very uncommon in patients under 20 years of age and is increasingly common in older patients. In people over 65, cerebral aneurysm may be found in as high as 5% of the population. It appears cerebral aneurysm is related to an absence of a muscular layer that makes up part of the blood vessels; over time, it stretches and thins and creates the aneurysm. Smoking appears to markedly increase the chance that one will develop a cerebral aneurysm.

Indications of the presence of an aneurysm depend on the location of the aneurysm. Aneurysm generally exhibits few symptoms and is discovered by accident on x-ray films or imaging scans performed for some other reason.

The rupture or hemorrhage of an aneurysm usually produces severe pain. The location of the aneurysm usually determines the amount of bleeding, shock, loss of consciousness, or if death will occur. In some cases, the aneurysm may leak blood, causing warning pain without the rapid deterioration and damage characteristic of a rupture. The threat of aneurysm goes beyond the immediate site damage it can cause. Blood clots often form in an aneurysm, creating danger of embolisms and clotting in distant organs or vessels.

Cerebral hemorrhagic problems occur when an aneurysm ruptures, causing internal bleeding. For example, aneurysm affecting the arteries supplying the brain can occur at any age, but occurs most often in people 60 years of age with a history of hypertension. The aneurysm may rupture, causing hemorrhage and blood leakage into the membrane surrounding the brain. A cerebral artery aneurysm is particularly important because it can lead to fatal subarachnoid hemorrhage which occurs underneath one of the layers of tissue lining the brain. This aneurysm frequently occurs from inherited vascular defects at the branch points of cerebral arteries.

If your physician suspects an aneurysm or the possibility of hemorrhage, he or she will probably recommend ultrasound testing, computed tomography scanning (CT scan), magnetic resonance imaging (MRI), or angiography of the area to determine the size and severity and to predict the possibility of rupture and subsequent hemorrhage.

Conventional Treatment
If an aneurysm is large and the risk of rupture is significant, surgery may be necessary.

When an aneurysm ruptures, emergency surgery is necessary to stop the bleeding. Surgical intervention into cerebral aneurysm or hemorrhage may be difficult or impossible because of the constraints of access to the damaged or threatened areas of the brain.

Hypertensive drugs may also be prescribed in an attempt to lower blood pressure and reduce the chances of additional aneurysm or cerebral hemorrhage (see the Cardiovascular Disease protocol for more information on natural ways to reduce blood pressure).

Integrated or Alternative Therapies
Researchers speculated in a 1998 issue of Life Sciences Journal that "an acute systemic oxidative stress condition might influence the rupture of intracranial aneurysm." Vitamin E was specifically identified by investigators to act as an antioxidant by scavenging free radicals and thus reducing the conditions that precipitate these cerebral vascular ruptures (Marzatico et al. 1998). We recommend taking 400-800 IU of vitamin E daily to reduce the risk of aneurysm ruptures. Vitamin C at 2000-5000 mg a day is suggested, along with 300 mg a day of the flavonoid proanthocyan i a din (from grape seed or pine bark) for further protection against underlying factors that cause cerebral vascular disease.

Magnesium is crucial for arterial structure, and it is suggested that 1500 mg a day of elemental magnesium be taken along with 1000 mg a day of calcium and 500 mg a day of potassium.

Mechanisms that regulate cerebral circulation have been intensively investigated in recent years, and this research is increasingly focused on the effects of nitric oxide. Nitric oxide is an important regulator of cerebral vascular tone. Nitric oxide maintains the cerebral vasculature in a dilated state. Arginine, a natural supplement, specifically enhances nitric oxide synthesis. Persons with cerebral vascular disease may consider taking 4-5 grams of arginine 3 times a day to better maintain the health of vessels.

Activation of potassium channels appears to be a major mechanism for dilatation of cerebral arteries. Agents that increase the intracellular concentration of cyclic adenosine monophosphate (cAMP) produce vasodilatation. Supplementation with 500 mg a day of potassium and 5-20 mg a day of Hydergine may enhance vasodilatation in cerebral vascular disease, helping to restore vessels to a healthier state.

Additionally, alcohol consumption poses a risk for development of hypertension (high blood pressure), strokes, and sudden death through the depletion of magnesium from the body. The dietary intake of magnesium modulates the hypertensive actions of alcohol (Altura et al. 1999). Experiments indicate that chronic ethanol ingestion results in the contraction of the cerebral arteries and capillaries, a contraction that causes increased cerebral vascular resistance. Chronic ethanol ingestion increases the reactivity of intact microvessels to vasoconstrictors and results in decreased reactivity to vasodilators. However, pretreatment of animals with magnesium prevents ethanol from inducing a stroke and prevents the adverse cerebral vascular changes from taking place. Magnesium influences the response of cerebral arteries to several other natural or synthetic stimulators (agonists) and has been shown to decrease cerebral vascular resistance. Contractility of cerebral arteries is dependent upon the actions and interactions of calcium and magnesium (Altura et al. 1994).

It is clear from published studies that magnesium can induce healthy vascular tone in all types of vascular smooth muscle. Magnesium appears to act on voltage-, receptor-, and leak-operated membrane channels in vascular smooth muscle. Standard channel blocker drugs do not have this uniform capability. Calcium channel-blocking drugs, however, can block calcium infiltration into brain cells, lower cerebral vascular resistance, relieve cerebral vasospasm, and lower arterial blood pressure.

Magnesium can also cause significant vasodilatation of intact cerebral arteries. Although magnesium is three to five orders of magnitude less potent than the standard calcium channel-blocking drugs, it possesses unique and potentially useful effects in maintaining healthy cerebral vascular circulation. Those with cerebral vascular disease, and especially those who consume alcohol, should take 1500 mg a day of elemental magnesium.

Nimotop (nimodipine) is an FDA-approved calcium channel-blocking drug specific to cerebral circulation and brain-cell activity. It has been shown to work better in the restoration of cerebral circulation than any other calcium channel-blocking drug yet tested. The normal dose is 30 mg of Nimotop taken 3 times a day.

Medical Device Advances the
Treatment of an Aneurysm
By using the device known as the Guglielmi coil, physicians can now correct an aneurysm that is not approachable surgically, either because of its position in the brain or because of other factors that present a high risk.

The coil is an extremely fine wire made from platinum--one of the softest metals--at the end of a longer stainless steel wire. Several coils, depending on the size of the aneurysm, are inserted inside the bubble-like aneurysm through a catheter (a long, narrow tube) threaded through the patient's blood vessels. When the coil is in the correct position--verified by a blood vessel X-ray called an angiogram--it is given a positive electrical charge. The charge causes the steel wire to dissolve at the point of a junction with the platinum coil and the positively charged coil attracts blood cells to form a clot within the aneurysm.

The coils and resulting blood clot fill up the aneurysm, essentially sealing it off. Eventually, the lining of the blood vessel grows over the "neck" of the aneurysm and the aneurysm is essentially healed.

Conclusion
Cerebral vascular disease can be life - threatening. Aneurysm and the subsequent rupture-causing hemorrhage are caused by inherited vascular defects and may be unavoidable. Aneurysm is often precipitated by atherosclerosis and hypertension. High blood pressure increases the risk of aneurysm. Reduction of high blood pressure is imperative in reducing the risk of cerebral vascular disease. Natural supplements combined with lowered blood pressure can reduce the risk and/or damage caused by cerebral vascular disease.

Refer to the Age-Associated Mental Impairment protocol for additional suggestions about restoring cerebral circulation. See the Cardiovascular Disease protocol and the Hypertension protocol for more information on hypertension, cholesterol reduction, and atherosclerosis.

The following nutrients and drugs should be considered:

1. To maintain cerebral vasculature, thus lowering the risk of a cerebral aneurysm or hemorrhagic stroke, the following supplements should be considered:
   1. Magnesium, 1500 mg daily.
   2. Arginine, 4-5 grams daily.
   3. Calcium, 1000 mg daily.
   4. Grape-seed skin extract, two 200-mg capsules daily.
2. To enhance vasodilation and improve the health of vessels, consider the following:
   1. Potassium, 500 mg daily.
   2. Hydergine, 5-20 mg daily. (Hydergine may be obtained by prescription or from offshore pharmacies.)
3. Antioxidants scavenge free radicals and protect against underlying factors that lead to cerebral vascular disease:
   1. Vitamin E containing tocopherols and toco - trienols provide the most broad spectrum protection, 1-2 softgels daily of Gamma E Tocopherol/Tocotrienols. (Provides 210 mg of gamma - tocopherol and full spectrum tocotrienols.)
   2. Vitamin C, 2000-5000 mg daily.

For more information

Contact the National Institute of Neurological Disorders and Stroke, (800) 352-9424.

Product availability

Vinpocetine, low-dose aspirin, CDP-Choline Caps, Policosanol Tabs, Super Ginkgo Extract, vitamin E succinate, Gamma E Tocopherol/Tocotrienols, Super GLA/DHA, Mega EPA, alpha lipoic acid, selenium, green tea extract, liquid emulsified vitamin A, beta carotene, No Flush Niacin, policosanol, pregnenolone, DHEA, Super Carnosine, L-theanine, Mineral Formula for Men, Mineral Formula for Women, magnesium, calcium, arginine, potassium, vitamin C, grape seed-skin extract, TMG, vitamin B6, Methylcobalamin (B12 sublingual tablets), vitamin B12 powder, folic acid + B12, melatonin, Kyolic Garlic, and Pure-Gar Caps can be ordered by calling (800) 544-4440 or by ordering online. You may also ask for a list of offshore suppliers of Hydergine, Piracetam, and Aminoguanidine. Coumadin is a prescription medication.