Stroke

Abstract

Stroke as the second leading cause of death after ischemic heart disease is a preventable and treatable disease; however, it has become a global epidemic of the 21st century. Inadequate delivery of blood supply to the brain causes the cerebrovascular accident or stroke and can potentially lead to functional impairments, severe brain damage, and, consequently, death. Common long-term effects include contralateral limb paralysis, memory loss, and cognitive impairment. The introduction of brain imaging technology has revolutionized the diagnosis of stroke. This has been followed by a gradual decrease in the occurrence of stroke in developed countries; however, it is still a burden in low- and middle-income countries. Due to the limited effectiveness of stroke treatment options, the main approach for stroke management has become secondary prevention. This strategy focuses on controlling risk factors such as hypertension, high LDL cholesterol levels, and diabetes. The range in orofacial clinical manifestations of stroke is determined by size and location of the affected brain region. The most prevalent signs and symptoms include sensory and motor deficits: facial droop, paresis in extraocular muscles and eye movements, slurred speech, seizures, and neurocognitive deficits. Because of the potential adverse drug reactions, it is crucial that prior to any surgical or procedure treatment, close collaboration between health practitioners occurs to assess the bleeding risks of continued anticoagulant medication against the risk of post-thrombosis in ceasing anticoagulant medication.

Background of Stroke

Despite being a preventable and treatable disease, stroke has become a global epidemic of the 21st century. In 2010, an estimated 16.9 million stroke incidents occurred, of which 5.9 million lives were lost; this makes stroke the second leading cause of death after ischemic heart disease.¹ Caused by an inadequate blood supply to the brain, cerebrovascular accident or stroke can potentially lead to functional impairments, severe brain damage, and, consequently, death.² Common long-term effects include contralateral limb paralysis, memory loss, and cognitive impairment.²

Evidence accumulated over the past 20 years has negated the conventional perception of stroke as merely a consequence of aging.³ In the 1970s, evidence showed that aspirin could prevent stroke, followed by the establishment of the first stroke unit in 1975 and subsequently, the introduction of brain imaging technology, which has revolutionized stroke diagnosis.³ Although there has been a gradual decrease in stroke occurrence in developed countries, 85% of the global burden of stroke is carried by low- and middle-income countries.⁴ This has ledcurrent research to steer more toward further effective primary and secondary prevention strategies, cooperation among major government and nongovernment stakeholders, and incorporation of stroke management education and training for healthcare professionals.⁴

Due to the limited effectiveness of stroke treatment options, the main approach for stroke management has become secondary prevention. This strategy focuses on controlling risk factors such as hypertension, high LDL cholesterol levels, and diabetes.⁵

This chapter discusses the diagnosis, epidemiology, pathological, and genetic factors, as well as current available medical and dental treatment and prevention strategies of cerebrovascular accidents.

Description of Stroke

Stroke is defined as an “acute episode of focal disturbance of cerebral function” that lasts longer than 24 hours or of any duration if “diagnostic imaging shows any focal haemorrhage.”¹

There are two major classifications of stroke: ischemic stroke and hemorrhagic stroke.

Ischemic Stroke

Eighty-five percent of strokes are ischemic, which is caused by abrupt blockage of a cerebral artery leading to insufficient blood supply to a part of the brain.² Ischemic strokes can be classified as thrombotic or embolic. Thrombotic strokes are caused by a blood clot (thrombus) formation that blocks an artery supplying blood to the brain.² In embolic strokes, the blood clot is carried from another part of the body through the bloodstream to the brain, where it is lodged in the arteries.²

Hemorrhagic Stroke

A hemorrhagic stroke occurs due to the rupture of a blood vessel in the brain, causing bleeding in the surrounding tissue.⁶ Due to the increased blood pressure inside the artery, as it bursts, it may potentially damage the surrounding tissue.⁶ This results in a larger clot that places pressure on the brain, ultimately causing brain death. There are two main subtypes of hemorrhagic stroke, intracerebral and subarachnoid.⁶

In an intracerebral hemorrhage (ICH), bleeding within the brain exerts pressure on the surrounding tissues.⁶ Common causes include high blood pressure, bleeding disorders, and blood vessel deformities such as aneurysm. In the subarachnoid hemorrhage (SAH), a blood vessel on the surface of the brain ruptures, and the blood from the ruptured vessel accumulates in the subarachnoid space.⁶ Due to the blood build-up, pressure within the space increases, causing a common symptom of SAH called “thunderclap headache,” one of the most severe headaches described by patients.⁶

Transient ischemic attacks are strokelike episodes (having the same symptoms) that last for a short time, usually within 24 hours.²

Epidemiology of Stroke

Cerebrovascular accident (stroke) was the third leading cause of death in 2015.⁷ In 2015, fifteen million people worldwide suffered from stroke; 5 million of these cases passed away while 5 million were left with permanent disability.⁵ It was estimated, in 2001, that the number of deaths attributed to stroke was approximately 5.5 million worldwide. Two-thirds of these deaths occurred in developing countries, and the subjects were less than 70 years old in 40% of these deaths.⁸ Over 80% of strokes occur in people aged 65 years and older.⁹ Stroke was the cause of 9.4% of deaths in Australia in 2001. On top of these mortality figures, stroke is also a leading global cause of permanent disability. In 2001, cerebrovascular disease contributed 2.2% of the morbidity rate in people aged 55 and older.¹⁰ The burden of stroke is estimated to increase from 38 million disability-adjusted life years (DALYs) in 2000 to 61 million DALYs in 2020.⁵ The average age when stroke occurs in developed countries is approximately 73 years, and it may be associated with the aging population within these countries. However, in developing countries, the average age of stroke occurrence is younger, due to different competing causes of death in these countries, such as communicable disease.⁸ It has been reported that in countries with a higher gross domestic product (GDP) per capita, women and men experience cardiovascular events, such as stroke, at an older age than those with a lower GDP per capita.¹¹

The prevalence of each type of stroke is seen to vary between different populations. For example, studies in the 1990s in Caucasian populations found that approximately 80% of strokes are ischemic, while 10 to 15% were ICH and 5% SAH. The remaining percentages were due to other causes of stroke. On the other hand, studies in Asian populations have indicated a higher incidence of ICH causing 20 to 30% of all strokes in those countries.⁸ In addition, ICH has been demonstrated as the most fatal form of stroke in the United States, causing the highest proportion of in-hospital mortality due to stroke between 1997 and 2006.¹² Following coronary heart disease, stroke was considered the second highest cause of mortality due to cardiovascular disease in the United States in 2007.¹²

In 2015, stroke was the third leading cause of years of life lost (YLLs), whereas it was the fifth leading cause of YLLs in 2000.⁷ The average YLLs due to stroke around the world was similar for males and females, at approximately 6 years per 1,000 men and women in 2000.⁸

Important risk factors for stroke include hypertension, body mass index (BMI), age, and blood cholesterol concentration.¹³ Tobacco use is also an important modifiable risk factor.¹⁴ Hypertension is closely associated with the development and severity of a stroke attack. Individuals who suffer from hypertension are more susceptible to stroke, as it predisposes atherosclerosis that promotes the formation of a cerebral embolism in the event of plaque rupture.⁹ It can also be seen that alterations in vasculature with age render individuals more susceptible to the damaging effects of cardiovascular diseases, including stroke. The risk of stroke doubles for every 7.5 mm Hg increase in the diastolic blood pressure, and thus, the use of different antihypertensives have been shown to reduce the risk of stroke by 38%.¹⁵ These risk factors have been proven by findings in cohorts of women and men in the United States, which have recognized that individuals with a healthier lifestyle: abstaining from smoking, participating in regular exercise, moderate alcohol consumption, and not being overweight, contributed to approximately an 80% lower risk of ischemic stroke compared to individuals not participating in any of these healthier behaviors.¹¹

Most of the risk factors for cerebrovascular accident can be classified into inherent biological traits, behaviors, and social, environmental, and medical factors. Examples of inherent biological traits include age, sex, and physiological characteristics such as blood cholesterol levels and blood pressure whereas behavior encompasses diet and physical activity. Social factors such as education and ethnicity, and environmental factors including altitude and temperature, geographical or psychosocial environments, can also contribute to the risk of stroke. Medical factors, such as previous stroke, ischemic heart disease, atrial fibrillation, carotid stenosis, cardiovascular diseases, or glucose intolerance, are also important indicators that can predispose the development of stroke.⁸

Etiology and Pathogenesis of Stroke

Cerebrovascular accident (stroke) is of multifactorial etiology, which is why the pathogenesis of ischemic stroke is closely associated with multiple risk factors, including hypertension, atherosclerosis, and hyperlipidemia (Fig. 6.1). The most common cause of ischemic stroke is the narrowing of arteries within the head and neck.¹⁶ On the other hand, the pathogenesis of ICH involves degenerative changes within smooth muscle and endothelial cells.¹⁷

Fig. 6.1 Etiology of stroke.

Hypertension promotes the formation of atherosclerotic plaques within medium-to-large arteries and microatheroma in smaller arteries. As a chronic disease directly influenced by diet, atherosclerosis can cause a high degree of arterial stenosis that leads to ischemic stroke symptoms. The narrowing of smaller arteries can also be emphasized due to the proliferation of endothelial cells and the hypertrophy of smooth muscles.¹⁸ Plaques that are the most vulnerable to rupture are built of a large lipid core, composed of more than 40% low-density lipoprotein-filled foam cells, as well as a thin, fibrous cap of depleted smooth muscle cells. Macrophage infiltration is as well a characteristic of atherosclerotic plaques, contributing to the vulnerability of the plaque to rupture.¹⁶

Furthermore, small noncoding microRNAs (miRNAs) have been showed to contribute to stroke etiology. miRNA can modulate the pathogenesis of atherosclerosis (miR-21, miR-26), hyperlipidemia (miR-33, miR-125a-5p), hypertension (miR-15), and plaque rupture (miR-222, miR-210), which are all risk factors for the development of stroke. miRNA directs macrophage recruitment to atheromatous plaque vascular adhesion molecule-1 (VCAM1), expressed in human conditions, which promotes atherosclerosis formation. The decreased expression of miR-126 upregulates VCAM1 expression that enhances leukocyte adherence to the vascular endothelium. This, thereby, leads to leaky vessels, hemorrhage, partial embryonic lethality due to the loss of vascular integrity, and defects in endothelial cell proliferation, migration, and angiogenesis.¹⁶

When considering changes in the blood vessel lumen, it is also important to consider adaptive structural changes relating to resistance within the vessel. When hypertension occurs, collateral blood vessels adapt via increasing the total peripheral resistance and, as a consequence, compromise the collateral circulation. This thus increases the risk of ischemic events such as stroke in connection with the hypotension occurring distal to the stenosis.¹⁷

Although there is a clear link that stroke is the manifestation of hypertension, atherosclerosis, and other cardiovascular diseases, the pathogenesis of stroke can also be as a result of the interactions of genes with environmental determinants. For example, a link has been made between the pathogenesis of multifactorial forms of stroke and genes that encode hormones affecting the cardiovascular system such as atrial natriuretic peptide (ANP).¹⁹

Genetic Component of Stroke

Cerebrovascular accidents are considered to be a syndrome, rather than a single disease, with its onset being primarily attributed to preexisting conditions. Obesity, diabetes, atrial fibrillation, coronary heart disease, and cholesterol are examples of risk factors and account for up to 60% of stroke cases. The other 40% of risk factors are of either an unknown origin or attributed to rare genetic mutations, which are categorized into single or polygenic disorders.²⁰ When referring to strokes as a cause of genetic factors, this encompasses the manifestation of contributing predisposing diseases as well as hereditary stroke syndromes.

Predisposing Disease

Atrial Fibrillation

Atrial fibrillation, a type of arrhythmia, is considered to be a contributing factor and therefore sufferers are at a greater risk for the development of a stroke. Genome-wide association studies have concluded that atrial fibrillation is the most frequent cause of cardioembolic stroke, a subtype of ischemic stroke. In addition, no other significant relationships were determined between atrial fibrillation and other stroke subtypes. Two genes have been identified in which mutations are associated with atrial fibrillation, gene PITX2 on 4q25, and gene ZFHX3 on 16q22.²¹

Coronary Artery Disease and Associated Diseases

Coronary artery disease has shown to be associated with large-artery stroke; this correlation is attributed to single nucleotide polymorphism (SNPs) of the chromosome region 9p21.²² Interestingly, mutations along the same locus have also been associated with intracranial and abdominal aneurysms, both of which are risk factors for strokes. Genes on this locus include CDK2MA and CDK2MB, variants of these genes are noncoding DNA sequences, an indication that mutations are determined by influences on gene expression.²¹

Single-Gene Disorder—Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL)

CADASIL is a single-gene disorder, in which its mode of inheritance is autosomal dominant. Of the monogenic disorders, CADASIL is the most common form of small vessel disease stroke. Offspring that present with this condition are characterized by deterioration of vascular smooth muscles cells. This is followed by arteriopathy causing impaired blood flow accompanied by blurred vision, migraines, and epilepsy. The reduction of blood flow in. the brain induces infarcts in 70% of CADASIL cases; recurrent strokes are also common.²³

CADASIL is thought to be the result of a mutation of the gene NOTCH3, which is essential for the regulation of blood vessel health. Pathogenic mutations of NOTCH3 have shown to increase the deposition of cysteine within the blood vessels, due to an increase of this amino acid in the extracellular domain of NOTCH3.²¹ However, little is known about the significance of this accumulation. Other studies have suggested that a defective NOTCH3 gene causes the accumulation of granular osmiophilic material within the vessels of the brain, damaging the white matter and obstructing blood flow.²⁴

Among individuals with CADASIL, including family members, there is a high degree of phenotypic variation. Therefore, utilizing genotypes does not provide an accurate representation of an individual’s phenotype.²⁵ Disparities among sufferers include the age of stroke onset, disease development, and prognosis.

Polygenic Disorder—Homocysteinemia

Homocysteinemia is an autosomal recessive inherited condition, which is characterized by elevated blood homocysteine levels. As it is a polygenic-induced condition, an interplay between various genetic and environmental factors is necessary for phenotypes to be expressed. Consequences of a marked increase in homocysteine levels can lead to the development of carotid stenosis, along with increased plaque thickness within the carotid artery. Therefore, homocysteinemia is a causative factor contributing to the manifestation of a stroke (large- and small-vessel disease subtype).²¹

Hyperhomocysteinemia cases are primarily the cause of abnormal metabolism of methionine; this is exacerbated by factors such as vitamin B12 and folate deficiencies along with renal failure.²⁶ Homocysteine levels are governed by the genes methylene-tetrahydrofolate reductase (MTHFR) and cystathionine-beta synthase (CbS); thus, polymorphism of these genes is associated with varied homocysteine levels. Common mutations include substitution of the gene responsible for encoding MTHFR, c.677C4T, as well as nucleotide variation of c.833C4T and c.919G4A on the CbS gene. More than 60 mutations related to both CbS and MTHFR genes have been discovered, resulting in moderate hyperhomocysteinemia.²⁶

The genetic causes of strokes are extensive, many of which are unknown and require additional research. Despite the few examples listed in this chapter, a vast array of gene disorders contribute to its manifestation. This serves to emphasize the complexity, modes of inheritance, and genes involved as causative factors for the development of a stroke.

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