Recent Advances In The Treatment Of Stroke

Medical and Health Science Project and Seminar Material

Recent Advances In The Treatment Of Stroke


Abstract


Stroke is a form of cardiovascular disease affecting the blood supply to the brain. To understand the signs and symptoms of stroke andwhy they can differ from patient to patient, it is necessaryto understand a little about the brain and how it functions. A number of stroke risk factors are the same asthose for heart disease, although their relative importancevaries. For example, a high blood cholesterollevel is a much more significant risk for heartdisease. This distinction is of little practical importance,because both coronary and stroke risk factorsshould be addressed in patients who are at risk or who have suffered, a stroke or a transient ischemic Attack (The latter, also called a TIA or a ministroke). The risk factors include high blood pressure, heart disease, smoking, diabetes, cholesterol, obesity and inactivity, oral contraceptives and estrogen replacement therapy, heredity and family history, an earlier stroke, and carotid bruit. the categories of stroke include ischemia stroke and hemorrhage stroke.Anyone experiencing symptoms of a stroke requiresimmediate medical help.Even if the ultimate diagnosis is not stroke, many diseases that can mimic astroke are also medical emergencies.Many types of strokerequire immediate treatment, and most of the promisingnew therapies for stroke are effective only ifstarted within a few hours of the onset of symptoms. The following methods are used to diagnose stroke Laboratory Tests, Imaging Studies, Cardiac Evaluation, Angiography, Ultrasound, and Blood-flow Studies. The primary goals of stroke treatment have changed,thanks to new drug therapy. Most treatment of stroke during the acute phase centerson maintaining fluids and electrolytes (chemicalsubstances in the blood, such as sodium and potassium),avoiding low blood pressure (hypotension),and avoiding the secondary complications of strokeand paralysis.


Table of Contents


Preliminary Page(s)

  • Title page
  • Certification page
  • Dedication
  • Acknowledgement
  • Abstract
  • Table of content

Chapter One

1.0 Introduction

  • 1.1 Stroke
  • 1.2 Stroke and the human brain

Chapter Two

2.0 Risk Factors and Stroke Prevention

  • 2.1 High blood pressure
  • 2.2 Heart diseases
  • 2.3 Smoking
  • 2.4 Diabetes
  • 2.5 Cholesterol
  • 2.6 Obesity and Inactivity
  • 2.7 Oral contraceptives and estrogen replacement therapy
  • 2.8 Heredity and family history
  • 2.9 An earlier stroke
  • 2.10 Carotid bruit
  • 2.11 Other risk factors

Chapter Three

3.0 Categories of Stroke

  • 3.1 Ischemia stroke
  • 3.2 Hemorrhage stroke
  • 3.2.1 Brain or Intracerebral Hemorrage
  • 3.2.2 Subarachnoid Hemorrhage
  • 3.2.3 Aneurysm
  • 3.2.4 Arteriovenous Malformation
  • 3.2.5 Other forms of stroke

Chapter Four

4.0 Diagnosing and Assessing Stroke

  • 4.1 History and Examination
  • 4.2 Laboratory Tests
  • 4.3 Imaging Studies
  • 4.4 Cardiac Evaluation
  • 4.5 Angiography
  • 4.6 Ultrasound
  • 4.7 Blood-flow Studies

Chapter Five

5.0 Recent Advances in the Treatment of Stroke

  • 5.1 Treatment of acute stroke
  • 5.2 Antiplatelet medications
  • 5.3 Surgery
  • 5.4 Pharmacological approach
  • 5.5 Alternative stroke treatment
  • References

Chapter One


1.0 Introduction

1.1 Stroke

Stroke is a form of cardiovascular disease affecting the blood supply to the brain. Also referred to as cerebrovascular disease or apoplexy, strokes actually represent a group of diseases that affect about one out of five people in the United States (Demarin et al., 2001). When physicians speak of stroke, they generally mean there has been a disturbance in brain function, often permanent, caused by either a blockage or a rupture in a vessel supplying blood to the brain.

In order to function properly, nerve cells within the brain must have a continuous supply of blood, oxygen, and glucose (blood sugar). If this supply is impaired, parts of the brain may stop functioning temporarily. If the impairment is severe, or lasts long enough, brain cells die and permanent damage follows (Kopito, 2001).Because the movement and functioning of various parts of the body are controlled by these cells, they are affected also. The symptoms experienced by the patient will depend on which part of the brain is affected.

While the incidence of stroke has decreased a great deal over the past few decades, there is evidence that this trend may be leveling off. Stroke is costly. The cost in human terms, to patients and their families, is impossible to estimate. Although stroke is often viewed as a disease of the elderly, it sometimes affects younger individuals. The incidence of stroke does increase with age, but nearly a quarter of all strokes occur in people under the age of 60 (Demarin et al., 2001).

Stroke patients are often cared for by neurologists, because of the complex nature of the symptoms caused by damage to the brain. However, strokes are very closely related to heart disease. Heart attacks(myocardial infarctions) and stroke are both caused by diseases of the blood vessels. They share many of the same risk factors, and modifying these risk factors may reduce the possibility of stroke. Many of the the rapies used for cardiac disease show promise for some types of stroke. People who already have coronary disease may be at greater risk for stroke, and vice versa.


1.2 Stroke and the human brain

To understand the signs and symptoms of stroke and why they can differ from patient to patient, it is necessary to understand a little about the brain and how it functions. There are literally thousands of possible symptoms that can result from a stroke, depending on which blood vessels and parts of the brain are involved (Safavi-Abbasi et al., 2006). It is also important to realize that except for a brief period after birth, brain cells are unable to divide and form new cells. When brain cells die, they are not replaced. This is part of the reason for the limited ability of the brain to repair itself after injury, and why recovery from stroke is only partial in many cases. While someone who suffers a heart attack, for example, can lose 10 percent of heart tissue and still run a marathon, losing 10 percent of the tissue in certain parts of the brain can result in a devastating disability.

The human brain is the most complex structure known. It is composed of 100 billion nerve cells, called neurons; each neuron may connect to thousands of other brain cells. The trillions of connections are necessary for the integrative power of the brain. They also control body movements, interpret all sensations(hearing, vision, touch, balance, pain, taste, and smell), and mediate thought and language. Different areas of the brain control different functions (Vahlgren et al., 2007).

Although the brain represents only 2 percent of the body’s weight, it uses about 25 percent of the body’s oxygen supply and 70 percent of the glucose(sugar). Unlike muscles, the brain cannot store nutrients, and thus it requires a constant supply of glucose and oxygen. If the blood supply is interrupted for as little as 30 seconds, unconsciousness results; permanent brain damage may follow in as little as four minutes. The brain’s high metabolic rate, sensitivity to changes in blood flow, and dependence on continuous blood flow are what can make strokes so dangerous. The brain can be divided into three areas: brain stem, cerebellum, and cerebrum. The brain stem controls many of the body’s basic functions, including breathing, chewing, swallowing, and eye movements (Safavi-Abbasi et al., 2006).

The major pathways from the cerebrum—the thinking part of the brain—also pass through the brain stem to the body. The cerebellum, attached to the back of the brain stem, coordinates movements and balance.
The cerebrum is divided into two hemispheres, left and right. In general, the left brain receives input(sensations) from the right side of the body and controls movement on the right side, so that a stroke in the right side of the brain will cause left-sided weakness. Conversely, the right brain controls the left side of the body. Each side of the cerebrum is further divided into four lobes. The frontal lobes control motor function, planning, and expression of language. The temporal lobes are involved with hearing, memory, and behavior. The parietal lobes interpret sensation and control understanding of language.

The occipitallobes perceive and interpret vision. The right and the left sides of the cerebrum are not identical, but rather have specialized functions. In almost all right-handed people and most left-banders, the left brain is “dominant” and performs most language functions. The right side of the brain controls the abilities to understand spatial relations and recognize faces, as well as musical ability. It also helps focus attention (Alexandrov et al., 2004).


Chapter Five


5.0 Recent Advances In The Treatment Of Stroke

The primary goals of stroke treatment have changed, thanks to new drug therapy. Doctors now attempt to halt the progression of the stroke and to prevent recurrence. In years past, when it was believed that all brain cells died after about four minutes without blood flow, stroke was considered to be largely untreatable (Candelise et al., 2007). Spurred on by observations in animals that at least partial recovery can occur after even an hour of complete ischemia (lack of oxygen), researchers have discovered that regions of the brain with very 08106362585minimal blood flow can survive-although they do not function normally-for several hours or perhaps days. These viable cells surrounding an infarct, called the “ischemic penumbra,” are the focus of numerous experimental drug therapies aimed at restoring blood flow or preserving cell function (Candelise et al., 2007).

As researchers learn more about the mechanisms of stroke, they are realizing that it is not simply a lack of blood flow that causes death of tissue; a progression of other processes (including inflammation and toxic buildup), called the ischemic cascade, may play an even greater role in causing lasting necrologic damage. Doctors believe that if they can interrupt this cascade, they may be able to prevent the devastating brain damage that was once the inevitable consequence of stroke.


5.1 Treatment Of Acute Stroke

Most treatment of stroke during the acute phase centers on maintaining fluids and electrolytes (chemical substances in the blood, such as sodium and potassium),avoiding low blood pressure (hypotension),and avoiding the secondary complications of stroke and paralysis. The latter includes pneumonia, urinary tract infections, muscle contractures, and pressure breakdown of the skin (bedsores). The physician willal so attempt to anticipate and avert deterioration after a stroke. This will require constant monitoring and evaluation and may necessitate a number of laboratory
tests. Anticoagulant medications such as heparin are sometimes used to treat an acute ischemic stroke (Diener, 2008).While heparin does not dissolve existing clots, it can prevent the formation of new ones. Thus it may help prevent subsequent strokes, which occur in up to 20percent of ischemic stroke cases.


5.2 Antiplatelet Medications

Platelets are cell fragments that circulate in the blood and play a key role in the formation of clots. Medications that inhibit platelet function, such as aspirin, lessen the tendency of blood to clot. Patients at high risk of stroke are known to benefit in several ways from taking aspirin daily. Aspirin therapy lowers the risk of stroke and stroke-related death.

Unfortunately, aspirin therapy is complicated by the fact that the optimal dose is unknown. If the do seis too low, the aspirin will not have an effect on the platelets; if it is too high, it may cause the blood vessel walls to release chemicals, resulting in the formation of more clots (Hofmeijer et al., 2006). Most authorities recommend between325 and 1,200 mg aspirin per day (one to four tablets),a higher dose than that usually recommended to prevent a heart attack. More recent evidence suggests that doses as low as 80 mg per day may also have a protective effect (WHO, 2010).


5.3 Surgery

The goal in surgery is to provide a pathway for blood to get to the brain. This is most commonly done usinga procedure known as carotid endarterectomy, in which a stenosis (narrowing) or ulceration of an atherosclerotic plaque in the carotid artery is removed.

Similar interim results were released in 1991 from two large studies of carotid endarterectomy. Participants in the study had experienced either a recent TIA or a nondisabling stroke, and each had a carotidartery blockage of more than 70 percent. Participants who underwent endarterectomies showed a sixfold reduction in strokes, compared to those who did not have surgery (Schellinger et al., 2007). This dramatic result suggests that carotid surgery is likely to play a key role in the prevention of recurrent stroke in the coming years.


5.4 Pharmacological Approach

“Neuroprotection” is a term used to describe the putative effect of interventions protecting the brain from pathological damage. Hundreds of neuroprotective strategies have been shown to improve outcome in animal models of focal cerebrali schemia, but thus far none of them have been shown to be clearly efficacious in patients. However, our increasing knowledge concerning the ischemic cascade is leading to considerable development of pharmacological tools suggesting that each step of this cascade might be a target for cyto protection. In stroke, the concept of neuroprotection involves inhibition of a cascade of pathological molecular events which occur under is chemia and lead to calcium influx, activation of free radical reactions, and cell death. Following a vessel occlusion, critical decrease in focal cerebral blood flow promote a complex biochemical cascade with inischemic tissue. This ischemia-induced biochemical cascade interferes with glucose metabolism and causes cell Na+pump failure. These events lead to neuronal depolarization and the release of excitotoxic neurotransmitters which are able to cause abrupt necrotic cell death within the infarct core (Vahlgren et al., 2007). In the surrounding greater volume of the ischemic tissue (the penumbra area), a dynamic process is initiated.

This process also involves intracellular calcium influx, multiple free radical production, and expression of adhesion molecules leading to inflammation and cell death. It is now clear that a stroke causes different types of cell death. Much like an earthquake, a stroke wreaks havoc around its epicenter, destroying cells in a devastating process called necrosis. But farther away from the epicenter, the stroke’s ripple effects cause cells within the penumbra to kill themselves by apoptosis. This slower process can take days, and it ultimately determines the extent of the ensuing spread of brain damage. Programmed cell death is probably the critical process in the evolution of the penumbra are a given that it is the main cause of neuronal death in this region (Jiittler et al., 2007). Besides the morphological and biochemical differences between necrosis and apoptosis, the main differential characteristic is that apoptotic path ways allow pharmacological intervention at the three established stages of programmed cell death: activation, commitment and execution. In the first stage, excitotoxic processes include rising calciumion concentrations and reactive oxygen species formation which promoteapoptotic gene expression.

Mitochondria, through a process mainly regulated bychanges in the permeability of their outer membrane, play a central role in the commitment stage, being considered thepoint-of-no-return. Finally, in the execution stage, degradation enzyme complexes such as caspases, calpains and endonucleases assume an active role. It is typically considered that only by preventing thefirst two stages it is possible to avoid neuronal damage, since acting on the executionstage can delay but not prevent impending cell death.

Another possibility is blocking the intracellular increase in calcium. Voltage dependent Ca2+ channels (L-, N-, T-, PandQ-type) have been widely recognized as an important regulator of the nervous system. Interestingly, several reports havesuggested that a blockade or lack of Ntype Ca2+ channels can suppress the neuronalpathologic processes of ischemic brain injury in animal models. Cilnidipineis a Ca2+ channel blocker with suppressive effects on L- and N-type Ca2+ channelsthat reduced neuronal damage in ischemicrat brains. Takaharaet al. proposed thatthis drug may be suitable for hypertensive patients with a risk of brain attack. Some patients had been enrolled in a multi-center, randomized, double-blind, active control, titrated dose,non-inferiority trial, the Cilnidipine.

Effect on High Blood Pressure and Cerebral Perfusion in Ischemic Stroke Patientswith Hypertension (CHERISH). Comparism was made between the effect of cilnidipine and losartan (angiotensin II receptorblocker) on cerebral blood flow andblood pressure in hypertensive patients with a previous history of ischemic stroke (Alexandrov et al., 2004).

A second approach to block risingintracellular calcium is by buffering intracellularcalcium concentration. We can doso by using a calcium chelator such asDP-b99. DP-b99 is a newly developedlipophilic, cell permeable derivative ofBAPTA (1,2-bis(2-aminophenoxy)ethane-N,N,N’,N’-tetraacetic acid),which selectively modulates the distribution
of metal ions in hydrophobic milieu, and is in clinical development as a neuroprotectant for cerebral ischaemic stroke (Kopito, 2001).

Sodium channel blockers have also been used in stroke therapy. Lubeluzole is a sodium channel blocker with additional effects on nitric oxide. Although a pilot study suggested that this agent was safe and might reduce the death rate in stroke, subsequent clinical trials found no significant effects in reducing deaths or improving outcomes. Fosphenytoin is a well known anticonvulsant agent that blocks voltage-dependent sodium and calcium
channels and prevents glutamate release.

However, its clinical efficacy in is chemicstroke has not been demonstrated. Sipatrigine, a sodium and calcium channel blocker, also failed to have any favorable effect on outcome measures in a phase II clinical trial using a continuous intravenous infusion in acute stroke (Kopito, 2001).

Besides calcium and sodium, reactive oxygen species participate in stroke by activating apoptotic pathways since brain ischemia initiates a complex cascade of metabolic events, several of which involve the generation of nitrogen and oxygen free radicals. In fact, reactive oxygen species activate Bax to induce mitochondrial cytochrome c release and apoptosis in response to chemical ischemia.

Ebselen, a selene-organic compound with antioxidant activity, improves the outcome of acute ischemic stroke. A randomized, double-blind, placebo-controlled trial of ebselen was conducted inpatients with complete occlusion of the middle cerebral artery (Reese, 1998). There was a corresponding significant reduction in the volume of cerebral infarct and an improvement in the outcome of patients who started treatment within 6 hours of onset.
Ebselen might be safe and effective in improving outcomes after stroke, and another clinical trial is under way.

On the other hand, preclinical data on tirilazad in animal models of acute ischemic stroke were neither comprehensive nor consistent. So, when studied in man, tirilazad not only did not improve outcome after stroke, but potentially appeared to marginally worsen it.

Preclinical studies have suggested that albumin has potentially neuroprotective effects. Recent data from a phase dose-escalation study provide evidence that human serum albumin is safe after stroke, despite a mild-to-moderate increase in pulmonary edema, even when given with thrombolytic therapy (Safavi-Abbasi et al., 2006).

The study provided preliminary evidence of efficacy, with patients in the highest dosetiers having about an 80% greater chance of good outcome at 3 months than the lower dose tiers. There also seemed to be a synergistic effect between albumin and thrombolytic therapy. A recently published phase I/II clinical trial confirmed the clinical benefit of albumin administered within 24 hours from symptom onset, showing that these effects were dose- and time-related. A more definitive phase-III trial (Albumin-in-Acute Stroke) is underway (Reese, 1998; Safavi-Abbasi et al., 2006).


5.5 Alternative Stroke Treatment

Alternative stroke treatment may not work for everyone as long as the doctor has given the go-ahead to try these approaches in addition to following the prescribed medications and therapy. Here are some alternative stroke treatment ideasand how they can help: (Jiittler et al., 2007)

Acupuncture:

Is an ancient practice in which tiny needles are inserted painlessly in the skin at designated points to stimulate your body’s nerves and muscles. Acupuncture can help to relieve pain and get your blood flowing more — and balance your energy, Asian cultures believe (Jiittler et al., 2007). Acupuncture can be used to help treat difficulties with language and swallowing, as well as paralysis. Acupuncture is a common part of stroke treatment in Japan and China.

Massage:

A study in Hong Kong found that regular massage lowered blood pressure and heart rate in stroke patients, and also eased anxiety. Massage is known to help with stress reduction and combat feelings of depression, both of which are common emotional health concerns of stroke patients. Keeping stress and depression under control is an important part of stroke treatment, for both mental and physical well-being (Safavi-Abbasi et al., 2006).

Herbal medicines:

There are studies being done to determine whether commonly used Chinese herbal medicines are actually effective as stroke treatments. It is thought that these medicines may boost blood flow in the brain and offer other protective benefits against ischemic stroke. But use caution: Further testing needs to be done because studies to date just don’t show enough evidence to either support or oppose using these medications. Some herbal medicines that need further study include Ginkgo biloba, Mailuoning, Xuesetong, Ligustrazine, and Acanthopanax (Safavi-Abbasi et al., 2006; Jiittler et al., 2007).

Aromatherapy:

The benefits of aromatherapy as stroke treatment have not been extensively studied, but one very small recent study did consider the use of aromatherapy along with acupressure (another alternative method involving applying pressure to certain points on the body to relieve pain and other symptoms). Researchers used lavender, peppermint, and rosemary fragrances in conjunction with acupressure, and found that it relieved pain better than acupressure without aromatherapy (Safavi-Abbasi et al., 2006).


Recent Advances In The Treatment Of Stroke


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