Understanding stroke:Pathophysiology, presentation, and investigation

Every 45 seconds, someone in the United States has an attack of stroke. K A L Carroll and J Chataway discuss the pathology and clinical features of stroke, in the first of a two part series

Stroke is an acute neurological injury in which blood supply to a part of the brain is interrupted. Five and a half million survivors of stroke are living in the world today.^w1 In the United States alone, half a million people have their first stroke each year, and 200 000 have a recurrent attack.^w2 The World Health Organization esti mates that 15 million people have strokes each year worldwide, 5.5 mil lion of which are fatal.^w1 In industri alised countries, stroke is the third most common single cause of death (after ischaemic heart disease and cancer). In the US, someone has an attack every 45 seconds, and there is a stroke related death every three minutes.^w2

Fig 1 Ischaemic cascade

Even if age specific stroke incidence remains stable or falls slightly because more people live into old age, the annual incidence will continue to rise. This increases mortality, but, because of the direct cost of treatment and the indirect costs of lost productivity, the result is a loss - of $57.9bn (£30.4bn; €45.1bn) a year in the US.^w2 A thorough understanding of stroke's pathophysiology, presentation, investigation, and current and future treatments is crucial.

Strokes may either be haemorrhagic or ischaemic. Eighty eight per cent of all strokes are ischaemic, 9% are due to intracerebral haemorrhage, and 3% are due to subarachnoid haemorrhage. ^w2

Haemorrhagic stroke

Intracranial haemorrhage may occur within the brain parenchyma (intracerebral haemorrhage) or within the surrounding meningeal spaces (including epidural haematoma, subdural haematoma, and subarachnoid haemorrhage).

In intracerebral haemorrhage, bleeding occurs directly into the brain parenchyma. In addition to the area of the brain injured by the haemorrhage, the surrounding brain can be damaged by pressure produced by the mass effect of the haematoma. A general increase in intracranial pressure may occur.

Non-traumatic intracerebral haemorrhage is usually due to hypertensive damage to blood vessel walls. Chronic hypertension causes lipohyalinosis, fibrinoid necrosis, and the development of Charcot-Bouchard aneurysms in arteries throughout the brain, which may then rupture. Non-traumatic intracerebral haemorrhage may also be due to excessive cerebral blood flow (for example, haemorrhagic transformation of an ischaemic infarct); rupture of an aneurysm or an arteriovenous malformation; an arteriopathy (for example, cerebral amyloid angiopathy); a coagulopathy; a vasculitis; haemorrhagic necrosis (for example, due to tumour or infection); or venous outflow obstruction (for example, cerebral venous thrombosis).

Non-penetrating and penetrating cranial trauma are also common causes of intracerebral haemorrhage.

Strokes due to hypertension more commonly occur in sites such as the basal ganglia, thalamus, pons, cerebellum, and other brainstem sites, whereas those due to other causes more commonly occur in lobar regions (particularly the parietal and occipital lobes).

Subarachnoid haemorrhage usually occurs after rupture of a berry aneurysm in the circle of Willis. Other uncommon causes include trauma, hypertensive haemorrhage, vasculitides, tumours, and coagulopathies. This results in blood accumulating in the basal cisterns and around the brainstem.

Ischaemic stroke

An acute vascular occlusion results in ischaemia in the dependent area of the brain. About 80% of ischaemic strokes are due to thromboses and emboli. The most common sites of thrombotic occlusion are cerebral artery branch points, particularly in the distribution of the internal carotid artery. Arterial stenosis precipitated by turbulent blood flow, atherosclerosis, and platelet adherence cause blood clots to form. Less common causes of thromboses, particularly seen in younger stroke patients, include cervical artery dissection, essential thrombocythaemia, polycythemia, sickle cell anaemia, protein C deficiency, fibromuscular dysplasia of the cerebral arteries, and cocaine misuse.^w3

Emboli may arise from the heart, the extracranial arteries, or, rarely, the right sided circulation (paradoxical emboli), and can occlude the vasculature. Furthermore, rarely infective causes of emboli, such as subacute bacterial endocarditis, may cause occlusion, as may emboli due to iatrogenic causes, such as a cardiac prosthesis.

Small vessel disease within the brain causes a further 20% of ischaemic strokes. These are usually in patients with generalised small vessel disease - for example, hypertensive and diabetic patients. Multiple small emboli or an in situ process called lipohyalinosis (in which multiple microatheromata occlude the vessels) are thought to be responsible.

A system of categories of subtypes of ischaemic stroke mainly based on cause has been developed for the "Trial of Org" 10 172 in acute stroke treatment (TOAST).^w4 This classification denotes five subtypes of ischaemic stroke - large artery atherosclerosis, cardioembolism, small vessel occlusion, stroke of other determined cause, and stroke of undetermined cause.

In all cases, loss of perfusion to a part of the brain results in an "ischaemic cascade"
(fig 1). Conse- quently the initial ischaemic insult is locally amplified.

The high intracellular calcium acti- vates various enzymes that cause the destruction of the cell. Free radicals, arachidonic acid, and nitric oxide are generated by this process leading to further neuronal damage. Within hours to days of a stroke occurring, specific genes are activated that cause the formation of cytokines and other factors that in turn cause further inflammation and microcirculatory compromise. The area of damage thus spreads rapidly after the initial ischaemic event.

Risk factors

Stroke has numerous risk factors, some of which (such as increasing age and systolic blood pressure) are risk factors for both ischaemic and haemorrhagic stroke, however, other factors are more specific for type of stroke. The table gives important risk factors and their relative risk.

Clinical presentation

Stroke should be considered in any patient presenting with an acute neu- rological deficit (focal or global) or altered level of consciousness. Patients' symptoms vary depending on the area of the brain affected and the extent of the damage.

Because of the importance of get- ting people who have had a stroke into hospital as rapidly as possible, there has been extensive research into prehospital assessment by patients themselves, family members, and prehospital care personnel, such as emergency medical technicians. The Cincinnati prehospital stroke scale has been developed using the three most important items (facial paresis, arm drift, and abnormal speech) derived from the stroke scale of the National Institutes of Health.^w16

The Los Angeles prehospital stroke screen assesses for a unilateral arm drift, handgrip strength, and facial paresis.^w17 Regardless of the scale used, it is important to increase public awareness as to the presenta- tion of stroke to decrease the time from onset to presentation in hospi- tal. In the UK, a campaign is cur- rently being run by the Stroke Association called FAST (the face arm speech test), which guides the public to present at hospital immedi- ately in the case of facial weakness, arm weakness, or speech disturbance.

No features of the history can accurately distinguish between ischaemic and haemorrhagic stroke. But haemorrhagic stroke is perhaps more likely if the presentation includes features of raised intracranial pressure (such as nausea, vomiting, and headache). Seizures are also more common in hemor- rhagic stroke than in ischaemic stroke, occurring in up to 28% of hemorrhagic strokes. Meningism, the symptoms of meningeal irritation associated with acute febrile illness or dehydration without actual infection of the meninges, may also result from blood in the ventricles after a haem- orrhagic stroke.

Four important stroke syndromes are caused by disruption of particular cerebrovascular distributions.

Anterior cerebral artery - This prima- rily affects frontal lobe function, which results in altered mental status, con- tralateral lower limb weakness and hypoaesthesia, and gait disturbance.

Middle cerebral artery - This com- monly results in contralateral hemi- paresis, contralateral hypoaesthesia, ipsilateral hemianopia, and gaze preference toward the side of the lesion. Agnosia, a loss in ability to recognise objects, persons, sounds, shapes or smells, in the absence of a specific sensory deficit or memory loss, is common.

Receptive or expressive aphasia may result if the lesion occurs in the dominant (mainly left) hemisphere. Neglect (behaviour as if the contralateral sensory space does not exist) may result when the lesion occurs in the parietal cortex.

Fig 2 Computed tomograph after ischaemic stroke, showing oedema in insular cortex, as shown by solid arrows (open arrows show normal side). Reproduced from Chokski et al ^w27 with permission of Anderson Publishing

Posterior cerebral artery - This affects vision and thought, producing homonymous hemianopia, cortical blindness, visual agnosia, altered mental status, and impaired memory.

Vertebrobasilar artery - causes a wide variety of cranial nerve, cerebellar, and brainstem deficits. These include vertigo, nystagmus, diplopia, visual field deficits, dysphagia, dysarthria, facial hypoaesthesia, syncope, and ataxia. Loss of pain and temperature sensation occurs on the ipsilateral face and contralateral body.

Investigations

After the necessary basic blood tests (including full blood count, biochemistry, and coagulation studies) and cardiac monitoring with electrocardiogram, a non-contrast head computed tomography scan is essential for rapidly distinguishing ischaemic from haemorrhagic stroke and may be able to define the anatomic distribution of the stroke. This is crucial because treatments for each type of stroke differ.

Within six hours of the onset of ischaemic stroke, most patients will have a normal computed tomography scan. After 6-12 hours, sufficient oedema may collect into the area of the stroke so that a region of hypo- density may be seen on the scan.

Radiological clues before this include:

• Insular ribbon sign (loss of definition of grey-white interface in the lateral margins of the insula due to oedema in the insular cortex; fig 2) ^w18
• Hyperdense middle cerebral artery sign (fig 3)^w19
• Hypoattenuation in the lentiform nucleus (fig 4)
• Sulcal obliteration
• Shifting due to oedema
• Loss of grey-white matter differentiation.^{w20 w21}

These are all due to an increasing level of oedema in the brain, however, they rely on a high level of expertise of the radiologist and are often not present. Computed tomography scans also may fail to show some parenchymal haemorrhages smaller than 1 cm as a result of low resolution.

Conventional magnetic resonance imaging is not as sensitive as computed tomography for detecting haemorrhage in the acute setting. But newer techniques, such as perfusion and diffusion weighted magnetic resonance examinations, are more sensitive imaging methods for diagnosis in acute settings. Ischaemic areas can be determined within minutes or hours. But use of these methods has been restricted because they are not generally available and are difficult to employ under emergency conditions, particularly as they involve a patient lying flat for 40 minutes when they may be agitated or have a level of cardiorespiratory compromise.

Fig 3 (below left) Computed tomograph after ischaemic stroke, showing hyperdense middle cerebral artery sign. Reproduced from Chokski et al ^w27 with permission of Anderson Publishing  

Fig 4 (below right) Computed tomograph after ischaemic stroke, showing hypoattenuation in the lentiform nucleus, as shown by solid arrows (open arrows show normal side). Reproduced from Chokski et al ^w27 with permission of Anderson Publishing

Perfusion brain computed tomography, conversely, is a new imaging method capable of providing information about ischaemic brain tissue, which can be used in emergency conditions.^{w22 w23} Perfusion is measured by monitoring the passage of contrast material (non-ionic iodine) through the brain using computed tomography. Perfusion examination of the entire brain is not possible yet, and because only a few neighbouring sections can be imaged, the anatomical region must be clinically determined. Various studies have shown that computed tomography perfusion scans yield comparable information to diffusion weighted magnetic resonance imaging scans.^{w24 w25} But the entire brain cannot be analysed using perfusion computed tomography scanning, which is the major drawback, and further research is required to obtain an ideal investigation. Both types of investigation used have a high detection rate for haemorrhagic stroke.

Further investigations may include carotid duplex scanning for patients in whom carotid artery stenosis or occlusion is suspected, and transcranial Doppler ultrasound for evaluating the more proximal vasculature, including the middle cerebral artery, intracranial carotid artery, and vertebrobasilar artery. Echocardiography may be used for patients in whom cardiogenic embolism is suspected, and trans- oesophageal echocardiography may be used to detect a suspected thoracic aortic dissection, or transthoracic echocardiography for suspected acute myocardial infarction.

Computed tomography angiography is useful for patients with acute ischaemic stroke in whom accurate analysis of the cerebrovascular anatomy is required, particularly preoperatively. ^w26

Competing interests: None declared.

References ^w1-w27 are on studentbmj.com.

K A L Carroll, fifth year medical student, Imperial College, London
Email: katherine.carroll@imperial.ac.uk
J Chataway, consultant neurologist, St Mary's Hospital, London



studentBMJ 2006;14:309-352 September ISSN 0966-6494

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