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Understanding stroke:Pathophysiology,presentation, andinvestigation

Stroke is an acute neuro-logical injury in whichblood supply to a part ofthe brain is interrupted.Five and a half million

survivors of stroke are living in theworld today.w1 In the United Statesalone, half a million people havetheir first stroke each year, and200 000 have a recurrent attack.w2

The World Health Organization esti-mates that 15 million people havestrokes each year worldwide, 5.5 mil-lion of which are fatal.w1 In industri-alised countries, stroke is the thirdmost common single cause of death(after ischaemic heart disease andcancer). In the US, someone has anattack every 45 seconds, and there isa stroke related death every threeminutes.w2

Even if age specific stroke inci-dence remains stable or falls slightlybecause more people live into oldage, the annual incidence will con-

tinue to rise. This increases mortality,but, because of the direct cost oftreatment and the indirect costs oflost productivity, the result is a loss—of $57.9bn (£30.4bn; €45.1bn) a yearin the US.w2 A thorough understand-ing of stroke’s pathophysiology, pres-entation, investigation, and currentand future treatments is crucial.

Strokes may either be haemor-rhagic or ischaemic. Eighty eight percent of all strokes are ischaemic, 9%are due to intracerebral haemor-rhage, and 3% are due to subarach-noid haemorrhage.w2

Haemorrhagic strokeIntracranial haemorrhage may occurwithin the brain parenchyma (intrac-erebral haemorrhage) or within the surrounding meningeal spaces(including epidural haematoma, sub-dural haematoma, and subarachnoidhaemorrhage).

In intracerebral haemorrhage,bleeding occurs directly into thebrain parenchyma. In addition to thearea of the brain injured by thehaemorrhage, the surrounding braincan be damaged by pressure pro-duced by the mass effect of thehaematoma. A general increase inintracranial pressure may occur.

Non-traumatic intracerebralhaemorrhage is usually due to hyper-tensive damage to blood vessel walls.Chronic hypertension causes lipo-hyalinosis, fibrinoid necrosis, and thedevelopment of Charcot-Bouchardaneurysms in arteries throughout thebrain, which may then rupture. Non-traumatic intracerebral haemor-rhage may also be due to excessivecerebral blood flow (for example,haemorrhagic transformation of anischaemic infarct); rupture of ananeurysm or an arteriovenous mal-formation; an arteriopathy (forexample, cerebral amyloid angio-pathy); a coagulopathy; a vasculitis;

haemorrhagic necrosis (for example,due to tumour or infection); or venous outflow obstruction (forexample, cerebral venous throm-bosis).

Non-penetrating and penetratingcranial trauma are also commoncauses of intracerebral haemorrhage.

Strokes due to hypertension morecommonly occur in sites such as thebasal ganglia, thalamus, pons, cere-bellum, and other brainstem sites,whereas those due to other causesmore commonly occur in lobarregions (particularly the parietal andoccipital lobes).

Subarachnoid haemorrhage usu-ally occurs after rupture of a berryaneurysm in the circle of Willis.Other uncommon causes includetrauma, hypertensive haemorrhage,vasculitides, tumours, and coagulo-pathies. This results in blood accu-mulating in the basal cisterns andaround the brainstem.

Ischaemic strokeAn acute vascular occlusion results inischaemia in the dependent area ofthe brain. About 80% of ischaemicstrokes are due to thromboses andemboli. The most common sites ofthrombotic occlusion are cerebralartery branch points, particularly inthe distribution of the internalcarotid artery. Arterial stenosis pre-cipitated by turbulent blood flow,atherosclerosis, and platelet adher-ence cause blood clots to form. Lesscommon causes of thromboses, par-ticularly seen in younger strokepatients, include cervical artery dis-section, essential thrombocythaemia,polycythemia, sickle cell anaemia,protein C deficiency, fibromusculardysplasia of the cerebral arteries, andcocaine misuse.w3

Emboli may arise from the heart,the extracranial arteries, or, rarely,the right sided circulation (paradoxi-cal emboli), and can occlude the vas-culature. Furthermore, rarelyinfective causes of emboli, such assubacute bacterial endocarditis, maycause occlusion, as may emboli dueto iatrogenic causes, such as a cardiacprosthesis.

Small vessel disease within thebrain causes a further 20% ofischaemic strokes. These are usuallyin patients with generalised small ves-sel disease—for example, hypertensiveand diabetic patients. Multiple smallemboli or an in situ process calledlipohyalinosis (in which multiplemicroatheromata occlude the vessels)are thought to be responsible.

A system of categories of subtypesof ischaemic stroke mainly based oncause has been developed for the“Trial of Org” 10 172 in acute stroke treatment (TOAST).w4 Thisclassification denotes five subtypes ofischaemic stroke—large artery athero-sclerosis, cardioembolism,small vessel occlusion, stroke

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

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Fig 1 Ischaemiccascade

Lack of oxygen supply to the ischaemic neurone

ATP depletion

Membrane ion transport systems stop functioning

Depolarisation of neurone

Influx of calcium

Release of neurotransmitters, including glutamate, activatesN-methyl-D-aspartate and other excitatory receptors on other neurones

Further depolarisation of cell

Further calcium influx

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n of other determined cause, andstroke of undetermined cause.

In all cases, loss of perfusion to apart of the brain results in an“ischaemic cascade” (fig 1). Conse-quently the initial ischaemic insult islocally amplified.

The high intracellular calcium acti-vates various enzymes that cause thedestruction of the cell. Free radicals,arachidonic acid, and nitric oxide aregenerated by this process leading tofurther neuronal damage. Withinhours to days of a stroke occurring,specific genes are activated that causethe formation of cytokines and otherfactors that in turn cause furtherinflammation and microcirculatorycompromise. The area of damagethus spreads rapidly after the initialischaemic event.

Risk factorsStroke has numerous risk factors,some of which (such as increasingage and systolic blood pressure) arerisk factors for both ischaemic andhaemorrhagic stroke, however, otherfactors are more specific for type ofstroke. The table gives important riskfactors and their relative risk.

Clinical presentationStroke should be considered in anypatient presenting with an acute neu-rological deficit (focal or global) oraltered level of consciousness.Patients’ symptoms vary dependingon the area of the brain affected andthe extent of the damage.

Because of the importance of get-ting people who have had a strokeinto hospital as rapidly as possible,there has been extensive researchinto prehospital assessment bypatients themselves, family members,and prehospital care personnel, suchas emergency medical technicians.The Cincinnati prehospital strokescale has been developed using thethree most important items (facialparesis, arm drift, and abnormalspeech) derived from the stroke scaleof the National Institutes of Health.w16

The Los Angeles prehospitalstroke screen assesses for a unilateralarm drift, handgrip strength, andfacial paresis.w17 Regardless of thescale used, it is important to increasepublic awareness as to the presenta-tion of stroke to decrease the timefrom onset to presentation in hospi-tal. In the UK, a campaign is cur-rently being run by the StrokeAssociation called FAST (the facearm speech test), which guides thepublic to present at hospital immedi-ately in the case of facial weakness,arm weakness, or speech disturbance.

No features of the history canaccurately distinguish betweenischaemic and haemorrhagic stroke.But haemorrhagic stroke is perhapsmore likely if the presentationincludes features of raised intra-

cranial pressure (such as nausea,vomiting, and headache). Seizuresare also more common in hemor-rhagic stroke than in ischaemicstroke, occurring in up to 28% ofhemorrhagic strokes. Meningism, thesymptoms of meningeal irritationassociated with acute febrile illness ordehydration without actual infectionof the meninges, may also result fromblood in the ventricles after a haem-orrhagic stroke.

Four important stroke syndromesare caused by disruption of particularcerebrovascular distributions.

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

Middle cerebral artery—This com-monly results in contralateral hemi-paresis, contralateral hypoaesthesia,ipsilateral hemianopia, and gazepreference toward the side of thelesion. Agnosia, a loss in ability torecognise objects, persons, sounds,shapes or smells, in the absence of aspecific sensory deficit ormemory loss, is common.

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Risk factors for stroke

Risk factor Description Relative risk*

Ischaemic stroke

Agew5 For each successive 10 years after age55

1.74

Family historyw6 Paternal history of stroke or transientischaemic attack

2.4

Maternal history of stroke or transientischaemic attack

1.4

Parental history of coronary heartdisease

3.33

Systolic blood pressurew5 For each 10 mm Hg increase 1.15

Atrial fibrillationw7 w8 For successive decade of life above age55, incidence doubles; non-valvularatrial fibrillation accounts for 1.5%strokes in people aged 50-59 years,rising to 23.5% in people aged 80-89years

3-5

Myocardial diseasew8 Coronary heart disease 2

Electrocardiographic left ventricularhypertrophy

3

Cardiac failure 3-4

Diabetes mellitusw9 People with diabetes mellitus haveincreased susceptibility toatherosclerosis and increasedatherogenic risk factors, particularlyhypertension, obesity and abnormalblood lipids; known diabetes mellitus

2.45

Asymptomatic people who have a highaverage blood glucose (≥225 mg/dl)

1.43

Cigarette smokingw10 — 1.9

Alcoholw11 Complex associated dependent onamount (J shaped association) and race

Previous transient ischaemic attackw2 — 2.3

Carotid stenosisw12 — 2.03

Haemorrhagic stroke

Agew13 w14 Incidence increases exponentially withincreasing age; relative risk for 85 yearolds compared with 70-74 year olds

2.5

Systolic blood pressurew15 110-139 mm Hg 1

140-179 mm Hg 4

≥180 mm Hg 8

Anticoagulation (internationalnormalised ratio)w14

<3.0 1

3.5-3.9 4.6

*Confidence intervals omitted for clarity

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Receptive or expressive aphasia mayresult if the lesion occurs in the dom-inant (mainly left) hemisphere.Neglect (behaviour as if the contralat-eral sensory space does not exist)may result when the lesion occurs inthe parietal cortex.

Posterior cerebral artery—Thisaffects vision and thought, producinghomonymous hemianopia, corticalblindness, visual agnosia, alteredmental status, and impaired memory.

Vertebrobasilar artery—causes awide variety of cranial nerve, cerebel-lar, and brainstem deficits. Theseinclude vertigo, nystagmus, diplopia,visual field deficits, dysphagia,dysarthria, facial hypoaesthesia, syn-cope, and ataxia. Loss of pain andtemperature sensation occurs on theipsilateral face and contralateral body.

InvestigationsAfter the necessary basic blood tests(including full blood count, biochem-istry, and coagulation studies) andcardiac monitoring with electrocar-diogram, a non-contrast head com-puted tomography scan is essentialfor rapidly distinguishing ischaemicfrom haemorrhagic stroke and maybe able to define the anatomic distri-bution of the stroke. This is crucialbecause treatments for each type ofstroke differ.

Within six hours of the onset ofischaemic stroke, most patients willhave a normal computed tomogra-phy scan. After 6-12 hours, sufficientoedema may collect into the area ofthe stroke so that a region of hypo-density may be seen on the scan.

Radiological clues before thisinclude:� Insular ribbon sign (loss of defini-

tion of grey-white interface in thelateral margins of the insula dueto oedema in the insular cortex;fig 2)w18

� Hyperdense middle cerebral

artery sign (fig 3)w19

� Hypoattenuation in the lentiformnucleus (fig 4)

� Sulcal obliteration� Shifting due to oedema� Loss of grey-white matter differ-

entiation.w20 w21

These are all due to an increasinglevel of oedema in the brain, however,they rely on a high level of expertise of the radiologist and are often notpresent. Computed tomography scansalso may fail to show some parenchy-mal haemorrhages smaller than 1 cmas a result of low resolution.

Conventional magnetic resonanceimaging is not as sensitive as com-puted tomography for detectinghaemorrhage in the acute setting.But newer techniques, such as perfu-sion and diffusion weighted magneticresonance examinations, are moresensitive imaging methods for diag-nosis in acute settings. Ischaemicareas can be determined within min-utes or hours. But use of these meth-ods has been restricted because theyare not generally available and aredifficult to employ under emergencyconditions, particularly as theyinvolve a patient lying flat for 40 min-utes when they may be agitated orhave a level of cardiorespiratorycompromise.

Perfusion brain computed tomo-graphy, conversely, is a new imagingmethod capable of providing informa-tion about ischaemic brain tissue,which can be used in emergency con-ditions.w22 w23 Perfusion is measured bymonitoring the passage of contrastmaterial (non-ionic iodine) throughthe brain using computed tomogra-phy. Perfusion examination of theentire brain is not possible yet, andbecause only a few neighbouring sec-tions can be imaged, the anatomicalregion must be clinically determined.Various studies have shown that com-puted tomography perfusion scansyield comparable information to diffu-sion weighted magnetic resonanceimaging scans.w24 w25 But the entirebrain cannot be analysed using perfu-

sion computed tomography scanning,which is the major drawback, and fur-ther research is required to obtain anideal investigation. Both types ofinvestigation used have a high detec-tion rate for haemorrhagic stroke.

Further investigations may includecarotid duplex scanning for patients inwhom carotid artery stenosis or occlu-sion is suspected, and transcranialDoppler ultrasound for evaluating themore proximal vasculature, includingthe middle cerebral artery, intracranialcarotid artery, and vertebrobasilarartery. Echocardiography may be usedfor patients in whom cardiogenicembolism is suspected, and trans-oesophageal echocardiography maybe used to detect a suspected thoracicaortic dissection, or transthoracicechocardiography for suspected acutemyocardial infarction.

Computed tomography angiogra-phy is useful for patients with acuteischaemic stroke in whom accurateanalysis of the cerebrovascularanatomy is required, particularly pre-operatively.w26

K A L Carroll fifth year medical student,Imperial College, London katherine.carroll@imperial.ac.uk

J Chataway consultant neurologist, St Mary’sHospital, London

Competing interests: None declared.

References w1-w27 are onstudentbmj.com.

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Fig 2 Computedtomograph afterischaemicstroke, showingoedema ininsular cortex,as shown bysolid arrows(open arrowsshow normalside).Reproducedfrom Chokski etalw27 withpermission ofAndersonPublishing

Fig 3 (below left) Computedtomograph after ischaemic stroke,showing hyperdense middlecerebral artery sign. Reproducedfrom Chokski et alw27 with permissionof Anderson PublishingFig 4 (below right) Computedtomograph after ischaemic stroke,showing hypoattenuation in thelentiform nucleus, as shown by solidarrows (open arrows show normalside). Reproduced from Chokski etalw27 with permission of AndersonPublishing