Stroke

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Stroke

Stroke follows heart disease and cancer as the third leading cause of death in developed countries, accounting for 10% of overall mortality in the UK. It is defined clinically as an acute neurological deficit of vascular origin that lasts more than 24 hours or causes death.

Types of stroke

Stroke is caused by inadequate tissue perfusion or ischaemia (Greek: isch-, restriction; haema, blood). The brain is particularly sensitive to ischaemia because neurons have a high metabolic rate and can only survive a few minutes without oxygen and glucose. Tissue death as a result of inadequate blood flow (e.g. due to an occluded blood vessel) is called infarction (Latin: infarctus, stuffed). The area of dead tissue is referred to as ‘an infarct’. There are two main types of stroke (Figs 10.1 and 10.2):

Fig. 10.1 Ischaemic stroke.
**(A)** Photograph taken during a post-mortem examination in a patient with an old (‘healed’) left hemisphere ischaemic infarct in the territory of the middle cerebral artery. Extensive resorption of brain tissue (leaving only a fluid-filled cyst cavity) indicates a prolonged period of survival after the stroke; **(B)** Coronal section of a fixed (preserved) brain slice in a different patient showing an old ischaemic stroke, also in the territory of the middle cerebral artery. From Ellison and Love: Neuropathology 2e (Mosby 2003) with permission.

Fig. 10.2 Haemorrhagic stroke.
**(A)** Coronal sections showing a typical hypertension-associated haemorrhagic stroke replacing the basal ganglia; **(B)** Coronal section showing an atypical (‘lobar’) haemorrhage due to cerebral amyloid angiopathy affecting the cortical and meningeal arteries. Note the superficial (cortical) position of the atypical haemorrhage. From Ellison and Love: Neuropathology 2e (Mosby 2003) with permission.

Ischaemic stroke (85% of cases) is caused by reduced blood flow to a particular part of the brain, usually following occlusion of a cerebral artery.

Haemorrhagic stroke (15% of cases) is due to a ruptured blood vessel. This is commonly associated with high blood pressure and diseases that weaken the arterial wall.

In both types of stroke the brain tissue normally supplied by the vessel is suddenly deprived of blood and its function is lost. This causes focal neurological deficits that develop very rapidly (e.g. sudden weakness or loss of speech) and abrupt onset is the clinical hallmark of stroke. In haemorrhagic stroke, there may also be mechanical damage, such as tearing and compression of brain tissue, caused by blood escaping under arterial pressure.

Key Points

Stroke follows heart disease and cancer as the third leading cause of death in developed countries, accounting for 10% of overall mortality in the UK.

It is defined as an acute neurological deficit of vascular origin that lasts more than 24 hours or causes death. Abrupt onset is the clinical hallmark of stroke.

The two main types of stroke are ischaemic (85%) and haemorrhagic (15%); in most cases, inadequate tissue perfusion (ischaemia) leads to death of brain tissue (infarction).

Ischaemic stroke

Ischaemic stroke can be divided into five groups based on cause: (i) large-artery atherosclerosis; (ii) cardioembolism; (iii) small vessel occlusion; (iv) other defined cause; and (v) unknown cause (cryptogenic stroke). This classification is derived from a multicentre trial of acute stroke treatment (‘TOAST’) in the 1990s and continues to be widely used in UK stroke trials. The ‘other defined cause’ category incorporates many uncommon and rare causes of stroke including abnormalities of blood coagulation, infectious diseases, arterial damage and inflammatory disorders.

Large vessel and cardioembolic stroke

Cerebral blood vessels may be occluded by an embolus (Greek: embolos, wedge or plug). This is a small piece of coagulated blood (or occasionally some other material such as fat) that travels in the circulation and lodges in the vascular tree of the brain. Emboli often originate from the heart (cardioembolic stroke) in association with valve disease or an abnormal heart rhythm (Clinical Box 10.1). Disease in the neck vessels or aortic arch may also give rise to emboli.

Clinical Box 10.1: Atrial fibrillation

This is the most common type of abnormal heart rhythm, affecting 1% of people over the age 65 and 10% of those over 80. It is characterized by disorganized atrial contraction (fibrillation) with an irregular heartbeat. There may be palpitations, fainting episodes or chest pain, but it is often asymptomatic. Blood tends to pool and coagulate in the poorly contracting atria, increasing the risk of cardioembolic stroke (from the left atrium to the brain) up to ten-fold. Predisposing factors for atrial fibrillation include hypertension, heart disease, hyperthyroidism and excessive alcohol consumption. It can be treated with anticoagulants (e.g. warfarin or newer agents such as the direct thrombin inhibitor dabigatran). Alternatively, drugs may be given to control the heart rate if it is fast (which can compromise cardiac output) or a defibrillator can be used to restore a normal heart rhythm (called cardioversion).

Some ischaemic strokes are caused by coagulation of blood within a cerebral vessel, termed in situ thrombosis (Greek: thrombos, blood clot) or large artery intracranial occlusive disease. This is more common in people of Asian and African origin, but is increasingly recognized in Caucasians.

Small vessel disease

Small vessel disease is particularly common in patients with arterial hypertension together with other vascular risk factors (e.g. diabetes, cigarette smoking, elevated cholesterol). High blood pressure damages the arterial wall and its smooth muscle is gradually replaced by collagen, termed hyaline arteriosclerosis. In some cases there is vessel wall necrosis with accumulation of lipid-laden foam cells, which is referred to as lipohyalinosis.

Both types of pathology cause arteriosclerosis or ‘hardening’ of the arteries (Greek: sklerōs, hard). Sclerotic vessels are unable to dilate in response to reduced flow, leading to lacunar infarcts (see Ch. 12, Figs 12.18 and 12.19). These are small areas of ischaemic tissue damage (often in the basal ganglia or internal capsule) measuring less than 1 cm in diameter (Latin: lacūna, hole or gap). Small vessel disease is also an important cause of vascular cognitive impairment and dementia (Ch. 12).

Transient ischaemic attacks

A brief period of cerebral ischaemia may cause a reversible neurological deficit that resolves when the blood flow is restored. This is a transient ischaemic attack (TIA). Involvement of the retinal blood supply causes temporary blindness in one eye, termed amaurosis fugax (Greek: amaurosis, dark; Latin: fugax, fleeting). Symptoms usually resolve within minutes (and never last more than 24 hours, by definition) but neuroimaging evidence suggests that permanent damage occurs in 10–20% of cases. TIAs are associated with increased risk of both stroke and heart attack.

Haemorrhagic stroke

Spontaneous intracerebral haemorrhage is more common in people with high blood pressure and frequently occurs in the basal ganglia, cerebellum or pons (Fig. 10.2A). However, the incidence of hypertensive intracerebral haemorrhage is declining in the UK and USA and an increasingly important cause is cerebral amyloid angiopathy, particularly in the elderly (see Ch. 12, Clinical Box 12.5). This is caused by deposition of amyloid beta peptide in the walls of cortical and meningeal arteries, leading to atypical (or lobar) haemorrhages that are close to the cortical surface (Fig. 10.2B).

Up to a third of spontaneous intracranial haemorrhages are caused by rupture of an aneurysm (a dilatation in the wall of an artery). Since the cerebral blood vessels travel and branch within the subarachnoid space, this results in subarachnoid haemorrhage (Clinical Box 10.2). Aneurysms that rupture in the substance of the brain may cause devastating brain damage or sudden death.

Clinical Box 10.2: Subarachnoid haemorrhage

Bleeding into the subarachnoid space accounts for a third of intracranial haemorrhages. Although this does not necessarily cause a focal neurological deficit, subarachnoid haemorrhage is normally regarded as a type of stroke, accounting for 5% of cases overall. It classically presents with a severe headache (‘the worst headache I have ever had’). The most common cause is a ruptured berry aneurysm, a medical emergency with a high mortality rate (Fig. 10.3). Berry aneurysms are small vascular swellings which develop at congenital weak spots in the arterial wall. They are usually found at points where blood vessels branch, especially in the circle of Willis at the base of the brain. Ischaemic stroke may occur as a late complication. This is due to blood in the subarachnoid space acting as an irritant and triggering vasospasm. Unruptured berry aneurysms are found incidentally in up to 2% of post-mortem examinations.

Fig. 10.3 Subarachnoid haemorrhage.
Post-mortem photograph of the brain (ventral aspect) in a patient who collapsed and died after a sudden, severe headache. The subarachnoid space at the base of the brain is filled with fresh blood, obscuring the circle of Willis. *Inset*: after removal of the blood a ruptured berry aneurysm was found in the region of the anterior communicating artery, indicated by the pointer. From Ellison and Love: Neuropathology 2e (Mosby 2003) with permission.

Key Points

Cerebral blood vessels are most commonly occluded by emboli. These are often cardiogenic (e.g. due to atrial fibrillation or valve disease) but may also arise from the aortic arch or neck vessels.

Small vessel disease is associated with hypertension and other cardiovascular risk factors. In addition to stroke, it is an important cause of vascular cognitive impairment and dementia.

Large artery intracranial occlusive disease (in situ thrombosis) is often associated with vessel wall disease, leading to a regional infarct. It is more common in people of African and Asian origin.

Brief periods of cerebral ischaemia cause transient ischaemic attacks which usually resolve within a few minutes and never last more than 24 hours (by definition).

Spontaneous intracerebral haemorrhage is more common in people with arterial hypertension and frequently occurs in the basal ganglia, cerebellum or pons. Cerebral amyloid angiopathy is an increasingly recognized cause, leading to ‘atypical’ (superficial/lobar) haemorrhages.

Subarachnoid haemorrhage usually presents with a sudden, severe headache and is most often due to a ruptured berry aneurysm. It is a medical emergency with a high mortality rate.

Blood supply to the brain

The brain is supplied by two pairs of arteries that arise from branches of the aortic arch (Fig. 10.4):

Fig. 10.4 MRI-angiogram showing the aorta and neck vessels. Note that the right common carotid and right subclavian arteries [seen here on the left side of the image, following radiological convention] both arise from a single brachiochephalic artery. In contrast, the left common carotid and left subclavian arteries each arise separately as direct branches of the aortic arch. Courtesy of Dr Andrew MacKinnon.

The internal carotid arteries ascend in the anterior part of the neck, arising from the bifurcation of the common carotid arteries.

The vertebral arteries arise from the subclavian arteries and ascend in the lateral cervical region, passing through foramina in the transverse processes of the upper six cervical vertebrae.

The arteries at the base of the brain are linked by communicating vessels to form the circle of Willis. This gives rise to anterior, middle and posterior cerebral arteries on each side, which supply most of the cerebral hemisphere. The cerebral blood supply can be divided into anterior and posterior circulations (Fig. 10.5A).

Fig. 10.5 The anterior and posterior circulations and their origins from the circle of Willis.
**(A)** Schematic, two-dimensional, representation of the circle of Willis, showing the anterior (internal carotid) and posterior (vertebrobasilar) circulations; **(B)** Illustration of the three-dimensional arrangement of the circle of Willis.

Anterior circulation

The internal carotid artery divides at the base of the brain, giving rise to the middle cerebral artery (MCA) and the anterior cerebral artery (ACA). The MCA is the larger of the two and receives 80% of the internal carotid blood flow. For this reason, cardiogenic emboli are much more likely to enter the MCA than the ACA. The middle cerebral artery continues laterally between the frontal and temporal lobes and emerges from the lateral sulcus to supply most of the hemispheric convexity (Figs 10.6A and 10.7).

Fig. 10.6 The anterior, middle, posterior and lenticulostriate arteries.
**(A)** Coronal view of the cerebral hemisphere showing the anterior and middle cerebral arteries. The lenticulostriate (deep perforating) vessels can be seen arising at right-angles from the middle cerebral artery; **(B)** Midsagittal view of the cerebral hemisphere showing the anterior and posterior cerebral arteries.

Fig. 10.7 Lateral view of the cerebral hemisphere showing the vascular territories of the middle, anterior and posterior cerebral arteries.
The dashed line indicates the arterial watershed zone between the main vascular territories.

The anterior cerebral artery passes forward and medially to meet its partner between the cerebral hemispheres. It winds around the corpus callosum and supplies the medial aspect of the hemisphere as far back as the parieto-occipital sulcus (Figs 10.6 and 10.8). Posterior to this point the posterior cerebral artery takes over to supply the occipital lobe. Perforating branches of the anterior circulation supply the optic radiations, so that anterior circulation strokes may cause a contralateral visual field defect.

Fig. 10.8 Medial view of the cerebral hemisphere showing the vascular territories of the middle, anterior and posterior cerebral arteries.
The dashed line indicates the arterial watershed zone between the main vascular territories.

Posterior circulation

The posterior circulation supplies the remainder of the cerebral hemisphere and the posterior fossa contents (brain stem and cerebellum). The two vertebral arteries unite in front of the brain stem, at the junction between pons and medulla, to become the basilar artery. For this reason, the posterior circulation is also known as the vertebrobasilar circulation. The basilar artery ascends along the basal pons to reach the midbrain where it splits into the two posterior cerebral arteries (PCA). These vessels wind around the midbrain and pass posteriorly, above the tentorium cerebelli, to supply the occipital lobe and the inferior surface of the temporal lobe (Figs 10.6B, 10.7 and 10.8).

Circle of Willis

The circle of Willis is a polygonal arrangement of blood vessels surrounding the optic chiasm and pituitary stalk. It connects the anterior and posterior circulations via the single anterior communicating artery and the paired posterior communicating arteries (Figs 10.5B and 10.9). The circle of Willis shows considerable anatomical variation and is incomplete in 50% of people. It is an example of a collateral circulation, an arrangement of interconnected vascular channels permitting blood flow via an alternative route in the event of an obstruction. Interconnections between vessels exist elsewhere (e.g. between the distal territories of the three main cerebral blood vessels) but are not always effective, particularly in the elderly. Some structures do not have a collateral blood supply (e.g. the internal capsule and basal ganglia) and are therefore more vulnerable to stroke.

Key Points

The anterior (internal carotid) and posterior (vertebrobasilar) circulations are united at the base of the brain to form the circle of Willis. This is an example of a collateral circulation.

The circle of Willis is formed by a single (short) anterior communicating vessel and two (long and thin) posterior communicating vessels.

The internal carotid artery divides at the base of the brain to become the middle cerebral artery (which passes laterally) and anterior cerebral artery (passing anteriorly and medially).

The MCA receives 80% of the carotid blood flow and the ACA receives 20%. Cardiogenic emboli are therefore more likely to enter the MCA than the ACA territory.

The MCA supplies the lateral surface of the cerebral hemisphere, whereas the ACA supplies the medial surface as far back as the parieto-occipital sulcus.

The posterior cerebral artery is the terminal branch of the basilar artery. The territory of the PCA includes the occipital lobe and the inferior surface of the temporal lobe.

Perforating vessels

The circle of Willis gives rise to a number of central perforating vessels which supply the internal substance of the brain. Perforating vessels from the anterior circulation enter the brain just lateral to the optic chiasm on each side, via the anterior perforated area. A second group arises from the posterior circulation and enters the brain at the interpeduncular fossa of the midbrain, via the posterior perforated area. The anterior group includes the lenticulostriate vessels (or ‘arteries of stroke’) which supply the basal ganglia and internal capsule (Fig. 10.6A). They are an important site of spontaneous intracerebral haemorrhage and lacunar infarcts (both caused by small-vessel disease).

The arterial territories of the three main cerebral vessels and deep perforating vessels are illustrated in coronal section in Figure 10.10. The regions between territories are the watershed zones and are particularly vulnerable to a sudden reduction in arterial blood pressure. This may lead to a characteristic pattern of watershed infarction at the arterial border zones following profound arterial hypotension (e.g. after cardiorespiratory arrest, anaphylactic shock or major blood loss).

Fig. 10.10 Coronal section of the cerebral hemispheres showing the vascular territories of the middle, anterior and posterior cerebral arteries and the watershed zones between them.
The grey zone is supplied by deep (perforating) branches of the circle of Willis.

Blood supply to the brain stem

The midbrain, pons and medulla are supplied from the posterior circulation by small perforating vessels, most of which are not named. They are arranged in three groups: (i) paramedian; (ii) short circumferential; and (iii) long circumferential. The paramedian vessels pass directly backwards through the full thickness of the brain stem (to the ventricular floor) to supply a portion of the pons and medulla on either side of the midline. The short and long circumferential vessels encircle the brain stem to supply more lateral and posterior portions.

Blood supply to the cerebellum

The cerebellum is supplied by three long circumferential vessels that arise from different parts of the posterior circulation (Figs 10.9 and 10.11):

The superior cerebellar artery (SCA) arises from the upper part of the basilar artery, immediately below the origin of the posterior cerebral artery.

The anterior inferior cerebellar artery (AICA) is a caudal (inferior) branch of the basilar artery.

The posterior inferior cerebellar artery (PICA) usually arises from the vertebral artery.

The posterior inferior cerebellar artery also supplies the lateral medulla. Occlusion of this vessel is associated with the lateral medullary syndrome (Clinical Box 10.3).

Clinical Box 10.3: Lateral medullary syndrome

Occlusion of the posterior inferior cerebellar artery (PICA), supplying the lateral part of the medulla, causes: (i) ipsilateral loss of pain and temperature sensation in the face; and (ii) contralateral loss of pain and temperature sensationin in the trunk and limbs. This results from damage to the trigeminal sensory nucleus and spinothalamic tract respectively (see Ch. 4). Sympathetic fibres passing from the hypothalamus to the spinal cord may also be affected, leading to loss of sympathetic innervation to the ipsilateral face. This is one cause of Horner’s syndrome, characterized by ptosis (drooping eyelid), miosis (small, constricted pupil) and facial anhidrosis (loss of sweating). Other features of the lateral medullary syndrome reflect damage to local brain stem structures and connections with the cerebellum: difficulty swallowing, double vision, poor coordination, vertigo and nausea.

Stroke syndromes

For practical purposes, ischaemic strokes can be classified into one of four major clinical categories based on the maximum deficit following a single stroke, illustrated in Figure 10.12:

Total anterior circulation syndrome (TACS).

Partial anterior circulation syndrome (PACS).

Posterior circulation syndrome (POCS).

Lacunar syndrome (LACS).

This system is easy to use and provides useful prognostic information. For example, the proportion of patients dying within the first year in each type is approximately 60% (TACS), 20% (PACS or POCS) and 10% (LACS). In the first week after a stroke, the most common cause of death is raised intracranial pressure due to brain swelling (cerebral oedema); this causes herniation of the cerebellar tonsils through the skull base, compressing the brain stem (which is referred to as ‘coning’, see Ch. 9).

Key Points

The watershed areas between the territories of the main named cerebral arteries are vulnerable in the event of very low blood pressure, leading to a ‘watershed infarction’.

Perforating branches of the anterior, middle and posterior cerebral arteries (and circle of Willis) supply the basal ganglia, thalamus and internal capsule.

The lenticulostriate vessels (‘arteries of stroke’) are prone to hypertension-associated small vessel disease and are a common site of spontaneous intracerebral haemorrhage.

The brain stem is supplied from the posterior (vertebrobasilar) circulation, via three groups of artery: paramedian, short circumferential and long circumferential.

The cerebellum is supplied by three long circumferential vessels, the: superior cerebellar artery (SCA), anterior inferior cerebellar artery (AICA) and posterior inferior cerebellar artery (PICA).

Atherosclerosis

The underlying pathology in a significant proportion of cerebrovascular (and cardiovascular) disease is atherosclerosis. This is a degenerative process affecting medium and large arteries throughout the body (Greek: sklērōsis, hardening). It is almost universal in the developed world, chiefly as a result of lifestyle factors including poor diet, cigarette smoking and lack of exercise.

Atheromatous plaques

The characteristic lesion in atherosclerosis is called an atheroma (from the Latin word for porridge). This is a deposit of lipid-rich material in the vessel wall that develops over many years. The process begins in the innermost (intimal) layer of large arteries and slowly expands. Atheromatous deposits therefore cause progressive stenosis (narrowing) of the vessel (Fig. 10.13). This gradually impinges on the lumen, but may remain asymptomatic for many years. The precursor lesions in atherosclerosis are known as fatty streaks. These are pale areas beneath the arterial endothelium that can be identified in the arteries of children and consist of lipid-laden macrophages.

Fig. 10.13 Effect of atheroma on arterial blood flow.
In a normal artery, the blood flow is smooth and laminar, but development of atheromatous plaques causes progressive stenosis (narrowing) of the arterial lumen and leads to abnormal, turbulent blood flow.

The distribution of atheromatous plaques is not random. Areas exposed to rapid, turbulent blood flow are particularly susceptible, especially arterial branch-points. These include the aortic arch and large arteries of the neck, both of which may be a source of emboli to the brain (Clinical Box 10.4). Atherosclerosis is also common in the intracranial portion of the internal carotid artery and at the origin and major branch-points of the middle cerebral artery.

Clinical Box 10.4: Carotid endarterectomy

Atherosclerosis in the neck vessels causes progressive stenosis and increases the risk of TIA and stroke. Patients with moderate to severe stenosis (>50% occlusion) may benefit from carotid endarterectomy, a procedure to remove the diseased vessel lining. This can be achieved by open neck surgery or as an endovascular procedure (using a catheter introduced via the femoral artery in the groin). Although the risk of stroke is significantly reduced, the surgery itself may precipitate a cerebral infarct (or even death in a small minority of patients) and trial data suggest that it is necessary to treat 80 asymptomatic patients in order to prevent a single adverse event. Current best practice guidelines therefore do not recommend the procedure for asymptomatic individuals, in whom the stroke risk is less than 1% with medical treatment alone.

Plaque formation

A key factor in plaque formation is dysfunction of the endothelium, which normally releases factors such as nitric oxide that prevent platelet and leukocyte adhesion. Endothelial dysfunction can be caused by toxic agents including aromatic hydrocarbons and free radicals that are present in cigarette smoke. Damage is also caused by physical shearing forces due to high blood pressure and turbulent flow. Platelets adhere to dysfunctional endothelial cells and become activated, releasing cytokines (inflammatory mediators) and platelet derived growth factor (PDGF). This initiates a chronic inflammatory response in the vessel wall.

Plaque progression

Inflammatory mediators released by activated platelets recruit monocytes from the bloodstream. These migrate into the vessel wall and differentiate into macrophages where they take up cholesterol and lipids to become foam cells. Growth factors and cytokines released by foam cells initiate a cascade of pathological events in which there is further accumulation of cholesterol and proliferation of intimal smooth muscle. This process is accelerated if the serum cholesterol is high (Clinical Box 10.5). Smooth muscle cells secrete extracellular matrix proteins including collagen, which generates a tough fibrous cap over the soft plaque core, creating a relatively stable fibrous plaque (Fig. 10.14A). If the fibrous cap ruptures or the overlying endothelial layer becomes ulcerated, the plaque is referred to as complicated (Fig. 10.14B). This may trigger thrombosis, leading to vessel occlusion and stroke.

Clinical Box 10.5: Good and bad cholesterol

Cholesterol is not water-soluble and is transported through the bloodstream by lipoproteins, a family of spherical particles composed of phospholipid and protein. Low-density-lipoprotein (LDL) particles deliver lipids to peripheral tissues and contribute to the development of atheromatous plaques. Raised LDL levels are therefore harmful and are said to represent ‘bad cholesterol’. Excess cholesterol is transported to the liver for disposal in high-density-lipoprotein (HDL) particles, which are sometimes referred to as ‘good cholesterol’. The ratio of HDH:LDL cholesterol may therefore be more important than the total serum cholesterol.

Fig. 10.14 Post-mortem photographs showing examples of atherosclerotic plaques in the abdominal aorta (the arteries have been opened to expose the endothelial lining).
**(A)** This image shows numerous yellow-white fibrous plaques in the wall of the aorta. These lesions have a cholesterol-rich core covered by a collagenous cap and they often remain stable (without causing symptoms) for many years; **(B)** This example (in a different patient) shows complicated atheromatous plaques, in which there has been rupture/haemorrhage of the collagenous cap or ulceration of the overlying endothelium – in this case adherent thrombus is clearly visible on some of the plaques. From Kumar et al: Robbins Basic Pathology 8e (Saunders 2007) with permission.

Key Points

Atherosclerosis is an almost ubiquitous degenerative process of medium and large arteries (e.g. neck vessels, aorta, coronary arteries) and is a major cause of stroke and heart attack.

Plaque formation is triggered by endothelial dysfunction (e.g. as a result of high blood pressure and toxins in cigarette smoke). This allows platelets to adhere to the blood vessel lining, releasing cytokines and PDGF, triggering an inflammatory response in the vessel wall.

Monocytes, which have been recruited from the bloodstream, enter the vessel wall and differentiate into macrophages, before taking up lipid and cholesterol to become foam cells.

Much of the cholesterol is derived from circulating low-density-lipoprotein (LDL) particles and is a key component of the plaque core, which is covered by a collagen-rich fibrous cap.

If a fibrous plaque ruptures it becomes a ‘complicated’ plaque, which predisposes to thrombosis and embolism. These events may occlude the vessel, resulting in a stroke (or heart attack).

Stroke management

Several large clinical trials have shown that the best outcomes in stroke care are achieved by dedicated stroke units (or by specialist multidisciplinary stroke teams). Key elements include:

Good nutrition and hydration, with early nasogastric or parenteral feeding, if necessary.

Speech and language therapy assessment and treatment in the first few days.

Early mobilization and physiotherapy, avoiding harmful consequences of immobility.

Prompt treatment of complications, such as infection.

The collective impact of these simple measures is a substantial reduction in long-term neurological impairment, with a 25% increase in the number of people returning to work. A small proportion of patients with ischaemic stroke may be suitable for thrombolysis (Clinical Box 10.6).

Clinical Box 10.6: Thrombolysis

Thrombus can be dissolved by intravenous administration of tissue plasminogen activator (tPA), an enzyme of the fibrinolytic (anti-coagulation) cascade. This must be done within four and a half hours of stroke onset to minimize the risk of a potentially fatal brain haemorrhage. It is therefore extremely important to determine the exact time of onset (and to perform a CT scan to rule out a haemorrhage) prior to thyrombolysis. Outcome data from clinical trials show that 10% of patients receiving thrombolysis will have ‘minimal or no disability’ at three months and another third will have some measurable degree of benefit. The incidence of haemorrhage is approximately 1 in 18, but overall mortality is not increased. It is important to note that most people do not qualify for thrombolysis, but all patients are likely to benefit from specialist care in a stroke unit.

Stroke prevention

Acute stroke treatment is currently limited, which increases the importance of preventative measures including the avoidance of known risk factors. Primary prevention aims to avoid a first stroke in someone who is at risk, whereas secondary prevention reduces the likelihood of recurrence.

Risk factors for stroke

Arterial hypertension is the most important factor and clinical trials show that a 5 mmHg reduction in diastolic blood pressure cuts stroke risk by around a third, even in patients with normal blood pressure. Decreasing serum cholesterol is also highly beneficial, and even people with normal levels may benefit from cholesterol-lowering agents such as statins (inhibitors of the cholesterol-synthesizing liver enzyme hydroxy-methyl-glutaryl-CoA reductase). Reduced consumption of saturated animal fats is also helpful, together with increased intake of polyunsaturated vegetable fats and fish oils (containing omega-3 fatty acids). In patients with diabetes, who are particularly predisposed to arterial disease, good control of blood sugar is essential. Daily low-dose aspirin and other antiplatelet agents may also of value (Clinical Box 10.7).

Clinical Box 10.7: Antiplatelet agents

Low-dose aspirin (75 mg/day) reduces the tendency of platelets to adhere to dysfunctional endothelial cells and cuts recurrent stroke risk by up to 25%. Alternative antiplatelet drugs such as dipyridamole and clopidogrel were previously used only in patients who are unable to tolerate aspirin but are now given in combination with aspirin or as first-line agents. Antiplatelet agents are not recommended for people who have never had a stroke as the increased risk of haemorrhage probably outweighs any potential benefits.

Other factors

Oral contraceptives with a high oestrogen content increase relative stroke risk by enhancing the tendency of blood to coagulate, but since the background risk is tiny in young females, the absolute risk remains extremely low. Elevation of the amino acid homocysteine in the serum, as a result of folate or vitamin B deficiency or in the rare genetic condition homocysteineuria, is also associated with premature vascular disease, but it is not clear if reducing homocysteine levels is beneficial in preventing stroke. Modest alcohol intake may reduce stroke risk (perhaps in part by increasing plasma HDL concentration) but consuming more than two units per day (i) begins to reverse the benefits, (ii) has other negative effects on health and (iii) is an important cause of haemorrhagic stroke in younger people (Fig. 10.15).

Fig. 10.15 Moderate alcohol consumption may have a beneficial effect on cardiovascular disease.
With increasing levels of consumption, the negative effects quickly outweigh the benefits. This is described as a J-shaped relationship.

Key Points

The best outcomes in stroke are achieved by dedicated stroke units, with a significant reduction in long-term neurological impairment and a 25% increase in the number of people returning to work.

Key elements include: (i) good nutrition and hydration; (ii) early speech and language therapy; (iii) prompt mobilization and physiotherapy; and (iv) aggressive treatment of any complications.

Thrombolysis is suitable in a minority of cases and must be administered within 4.5 hours of stroke onset, after a CT scan has been performed to exclude haemorrhage.

The principal modifiable risk factors for primary and secondary stroke prevention are high blood pressure, smoking, elevated cholesterol, diabetes and atrial fibrillation.

Antiplatelet agents (aspirin, dipyridamole, clopidogrel) reduce the incidence of stroke, but the risk of haemorrhage probably outweighs the benefit in people who have never had a stroke.

Pathophysiology of stroke

The average rate of cerebral blood flow is 50 mL per 100 g of tissue per minute. This high rate of blood flow is required to deliver enough oxygen and glucose to support the intense metabolic demands of neural tissue. If the blood supply fails, neurons begin to die within a few minutes.

Failure of the sodium pump

The sodium pump (Na⁺/K⁺-ATPase) is responsible for two thirds of the basal energy expenditure of the brain. It works constantly in the background to maintain the intracellular and extracellular sodium and potassium ion concentrations and is therefore essential for electrical activity in nerve cells (see Ch. 6). As the ATP supply falls to critical levels, the sodium pump fails. As a result, the sodium and potassium gradients dissipate and neuronal membranes depolarize. A critical point is reached when cerebral blood flow falls to less than 20% of normal (below 10 mL per 100 g per minute). Depolarized neurons reach their ‘firing thresholds’ and there is large-scale release of neurotransmitters, including the excitatory amino acid glutamate which is toxic at high concentrations.