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For personal use. Only reproduce with permission from The Lancet publishing Group. SEMINAR Stroke is defined by WHO as the clinical syndrome of rapid onset of focal (or global, as in subarachnoid haemorrhage) cerebral deficit, lasting more than 24 h or leading to death, with no apparent cause other than a vascular one. There are three pathological types (figure 1): ischaemic stroke (about 80% in white populations), primary intracerebral haemorrhage (about 15%), and subarachnoid haemorrhage (about 5%). 1 This article deals with the first two types. Transient ischaemic attack (TIA) differs from ischaemic stroke in its duration (less than 24 h, selected arbitrarily), differential diagnosis (eg, focal seizures are more likely to mimic TIA than stroke), and ease of diagnosis (the diagnosis of TIA is more difficult, depending almost entirely on a reliable history rather than signs or brain imaging). The 24 h cut-off is useful for epidemiological purposes because it can be applied consistently in different places and times. However, when patients are seen within 24 h of symptom onset, best clinical practice is to regard them all as having the medical emergency of “brain attack” (in analogy to heart attack), which may or may not recover in hours, days, or weeks. We do not think the recent suggestion of differentiating TIA from stroke on the basis of brain imaging 2 is helpful in routine clinical practice (or in epidemiological research), since this approach would require the availability of the same techniques and equipment worldwide. A TIA or stroke in one place might not be the same as a TIA or stroke in another place, or at another time, if the techniques differed or changed. In white people, about 50% of all ischaemic strokes and TIAs are probably due to atherothrombotic disease of the extracranial—or less commonly large intracranial— arteries; about 20% arise from emboli from the heart; about 25% are so-called lacunar infarcts, probably due to occlusion of one of the small, deep, perforating cerebral arteries; and the remainder are due to a miscellany of much rarer causes (eg, vasculitis, arterial dissection; figure 1). 1 These proportions are approximations because, Lancet 2003; 362: 1211–24 Division of Clinical Neurosciences, Western General Hospital, Edinburgh EH4 2XU, UK (Prof C Warlow MD, C Sudlow DPhil, Prof M Dennis MD, Prof J Wardlaw MD, Prof P Sandercock DM) Correspondence to: Prof Charles Warlow (e-mail: [email protected]) particularly in older people, there can be more than one potential cause (eg, atrial fibrillation and carotid stenosis), or no definite cause may be found even after reasonable investigations. Atheroma affecting the arteries to the brain (eg, of the aortic arch or basilar artery) cannot always be imaged easily, at least in routine clinical practice and particularly in population-based (and so unbiased by hospital admission) epidemiological studies. Global burden of stroke Stroke is the third commonest cause of death worldwide after ischaemic heart disease and all types of cancer combined. Two-thirds of stroke deaths occur in less developed countries. 3 Stroke also caused 3% of the world’s disability burden in 1990. By 2020, stroke mortality will have almost doubled, mainly as a result of an increase in the proportion of older people and the future effects of current smoking patterns in less developed countries. However, stroke attracts far less research funding than heart disease or cancer. 4 Stroke Charles Warlow, Cathie Sudlow, Martin Dennis, Joanna Wardlaw, Peter Sandercock Seminar THE LANCET • Vol 362 • October 11, 2003 • www.thelancet.com 1211 Stroke is a major public-health burden worldwide. Prevention programmes are essential to reduce the incidence of stroke and to prevent the all but inevitable stroke epidemic, which will hit less developed countries particularly hard as their populations age and adopt lifestyles of the more developed countries. Efficient, effective, and rapid diagnosis of stroke and transient ischaemic attack is crucial. The diagnosis of the exact type and cause of stroke, which requires brain imaging as well as traditional clinical skills, is also important when it will influence management. The treatment of acute stroke, the prevention and management of the many complications of stroke, and the prevention of recurrent stroke and other serious vascular events are all improving rapidly. However, stroke management will only be most effective when delivered in the context of an organised, expert, educated, and enthusiastic stroke service that can react quickly to the needs of patients at all stages from onset to recovery. Search strategy Systematic searching for articles about epidemiology, imaging, and other non-trial issues is difficult; we have done our best, using systematic reviews where possible. For treatment interventions we used the Cochrane Stroke Review Group’s register of trials, which now includes more than 6000 reports of trials relevant to the treatment, rehabilitation, and secondary prevention of stroke, 5 and Cochrane systematic reviews (abstracts available free of charge at http://www.dcn.ed.ac.uk/csrg/cliblist.asp). Where possible, we based recommendations on the strength of the evidence from large randomised trials and systematic reviews of trials. Additional useful sources of evidence-based and other sensible guidance are Clinical Evidence; 6 the Scottish Intercollegiate Guidelines Network; 7 the Royal College of Physicians National Clinical Guideline for Stroke; 8 the American Heart Association website, which provides free copies of its stroke guidelines; 9 and the Internet Stroke Center, an extremely useful resource for current and recently completed trials. 10 Further useful stroke trial links and resources can be found at www.dcn.ed.ac.uk/csrg. Where the available evidence runs out, we have resorted to medicine based on common sense, always realising that common sense can turn out to be wrong when evidence does emerge.
Transcript
Page 1: STROKE- Resumen de Warlow en Lancet

For personal use. Only reproduce with permission from The Lancet publishing Group.

SEMINAR

Stroke is defined by WHO as the clinical syndrome ofrapid onset of focal (or global, as in subarachnoidhaemorrhage) cerebral deficit, lasting more than 24 h orleading to death, with no apparent cause other than avascular one. There are three pathological types (figure 1):ischaemic stroke (about 80% in white populations),primary intracerebral haemorrhage (about 15%), andsubarachnoid haemorrhage (about 5%).1 This article dealswith the first two types. Transient ischaemic attack (TIA)differs from ischaemic stroke in its duration (less than24 h, selected arbitrarily), differential diagnosis (eg, focalseizures are more likely to mimic TIA than stroke), andease of diagnosis (the diagnosis of TIA is more difficult,depending almost entirely on a reliable history rather thansigns or brain imaging). The 24 h cut-off is useful forepidemiological purposes because it can be appliedconsistently in different places and times. However, whenpatients are seen within 24 h of symptom onset, bestclinical practice is to regard them all as having the medicalemergency of “brain attack” (in analogy to heart attack),which may or may not recover in hours, days, or weeks.We do not think the recent suggestion of differentiatingTIA from stroke on the basis of brain imaging2 is helpfulin routine clinical practice (or in epidemiologicalresearch), since this approach would require theavailability of the same techniques and equipmentworldwide. A TIA or stroke in one place might not be thesame as a TIA or stroke in another place, or at anothertime, if the techniques differed or changed.

In white people, about 50% of all ischaemic strokes andTIAs are probably due to atherothrombotic disease of theextracranial—or less commonly large intracranial—arteries; about 20% arise from emboli from the heart;about 25% are so-called lacunar infarcts, probably due toocclusion of one of the small, deep, perforating cerebralarteries; and the remainder are due to a miscellany ofmuch rarer causes (eg, vasculitis, arterial dissection;figure 1).1 These proportions are approximations because,

Lancet 2003; 362: 1211–24

Division of Clinical Neurosciences, Western General Hospital,Edinburgh EH4 2XU, UK (Prof C Warlow MD, C Sudlow DPhil,Prof M Dennis MD, Prof J Wardlaw MD, Prof P Sandercock DM)

Correspondence to: Prof Charles Warlow(e-mail: [email protected])

particularly in older people, there can be more than onepotential cause (eg, atrial fibrillation and carotid stenosis),or no definite cause may be found even after reasonableinvestigations. Atheroma affecting the arteries to the brain(eg, of the aortic arch or basilar artery) cannot always beimaged easily, at least in routine clinical practice andparticularly in population-based (and so unbiased byhospital admission) epidemiological studies.

Global burden of strokeStroke is the third commonest cause of death worldwideafter ischaemic heart disease and all types of cancercombined. Two-thirds of stroke deaths occur in lessdeveloped countries.3 Stroke also caused 3% of the world’sdisability burden in 1990. By 2020, stroke mortality willhave almost doubled, mainly as a result of an increase in theproportion of older people and the future effects of currentsmoking patterns in less developed countries. However,stroke attracts far less research funding than heart disease orcancer.4

Stroke

Charles Warlow, Cathie Sudlow, Martin Dennis, Joanna Wardlaw, Peter Sandercock

Seminar

THE LANCET • Vol 362 • October 11, 2003 • www.thelancet.com 1211

Stroke is a major public-health burden worldwide. Prevention programmes are essential to reduce the incidence ofstroke and to prevent the all but inevitable stroke epidemic, which will hit less developed countries particularly hardas their populations age and adopt lifestyles of the more developed countries. Efficient, effective, and rapid diagnosisof stroke and transient ischaemic attack is crucial. The diagnosis of the exact type and cause of stroke, whichrequires brain imaging as well as traditional clinical skills, is also important when it will influence management. Thetreatment of acute stroke, the prevention and management of the many complications of stroke, and the prevention ofrecurrent stroke and other serious vascular events are all improving rapidly. However, stroke management will only bemost effective when delivered in the context of an organised, expert, educated, and enthusiastic stroke service thatcan react quickly to the needs of patients at all stages from onset to recovery.

Search strategy

Systematic searching for articles about epidemiology,imaging, and other non-trial issues is difficult; we have doneour best, using systematic reviews where possible. Fortreatment interventions we used the Cochrane Stroke ReviewGroup’s register of trials, which now includes more than6000 reports of trials relevant to the treatment,rehabilitation, and secondary prevention of stroke,5 andCochrane systematic reviews (abstracts available free ofcharge at http://www.dcn.ed.ac.uk/csrg/cliblist.asp). Wherepossible, we based recommendations on the strength of theevidence from large randomised trials and systematic reviewsof trials. Additional useful sources of evidence-based andother sensible guidance are Clinical Evidence;6 the ScottishIntercollegiate Guidelines Network;7 the Royal College ofPhysicians National Clinical Guideline for Stroke;8 theAmerican Heart Association website, which provides freecopies of its stroke guidelines;9 and the Internet StrokeCenter, an extremely useful resource for current and recentlycompleted trials.10 Further useful stroke trial links andresources can be found at www.dcn.ed.ac.uk/csrg. Where theavailable evidence runs out, we have resorted to medicinebased on common sense, always realising that commonsense can turn out to be wrong when evidence does emerge.

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MortalityStroke mortality varies widely among countries for whichroutine death-certificate data are available. In the early1990s it was lowest, and had been declining steeply, inwestern Europe, the USA, Australia, and Japan, but wastwo or three times higher in South America. Mortality wasup to ten times higher, and increasing, in eastern Europeand the countries of the former Soviet Union.11 Routinemortality data are, however, limited by the inaccuracies ofdeath certificates and the lack of reliable informationabout different pathological types of stroke. Furthermore,mortality depends on both the incidence of stroke andcase-fatality and can give no information about strokesthat are disabling but not fatal.

IncidenceFew population-based studies on the incidence of strokehave had rigorous enough methods to be comparable, andthey have been carried out almost exclusively in whitepopulations in Europe, Australasia, and the USA.12–18

These studies have shown little difference betweencountries in the incidence of stroke standardised for ageand sex, although the incidence may be somewhat lowerin some parts of France and higher in Siberia.12,19 A recent,well-conducted study in the mainly black Caribbeanpopulation of Martinique in the West Indies showed

similar stroke incidence to that found in white people,21

but there are virtually no comparable data from lessdeveloped countries (Africa, South America, Asia).Although stroke does sometimes affect children andyoung adults, it is mainly a disease of older people. Thereis a steep rise in incidence with age, with three-quarters ofall first strokes occurring after the age of 65 years, at leastin white populations.12,19

For reliable comparisons of the distribution ofpathological types of stroke between populations, studieshave to have high enough rates of brain imaging,undertaken sufficiently early after stroke onset to becertain that a substantial proportion of intracerebralhaemorrhages are not missed; existing studies have hadsuboptimal rates and timing of imaging.22 For what it isworth, the studies with the highest rates of brain imaginghave shown very similar distributions of pathologicaltypes.12–18,19 Although there may well be a higherproportion of stroke due to primary intracerebralhaemorrhage in Asia and Africa, there have not been anysufficiently well-conducted population-based studies toconfirm this difference.

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5% subarachnoidhaemorrhage15% primaryintracerebralhaemorrhage

80% ischaemicstroke

Rare causes5%

Atherothromboembolism50%

Cardiac sourceof embolism

20%

Intracranial small-vessel disease

25%

Figure 1: Approximate frequency of three main pathologicaltypes of stroke (in white populations) and of main subtypes ofischaemic stroke as shown by population-based studies1

100

80

60

40

20

0

All st

rokes

Prop

ortio

n of

pat

ient

s (%

)

Type of stroke and ischaemic stroke subtype

PICH

SAH

Ischa

emic

TACI

PACI

LACI

POCI

IndependentDependentDead

Figure 2: Proportion of patients who are dead, dependent, orindependent a year after first stroke by type of pathology andby clinical subtype of ischaemic strokePICH=primary intracerebral haemorrhage; SAH=subarachnoidhaemorrhage; TACI=total anterior circulation infarct; PACI=partial anteriorcirculation infarct; LACI=lacunar infarct; POCI=posterior circulation infarct.Reproduced with permission from Warlow and colleagues.20

Figure 3: Imaging in a patient who presented 10 days after aminor left-hemisphere lacunar strokeBrain CT (A) shows low density in the left basal ganglia (arrow) in keepingwith an infarct. However, T2-weighted MR (B) shows a dark haemosiderinring (arrow), which indicates that the lesion was a primary intracerebralhaemorrhage. CT would have to have been done within about 8 days ofthe stroke to show distinct features of haemorrhage.

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Methodologically rigorous studies examining trends inthe incidence of stroke over time are even more limited innumber.19,23–27 Their results vary, but overall they showlittle change in standardised incidence rates over the pasttwo to three decades in the white populations studied;thus, lower case-fatality, perhaps due to better medicalcare or reduced stroke severity, may explain any decline inmortality.

OutcomeEarly death after stroke is generally due to thecomplications of the brain lesion itself (eg, mass effect,disruption of vital centres). Later, the complications ofdependency are a more likely cause (eg, pulmonaryembolism, infection). About 30% of patients die within ayear of a stroke. Recovery after stroke occurs throughseveral overlapping processes. In the first hours and daysthese processes may include resolution of the ischaemicpenumbra, cerebral oedema, and comorbidities (eg,infection) that exacerbate the functional effects of thestroke itself. Later, neural plasticity by which neurons takeon new functions, the acquisition of new skills throughtraining (eg, physiotherapy and occupational therapy),and modification of the patient’s environment lead tofurther gains in function. Of stroke survivors, nearly halfare left dependent. However, the outcome depends on thepathological type of stroke, and the subtype of ischaemicstroke (figure 2). Simple models based on age, livingalone, independence before the stroke, arm power, theability to walk, and the verbal component of the Glasgowcoma scale can provide more reliable estimates ofprognosis for groups of patients.28

Risk factorsSince stroke is pathologically heterogeneous, the risk-factor patterns for all types and subtypes of stroke wouldnot be expected to be the same. However, the largeprospective studies of risk factors have rarely distinguishedbetween the main pathological types, let alone the varioussubtypes of ischaemic stroke. Most conventional vascularrisk factors—age, cigarette smoking, diabetes, andobesity—are broadly similar for ischaemic stroke and forvascular disease in other parts of the arterial tree.However, the continuous relation between stroke andblood pressure is steeper than that for ischaemic heartdisease.29 Also, by contrast with ischaemic heart disease,there is no overall association between plasma cholesterolconcentration and stroke.30,31 Potential sources ofembolism from the heart (including atrial fibrillation,cardiac valve disease, and patent foramen ovale) areassociated with an increased risk of stroke. Atrialfibrillation is by far the most important because it is so

common, carries a high relative risk ofstroke, and is definitely causal in manycases. There is much more uncertaintyabout patent foramen ovale.32

Recent years have seen an increasinginterest in novel risk factors forvascular disease, including stroke.Most are thought to operate byaccelerating atherosclerosis. Theyinclude infections (eg, Helicobacterpylori and Chlamydia pneumoniae),inflammatory and rheological markers(eg, C-reactive protein and plasmafibrinogen), plasma homocysteineconcentration, and various geneticpolymorphisms.33–36 At present, anyassociations with stroke remain

uncertain because most of the studies have been small andmany were methodologically flawed. For ischaemic heartdisease, larger, more reliable studies (and overviews ofthese) are available; here, there are more convincingassociations with some inflammatory and rheologicalmarkers.37 However, clear associations with other novelrisk factors, including genetic factors, remain generallyunproven.38–40 The “Barker hypothesis”, that the origins ofadult vascular disease are to be found in fetal health, isincreasingly being challenged by systematic reviews of allthe available data as opposed to selective emphasis of theresults of particular studies.41

Diagnosis of acute stroke: role of brainimagingClinical diagnosis before imagingThe longer treatment is delayed, the less scope there is forbenefit from treatment—“time is brain”. Acute stroke is amedical emergency, and the clinician must work quicklyto answer several questions. Was the onset sudden? Canthe symptoms be attributed to a focal brain lesion? Is thecause likely to be vascular? The diagnosis of stroke (versusnot stroke) is made reasonably accurately on clinicalgrounds alone by specialists, but in general medical andemergency-department settings up to 20% of patientswith suspected stroke turn out to have another diagnosis.42

Furthermore, although clinical scoring systems can help,43

infarction cannot be reliably distinguished fromhaemorrhage without brain imaging. Whichever imagingmethod is used, the radiologist needs to know the timeand date of stroke onset to interpret the images properly.

Diagnosis of haemorrhagic strokeComputed tomography (CT) is the most reliable methodof demonstrating acute haemorrhage within the first weekafter stroke onset. Generally, a non-enhanced scan is allthat is required. After that, small haemorrhagesprogressively lose their characteristic white (hyperdense)appearance and can easily be mistaken for infarcts(figure 3). Therefore, if patients delay seeking medicalattention, perhaps because the stroke symptoms weremild, or if their doctors delay scanning, imaging might notbe done until 2 weeks or longer after the stroke; an infarctcould then be misdiagnosed on CT, and inappropriatemanagement could follow.22,44

Magnetic resonance (MR) imaging may not identifyacute haemorrhage correctly within the first few hoursbecause the haematoma can be mistaken for a tumourbefore the characteristic MR signs of haemorrhage appear,even when extremely “blood-sensitive” sequences areused (figure 4). Thereafter, haemorrhage can bediagnosed reliably on MR by its characteristic appearance,

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Figure 4: Imaging in a patient 2·5 h after a major left-hemisphere strokeA: Diffusion-weighted MR image shows a large hyperintense left basal ganglia/hemispheric lesion. B:Gradient echo image shows a mass lesion with few signs of haemorrhage-specific features on themedial border (dark areas due to haemosiderin). C: CT immediately afterwards clearly shows anintracerebral haemorrhage with extension into the left lateral ventricle.

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which changes as the haemorrhage matures.45 Inparticular, haemosiderin, the breakdown product storedindefinitely in macrophages in most patients, is visible as adark (hypodense) ring or smudge around the lesion.Thus, when a patient presents longer than a week afterstroke and when it may be extremely important to knowwhether the lesion was an infarct or haemorrhage(influencing a decision to give anticoagulants, forexample), MR with gradient echo imaging (also known asT2*) should be used.46

Gradient echo imaging also detects apparentlyasymptomatic microhaemorrhages. These are thought tobe associated with white-matter hyperintensities,increasing age of the patient, amyloid angiopathy, and

future risk of haemorrhage, but their true clinicalsignificance is unknown.

Diagnosis of ischaemic strokeCT may or may not show a definite infarct, but a normalscan does not necessarily mean that the patient has nothad a stroke. CT is quick and can be done in almost allpatients, however ill. Its value in excluding haemorrhagesand tumours more than outweighs any deficiency inpositively identifying infarcts. After all, during the first fewhours, the idea is to prevent infarction, not display it.About 50% of infarcts never become visible on CT; the

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Figure 5: Comparison of CT and DWIA: Brain CT scan 4 h after a left-hemisphere stroke. Note the subtle lowdensity in the left external capsule and insular region (arrows). B: DWI MR(same patient as in figure 3) 4·5 h after stroke, showing early increase insignal (bright area) in the left insular/sylvian region. The bright lesion onthe dark background on MR is much more easily seen than the darklesion on the light background on CT.

Figure 6: A patient 2 days after a mild right-hemisphere lacunarstrokeCT (A) suggests several possible infarcts in both hemispheres but DWIMR (B) clearly shows the small lacunar infarct (arrow) in the posterior limbof the right internal capsule that caused the recent symptoms.

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proportion is higher in patients with milder strokes(lacunar and small cortical or brainstem infarcts) andlower in patients with severe strokes (medium to largecortical or cerebellar infarcts). The proportion visible alsodepends on the timing of scanning. Within the first fewhours, few infarcts can be seen,47 but they become visibleover the first 1–7 days as dark hypodense wedge-shapedareas (or round if lacunar), with mass effect. After that,about 20% become invisible again for a few weeks(fogging), thereafter reappearing as cerebromalacia, ashrunken area of cerebrospinal-fluid (CSF) density,indicating permanent damage.48

MR imaging with conventional T2 weighting is ingeneral no better than CT; fogging also occurs49 and,although more “holes” are shown, most are probablyirrelevant. The advent of diffusion-weighted imaging(DWI), however, has justified the wider use of MR inacute stroke. DWI can identify ischaemia or infarctionwithin a few minutes as bright (increased signal) areas thatare very easy to identify (figure 5). But even with DWI,some infarcts never become visible. Some severe infarctsdo not appear for several days, though the proportion ofinfarcts not seen at all is much smaller than with CT. Inclinical practice, as well as in research, DWI is especiallyuseful in patients with minor stroke symptoms (the group

in whom CT or T2 MR is least likely to show the lesion;figure 6).50 It is also useful in patients with suspectedrecurrent stroke (to discriminate from worseningneurological deficit due to intercurrent illness) and toidentify multiple infarcts in different arterial territories,which suggest cardioembolic stroke (figure 7). However,MR cannot be used in patients with pacemakers, thosewho are claustrophobic, or in the very ill safely, so it is notas universally useful as CT.

Management of acute strokeTable 1 shows the benefits of treatments for acute strokethat are supported by evidence from randomised trials.51

Specific drug treatments for acute ischaemic strokeAspirin should be given as soon as CT or MR hasexcluded intracranial haemorrhage. Sometimes the scancannot be done until after treatment has started, but theredoes not seem to be any influence on outcome. Ideally,CT scanning should be done immediately, onpresentation. The aspirin dose is 160–300 mg by mouth ifthe patient can swallow safely, or per rectum as asuppository or intravenously.7,8,52–54 The daily dosethereafter is not crucial, but 75–150 mg daily is sufficient.Immediate aspirin treatment slightly lowers the risk ofearly recurrent stroke and increases the chances of survivalfree of disability; about one fewer patient dies or is leftdependent per 100 treated. However, because aspirin isapplicable to so many stroke patients, it has the potentialto have a substantial public-health effect (table 1).53

Aspirin is also likely to reduce the risk of venousthromboembolism.52 In patients treated withthrombolysis, aspirin should be delayed for 24 h.

Heparins or heparinoids lower the risk of arterial andvenous thromboembolism, but these benefits are offset bya similar-sized risk of symptomatic intracranialhaemorrhage.55 There is no reliable evidence to supportthe routine unselective use of these drugs. Nor is there anyevidence that low-molecular-weight heparins orheparinoids offer any net advantage over unfractionatedheparin in acute stroke.56 For patients at high risk of deep-venous thrombosis, low-dose subcutaneous heparin orgraded compression stockings may be worthwhile; 57 theseinterventions have been approved for patients with acuteischaemic stroke in North America and several Europeancountries, but use in routine clinical practice is stilllimited.

Thrombolysis with intravenous recombinant tissue-plasminogen activator (alteplase; 0·9 mg/kg over 1 h)almost certainly increases survival free of disability for afew, highly selected patients who can be assessed andtreated within 3 h of onset of symptoms, althoughtreatment is associated with a chance of fatal intracranialhaemorrhage of about one in 20.58 The trial evidence islimited, so guidelines vary. On the one hand, the Royal

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Figure 7: DWI MR 6 h after a stroke causing right-hemispherecortical symptoms and signsIn addition to the right parietal infarct (bright area) there is a furtherrecent infarct in the left parietal cortex. Multiple infarcts in disparatearterial territories suggest a cardiac source of embolus. The patient wasin atrial fibrillation.

Treatment Effects measured in trials Effects on the population Indication to use

Relative-risk Numbers avoiding Number that can be Number of treated reduction (%) death or dependency treated (% of all patients who avoid

per 1000 treated 2400 strokes) death or dependency

Admission to a stroke unit 9 56 1920 (80%) 107 Admit routinely

Aspirin 3 12 1900 (80%) 23 Use routinely inischaemic stroke

Intravenous thrombolytic drug 10 63 240 (10%) 15 Very selective use <3 h; more trials needed

From reference 51.

Table 1: Benefits and effect on the population of treatments for acute stroke in a population of a million people, among whom 2400first and recurrent strokes may occur in 1 year

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College of Physicians of London recommends that alteplaseshould be used only in the context of randomised trials, andboth the US and Canadian emergency guidelines forphysicians are similarly cautious. On the other hand, thisregimen has been approved in North America and severalEuropean countries, albeit with very tight criteria, but ratesof use in routine clinical practice are still low.

Large-scale trials are needed to answer several questionsreliably. What is the precise duration of the therapeutictime window in which the benefits outweigh the risks—is itlonger than 3 h? What are the optimum selection criteria—

eg, severe strokes only or all strokes, old as well as youngpatients? What is the best agent, dose, and route ofadministration?58–60 How cost-effective is the treatment?60

Trials are under way to clarify these issues.10

There are many other uncertainties. For example, isvisible infarction on CT a contraindication to thrombolysis?Some trials have suggested that patients with visibleinfarction involving more than a third of the territory of themiddle cerebral artery should not be given thrombolysis,61

but others have not.62,63 Furthermore, although scoringsystems help observers to recognise visible infarction, the

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Stroke, or atypical ormultiple cerebral TIAs

Brain imagingCT scan as soon aspossible, if >7 daysafter onset MRI toexclude intracerebralhaemorrhage

Antiplatelet drugsAspirin – 160–300 mg stat,then 75–150 mg dailyClopidogrel 75 mg daily – if aspirin intolerant*Aspirin 75 mg + dipyridamolemodified release 200 mg twice daily – if cerebrovascularevent while on aspirin

Lower blood pressure (target, perhaps 130/70 mm Hgif no adverse effects)‡Thiazide diureticACE inhibitor (check renalfunction)Other agentsUsually wait 1–2 weeks after onsetof any stroke before starting

Lower cholesterolIf plasma concentration>3·5 mmol/LSimvastatin§40 mg at nightCheck liver function

Warfarin if nocontraindicationsTarget INR 2–3unless prostheticvalve†Usually wait 1–2weeks after onsetof any stroke before starting

Considercardioversionantiarrhythmic(eg, amiodarone)

Single typical cerebralTIA, or amaurosis fugax

Carotid territory, goodrecovery and surgerya possible option

If contraindications towarfarin—eg, bleeding,falls, binge drinking,poor compliance

Refer if >70% stenosison symptomatic side,for further vascularimaging and expertadvice

Infarct or no evidenceof haemorrhage

Carotid endarterectomy

Carotidduplex

Haemorrhagic

ECG

Atrialfibrillation

Lifestyle modification¶Smoking cessationLower salt intakeLower fat intakeLower excess alcoholIncrease exerciseLose excess weight

Reduce risk of futurevascular eventsStroke, myocardialinfarction, or vasculardeath

Arrange thyroid functionand echocardiogram ifnot done previously

Sinusrhythm

Figure 8: Guidelines for secondary prevention after stroke or transient ischaemic attack (see table 2)ACE=angiotensin converting enzyme; INR=international normalised ratio. Currently there is evidence to support combinations: *Aspirin and clopidogrel onlyin patients with unstable angina with electrocardiographic or enzyme changes. †Warfarin and aspirin in patients with prosthetic heart valves. ‡Take care inlowering blood pressure if the patient has postural hypotension, abnormal renal function, or severe carotid stenosis. §Consider pravastatin for use incombination with warfarin or digoxin. ¶No clear randomised evidence, but most believe this strategy to be helpful.

Intervention Relative-risk reduction of Absolute risk of stroke Absolute stroke-risk Numbers needed to treat over stroke (%) without treatment over reduction over 2 years (%)† 2 years to prevent one stroke‡

first 2 years (%)*

Aspirin in sinus rhythm 20 15 3 33Systolic blood pressure 25 15 4 25lower by 9 mm Hg

Cholesterol lower by 25 15 4 251·2 mmol/L

Carotid endarterectomy for 40 25 15 7>70% stenosis

Warfarin in atrial fibrillation 67 24 16 6

All values are approximate. *Approximate averages; many individuals are at higher risk, and many at lower risk. †From columns 1 and 2. ‡From column 3. Apart fromsurgery, these interventions will also reduce the risk of coronary events.

Table 2: Interventions to reduce risk of stroke after a transient ischaemic attack on ischaemic stroke

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signs are subtle (figure 5) and patients may be wronglydenied an effective treatment on the basis of a poorlyidentified sign. Further details and an opportunity toparticipate in improving CT reading are available atwww.thalia.dcn.ed.ac.uk. Another uncertainty is whether acombination of DWI and perfusion MR can really identifythe ischaemic penumbra and so perhaps improve thetargeting of treatment for just those patients with still viablebrain.64

Intra-arterial thrombolysis and mechanical clot removalfrom large arteries are technically feasible options for thefew centres with appropriate skills and resources, butfurther trials are needed to establish their place in widerpractice.

Inhibitors of glycoprotein IIb/IIIa may be useful in thetreatment of acute ischaemic strokes65 and in strokescomplicating endovascular procedures on the coronary andcerebral circulation.66 Trials comparing these agents withplacebo and with thrombolytic agents are under way.10

There is no indication to use these agents routinely.Fibrinogen-depleting agents show promise, but more

reliable estimates of their effects will not be available untilthe results of two recent large trials are included in theCochrane review.67

Despite huge efforts, none of the large number ofcompounds tested for neuroprotection seems to be effectivein practice and none has yet gained a product licence.60

Intravenous magnesium appears safe and a promisingtreatment for prehospital use; trials are under way.68,69

Specific treatments for intracranial haemorrhageAppropriately selected patients with acute, spontaneousintracerebral haematomas may benefit from urgent removalof the clot, particularly if it is in the cerebellum.70 However,selection criteria and choice of surgical procedure varywidely between centres. Trials are investigating the place ofsurgery and other invasive interventions.10

Intracranial bleeding in patients on anticoagulantsPatients who develop headache or focal neurologicalsymptoms while receiving oral anticoagulants shouldundergo immediate CT to exclude intracranialhaemorrhage. If haemorrhage is shown, urgent reversal ofthe anticoagulation (generally by intravenousadministration of clotting-factor concentrates) seemssensible, despite the lack of formal evidence. However, thisapproach can be hazardous and the choice of reversalmethod depends on several factors. It should be used onlyunder the guidance of the local haematologist.7

Secondary prevention of stroke (and of otherserious vascular events)Survivors of stroke and patients with TIA worry. Many ask“Will I have another?” and “What are you going to doabout it?”. The risk is not just of stroke but also ofmyocardial infarction and sudden presumed coronarydeath. Recently, an encouraging amount of newinformation has emerged to modify clinical practice insecondary prevention of ischaemic stroke and TIA (figure 8; table 2). There is now much more to offer thanjust antithrombotic drugs and carotid endarterectomy. Lessis known about lowering long-term risk after primaryintracerebral haemorrhage, other than lowering the bloodpressure.

What are the risks after ischaemic stroke and TIA?Commonly quoted risks are 5% per year for stroke(maybe 10% in the first year), 3% per year for myocardialinfarction, and 7% per year for any one of stroke,

myocardial infarction, or vascular death.71 But theseestimates come from older series in which, for manyreasons, patients were not seen until some time after thecerebrovascular event—the very early prognosis wasmissed. We now know that the early risks are higher. 10%of patients with TIA presenting to an emergencydepartment in the USA had a stroke within 90 days (evenwith standard treatment).72 And, in a reanalysis of the dataform the Oxfordshire Community Stroke Project, the riskof stroke in the first 30 days may have been as high as12%.73 Clearly, patients must be investigated andtreatment started as quickly as possible for greatest effect.

Antiplatelet drugs after ischaemic stroke and TIAAspirin lowers the relative risk of serious vascular events:stroke by about a fifth; myocardial infarction by a quarter;and stroke, myocardial infarction, and vascular death byabout a fifth. 75–150 mg per day is the best dose. Forlower doses there are not enough data, and for higherdoses there is no added effectiveness but more adverseevents.74 Are any other antiplatelet regimens better? Theaddition of modified-release dipyridamole to aspirin mayfurther lower stroke risk (but not risk of myocardialinfarction), and more trials are in progress.74 Our practiceis to add dipyridamole to aspirin if the patient has anotherischaemic cerebrovascular event on aspirin (“aspirinfailures”, or a better term might be “breakthrough eventson aspirin”), but this is not strictly evidence based.Clopidogrel may be slightly better than aspirin alone,albeit at very high cost. It is a useful substitute for the fewpatients who are genuinely aspirin intolerant.75 Thecombination of clopidogrel with aspirin is better thanaspirin alone in unstable angina76 and is now being testedafter ischaemic stroke.

Oral anticoagulantsLong-term anticoagulation is not definitely better thanaspirin for patients with ischaemic stroke or TIA who arein sinus rhythm.77,78 However, it does decrease stroke riskby about two-thirds compared with control in those withatrial fibrillation, and it is certainly better than aspirinalone.79 Patients with TIA or very mild ischaemic strokescan start oral anticoagulants within a day or so, but inpatients with larger infarcts anticoagulation shouldprobably be delayed a week or two. The targetinternational normalised ratio is 2·5 (range 2·0–3·0).80 Forpatients in atrial fibrillation who cannot for whateverreason cope with anticoagulation, aspirin still offers someadvantage.74

Blood pressureLowering of blood pressure has been known for years toreduce the risk of a first stroke.81 The recent PROGRESStrial showed that the same applies for secondary strokeprevention, whether ischaemic or haemorrhagic,notwithstanding theoretical concerns of causing stroke byovertreatment.82 Before PROGRESS, the trials were toosmall or the results only preliminary.83 The relative-riskreduction of about a quarter associated with a decrease inblood pressure of 9 mm Hg systolic and 4 mm Hgdiastolic is similar whatever the baseline blood pressure,although the risks of stroke without treatment and hencethe absolute risk reductions are greater with higherpressures, and thus the numbers needed to treat aresmaller. PROGRESS tested a combination of perindopriland indapamide, as well as perindopril alone, and thereduction in stroke risk was of the size predicted fromepidemiological observations. In other words, there wasprobably no additional effect of the drugs tested over and

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above their blood-pressure-lowering effect. Similar drugswould probably do as well for the same blood-pressurereduction, although extrapolation to �-blockers, calciumantagonists, and other compounds is perhaps less certain.Clearly, control of blood pressure must take into accountadverse effects in individual patients, with particular carein those with severe arterial disease in the neck, but ingeneral the lower the pressure the better, down to perhaps130/70 mm Hg, provided any adverse effects areacceptable to the patient. Blood-pressure lowering shouldprobably wait until the acute phase of any stroke hasresolved, perhaps for a week or two, and be introducedslowly; trials of very early blood-pressure lowering are inprogress.

CholesterolAlthough higher plasma cholesterol concentrations do notseem to be associated with increased stroke risk, loweringthe concentration definitely decreases the risk.84 The riskof stroke, myocardial infarction, and the need for vascularprocedures is also reduced by about a quarter forreduction of a fifth in cholesterol concentration. Thisdecrease can be achieved with statins, the natural statins(simvastatin and pravastatin) being a well-tolerated classof drugs provided they are not given to patients withactive liver or muscle disease. The dose should beequivalent to 40 mg daily of simvastatin. The relative riskreductions are much the same for any baseline cholesterolconcentration above 3·5 mmol/L.

Carotid endarterectomyStroke risk ipsilateral to a recently symptomatic carotidstenosis is higher the more extreme the stenosis until theartery distal to the stenosis begins to collapse, and highestsoon after the presenting event. Provided that the surgicalrisk of stroke is less than about 7%, carotidendarterectomy is a reasonable (although quite expensive)option for patients with stenosis of more than 70% by theNASCET method used in the North American trial(>80% by the European trial method). However, patientshave to be prepared to take the small initial surgical risk togain the longer-term benefit in terms of almost abolishingthe high risk of ipsilateral ischaemic stroke.85

Standard practice used to be to carry out an intra-arterial carotid angiogram to assess stenosis severity, butdelays due to waiting for a hospital bed, risks of invasiveangiography in this predominantly older population withsymptomatic vascular disease, and the substantialimprovement in non-invasive vascular imaging havetogether meant that many centres have adoptedalternative policies. Because the surgery trials were allbased on intra-arterial angiographic measurement ofcarotid stenosis, whatever method is used nowadays in itsplace must be accurate compared with angiography,otherwise patients may be denied endarterectomy whenthey need it or offered surgery when they don’t.

Colour doppler ultrasonography, in experienced handswith modern equipment, is a quick, practical, inexpensive,and reliable tool for identifying carotid, vertebral, andsubclavian disease.86 The available evidence, though notextensive,87 suggests that MR angiography tends tooverestimate the degree of stenosis, CT angiography tendsto underestimate it, and colour doppler ultrasonography isin the middle88—compared with the gold standard ofcatheter angiography. Thus, a reasonable strategy is toundertake ultrasonography first and, if severe stenosis issuspected, arrange a further confirmatory non-invasiveimaging test (MR or CT angiography or repeatultrasonography) by an independent observer. If these two

disagree, addition of a third non-invasive test would resultin very few misclassified carotid stenoses. Furthermore,any minor loss of accuracy with the use of non-invasivetests probably more than offsets the complications ofintra-arterial angiography.

It is important to realise that the surgery decision isfinely balanced and depends not just on the degree ofstenosis but also on other factors that put an individualpatient at particular risk without surgery or as a result ofsurgery.90 Whether angioplasty and stenting will turn outto be as effective and durable as endarterectomy remainsto be seen91 and trials are in progress.10

Hormonal treatmentsThere is now reasonably strong evidence fromrandomised trials that in postmenopausal women, with orwithout a history of vascular disease, hormone-replacement therapy increases the risk of stroke and ofvenous thromboembolism and may increase the risk ofmyocardial infarction.92 For women who have had a strokeor TIA, the long-term absolute risks of HRT will generallyoutweigh its benefits. Thus, most postmenopausal womenwith a history of cerebrovascular disease should avoidHRT, unless there are very pressing indications.

LifestyleThe undoubted effectiveness of medical and surgicalinterventions must not detract from lifestyle modification,which should provide additional benefits, perhaps morepleasantly and at lower cost, though with more effort bythe patient. There is no formal randomised evidence

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Patient withstroke or TIA

Generalpractitioner

Ambulatory neuro-vascular assessment(in emergency departmentor clinic) with one-stopinvestigation andinitiation of secondaryprevention

*Early supporteddischargewith continuingrehabilitation at home

EmergencydepartmentBrain attack teamBrain imagingHyperacute treatment(eg, thrombolysis)*

Stroke unit*Acute managementEarly rehabilitationProlonged rehabilitationThe stroke unit may provideall three (comprehensiveunit) or be split into acuteand rehabilitation units

Accelerated referralto hospital

Institutional careTailored to meet needsof patient and family

Long-term follow-up*GP or hospital basedto monitor secondaryprevention and deal withlate-onset and persistingproblems

Homewith care needsprovided andpossibly a familycare worker*

Day hospitalor domiciliaryrehabilitation

Figure 9: Components of a comprehensive stroke service*Supported by reviews in The Cochrane Library.89

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Problem Estimate of frequency Importance Preventive measures Interventions for Potential adverse Evidence to established problem effects of define balance of risk

intervention and benefit

Physiological abnormalitiesHigh Common, especially Associated with poorer Routine antipyretics; Fanning; antipyretics; Prophylaxis may Some small RCTs temperature in first few days outcomes but may be aggressive cooling treat underlying cause delay detection of have shown lower

a marker of other therapy underlying cause; temperatures with complications aggressive cooling regular antipyretics;*

has many potential active cooling not adverse effects adequately evaluated

in stroke†Low arterial Common in severe Likely to increase Positioning; avoidance Supplementary oxygen Oxygen free radicals A single quasi-oxygen stroke and patients brain ischaemia of cardiorespiratory may be harmful randomised trial of saturation with cardiorespiratory problems routine oxygen

disease therapy showed no benefit95

Low blood Uncommon but may May increase brain Avoid causes Treat causes May lead to fluid No studiespressure reflect dehydration ischaemia overload

(common),gastrointestinal (3%) or other bleeding, cardiac failure, or drugs

High blood Very common but May reflect pre-existing ·· Blood-pressure Adverse effects of Current guidelines pressure settles spontaneously hypertension or lowering drugs; could suggest avoidance of

during first week in reaction to acute stroke; increase brain blood-pressure most patients may increase brain ischaemia lowering in acute

oedema or bleeding; phase but RCTs are and may increase risk now in progress†of recurrence

High blood Plasma glucose Associated with worse Many units avoid Insulin sliding scale or Hypoglycaemia A large RCT testing a glucose >6·7 mmol/L reported outcomes but may dextrose infusions in infusions of glucose, aggravating brain glucose, potassium,

in 20–43% of patients reflect diabetic first few days potassium, insulin dysfunction insulin infusion in the admitted to hospital comorbidity or first 24 h is in

increased stroke progress96

severity

Neurological complicationsRaised Reduced Most common cause Raising head of bed; Antioedema agents; Adverse effects of Overview of intracranial consciousness level of death in first week avoid overhydration ventilation; drugs; increased inadequate number ofpressure is common after decompressive pressure gradients trials of glycerol†,

severe stroke; reflects surgery between brain mannitol† and other raised intracranial compartments; antioedema agents;pressure in most cases complications of RCTs of ventilation

ventilation and and decompressive surgery surgery in progress*

Sleep Identified in up to Importance unclear Avoid sedatives; avoid Continuous positive Not well tolerated; Small RCTs in disordered two-thirds of patients supine lying airways pressure resource intensive rehabilitation patients breathing admitted to hospital97 but no reliable

evidence of benefitDysphagia Up to half of patients Prevents oral hydration Routine screening for Nil by mouth; Dehydration and Optimum tube feeding

admitted to hospital and feeding; increases dysphagia with bedside parenteral fluids or poor oral hygiene; regimen being risk of chest infection test; speech and enteral-tube feeding; infected intravenous tested98†

language therapy physical therapy or cannulae; aspiration Orthotics and therapy assessment for those orthotic devices of stomach contents not assessed who fail screen and tube adequately†

complicationsEpileptic Seizures occur in An important cause of Prophylactic Anticonvulsants, but Adverse effects of Not evaluated in seizures about 5% of patients neurological worsening anticonvulsants not uncertainty about drugs context of stroke

within first couple of after stroke widely used and not which drug is best specifically*weeks, most within evaluated and whether to start 24 h99 after first seizure

Spasticity Frequency depends Limit function, may be Positioning, relief of Physiotherapy; Adverse effects of Orthotic devices beingand on preventive painful, and if severe factors that increase splinting; tone- drugs assessed* RCTs havecontractures measures and timing impede skin hygiene tone (eg, pain, anxiety, modifying drugs; shown benefit from

of assessments and lead to pressure overuse of unaffected botulinum toxin; botulinum toxin in sores limbs) denervating selected patients*

proceduresEmotionalism Affects about 1 in 6 May interrupt therapy, ·· Antidepressants; Adverse effects of RCTs of (pathological patients; improves inhibit communication, cognitive behavioural drugs antidepressants crying, with time in most100 and lead to social therapy suggest that they are emotional isolation effective*incontinence)

General complicationsUrinary Occurs in about 1 in 4 Commonly makes Maintain hydration and Antibiotics Adverse effects of Prophylactic infection patients admitted to patient less well and avoid unnecessary antibiotics; infection antibiotics not

hospital within the functional level may fall catheterisation related to adequately evaluatedfirst month or two intravenous cannulae RCTs of antibiotics

probably not needed

(continues next page)

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Problem Estimate of frequency Importance Preventive measures Interventions for Potential adverse Evidence to established problem effects of define balance of risk

intervention and benefit

Chest Occurs in about 1 in 5 Increases hypoxia and Early mobilisation; chest Appropriate Adverse effects of No RCTs availableinfection patients admitted to decreases functional physiotherapy; avoidance antibiotics; antibiotics

hospital within the abilities; difficult to of aspiration chest physiotherapy; first month distinguish from oxygen

pulmonary embolism; common terminal condition

Undernutrition Affects about 1 in 5 Independently Nutritional screening; Oral supplementation Excessive weight Routine oral patients and may associated with poor routine oral supplements or enteral-tube feeding gain and poor supplements being increase during outcomes glycaemic control; tested in FOOD admission especially if reduction of food trial†98

feeding difficulties intake; complicationsof tube feeding

Electrolyte Abnormalities of May cause neurological Ensure patient has Manage fluid status Aspiration with oral Small RCTs comparingdisturbance sodium and potassium sequelae (confusion, access to fluids and or nasogastric fluids; routes of hydration;

are common due to seizures) which monitor biochemistry infection at site of RCTs of dehydration, aggravate stroke regularly intravenous or haemodilution may inappropriate fluids, deficits subcutaneous have some relevance†diuretics, and cannulaeinappropriateantidiuretic hormone

DVT and PE DVT detected with DVT may cause pain Early mobilisation; Anticoagulation for Even prophylactic Haemodilution radiolabelled and fever but mainly adequate hydration; established venous interventions have associated with fewer fibrinogen affects important as source of low-dose heparin; thromboembolism potential problems; DVTs;† RCTs suggest about half of patients PE; PE may cause antiplatelet drugs; but risk-benefit falls due to early that benefits of with hemiplegia but hypoxia and graduated unclear in patients mobilisation; heparin offset by clinically apparent DVT hypotension and thus compression with haemorrhagic bleeding into the bleeding risk;† aspirinin less than 5% cerebral ischaemia and stockings; stroke brain with associated with slight PE diagnosed rarely is a quite frequent intermittent external antithrombotics; reduction in PE;†but is common at cause of death compression ischaemic skin graduated autopsy damage from compression

compression stockings currently stockings being evaluated in

CLOTS trial;† very few data on intermittent externalcompression†

Urinary and Affects up to half of Demeaning and can Avoid exacerbating Treat underlying ·· Small RCTs available faecal patients admitted to cause skin breaks factors—eg, diuretics, causes if possible; but no definitive incontinence hospital; multifactorial excessive aperients bladder retraining;† results†

in most incontinence devices (pads, catheters)

Pressure Frequency varies Painful, depressing Avoidable by positioning, Relieve pressure and Adverse effects of Small RCTs havesores depending on and can be fatal regular turning, and pain, treat infection, antibiotics; shown effectiveness

definitions and pressure relieving and maintain nutrition avoidance of sitting of pressure relief; amount of nursing mattresses and cushions and hydration; may lead to other interventions care, generally less dressings; respiratory problems not adequately than 3% debridement; physical tested†

treatments (eg, ultrasound);supplements(eg, vitamin C)

Falls and Falls reported in Loss of function due to Careful supervision; .. Limitation of RCTs have shown fall-fractures about a third patients soft-tissue and bony avoidance of independent mobility prevention

admitted to hospital; injury, pain and precipitating factors; hip may slow recovery programmes and hip less than 5% result reduced confidence protectors; drugs to protectors are in fractures prevent osteoporosis effective in elderly

patients;† drugs not tested specifically in stroke†

Painful Common but probably Limits function and Avoid traction injury with Physiotherapy; Pain due to No reliable evidence shoulder depends on affects mood careful handling and supports; analgesia; physiotherapy; poor from RCTs†

preventive measures positioning local steroid injections posture due to support device; adverse effects of drugs

Low mood, Very common and Associated with poor Maintain positive attitude Antidepressants; Drug adverse Small RCT of drugs ("post-stroke persistent; difficult to outcome among stroke-unit staff cognitive behavioural effects; opportunity show benefits indepression") assess in patients therapy costs mood;* cognitive and negative with communication behavioural therapy attitudes difficulties not adequately

evaluated

RCT=randomised controlled trial; DVT=deep-venous thrombosis; PE=pulmonary embolism. *Cochrane review protocol available.89 †Cochrane review available.89

Table 3: Physiological abnormalities and complications after acute stroke and their prevention and management

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(which would be very difficult to obtain) that quittingsmoking, losing weight, taking regular exercise,abandoning heavy alcohol consumption, and improvingdiet (less salt and saturated fat) reduce vascular risk, butthese changes probably do all help.

“Taking the medicine”A previously healthy person with a mild ischaemic strokeor TIA is likely to be shocked when offered three drugs(aspirin, simvastatin, and indapamide; or possibly evenfive with perindopril and modified-release dipyridamole)for life and asked to consider carotid surgery. All theoptions must be presented sensitively by physicians whoknow the risks (large and small) and benefits (large andsmall) of the treatments, and quickly—on the day ofpresentation or at the most within a week of onset becauseof the high risk of stroke early on. Perhaps the drugsshould be introduced one at a time so that any earlyadverse effects can be correctly attributed. This isemphatically not cook-book or protocol-driven medicine;the results of trials and meta-analyses (along withcommon sense) have to be interpreted for, and applied to,individual patients.

An integrated approach to meeting the patient’s needsStroke services include both acute care and rehabilitation.They aim, through the application of pharmacological,surgical, and physical interventions, to achieve thegreatest recovery and the lowest risk of complications andfurther vascular events. There is much variation intreatment policies between units, probably because so fewinterventions have been adequately assessed inrandomised controlled trials. However, if a particulartreatment definitely affects outcome, any variation mustbe unacceptable since it means that some patients arereceiving suboptimal treatment. The idea is to define thebest treatment and ensure that all appropriate patientsreceive it.

Components of a specialised stroke serviceA patient with an acute stroke, a TIA, or one of the manydisorders that can mimic either diagnosis needsimmediate access to a specialised stroke service, whichshould provide an integrated approach to their evolvingneeds (figure 9).89 Depending on the patient’s condition,this may include: rapid and accurate clinical andradiological diagnosis; immediate medical (or surgical)treatment; general care to limit the risk of complicationsand to treat any comorbidity; a detailed assessment frommembers of a multidisciplinary team (physician, nurse,physiotherapist, occupational therapist, and speech andlanguage therapist); a period of rehabilitation duringwhich both short-term and long-term functional goals canbe agreed between the patient and team member; andinterventions to reduce the risk of further vascular events.

The notion of providing a comprehensive regionalstroke service is attractive, although its precise structurewill vary according to local geography, politics, prejudice,history, funding arrangements, and the expectations ofpatients and professionals. For example, the extent towhich a stroke service is provided as an outpatient serviceor by admission to an acute or rehabilitation facility willvary substantially between health-care systems (influencedby payment systems) and will depend on the patient’sfunctional level.

Patients with mild or transient symptoms who do notnecessarily need admission can be managed in emergencydepartments that provide immediate access to a specialist,brain and vascular imaging, and other investigations.

Alternatively, these facilities can be brought together in arapid-access outpatient clinic, although some delaybetween the event, assessment, and treatment isinevitable. There is a trade-off between practicality ofdelivering the service equitably to all who may benefit andthe risk of patients developing avoidable problems beforeassessment.

Inpatient care should be provided on stroke units withearly access to a specialised multidisciplinary team thatcan coordinate all parts of care. There is reliable evidencefrom systematic reviews of randomised trials that thisapproach leads to lower mortality and better functionaloutcomes.93 Moreover, because stroke units are so widelyapplicable they prevent more death and dependency thanthrombolysis (table 1). But if thrombolysis is an option, itwill necessitate: education of the public and familydoctors; paramedical training; very well-organised systemsto bring patients with suspected acute stroke to hospitalquickly; efficient well-trained “brain attack” teams to lookafter them once they arrive; and sufficient spare capacityin imaging and high-dependency care to deal with cases atonce, within minutes.60

The features of stroke-unit care that lead to itseffectiveness are not clear.94 The stroke units included inthe systematic review did not regularly use thrombolyticagents or other acute specific treatments, and they did notprovide intensive monitoring of physiological variables.Other features of care must be important, by reducing therisks of complications and by identifying and treatingcomplications early. The number of potential post-strokephysiological abnormalities, neurological, and generalcomplications that need to be expected, prevented,detected, and effectively treated to optimise the outcomefor the patient is very extensive (table 3).89,95–100 Failure todeal with these later sequelae of stroke is likely to negateany benefits from acute pharmacological interventions.

Monitoring and treatment of physiological abnormalitiesMany studies have shown associations between abnormalphysiological measurements (eg, temperature, bloodglucose) shortly after stroke and poor outcomes. If theseabnormalities are found consistently and are shown to beindependent predictors of outcome (ie, not explained byan association with another prognostic factor such as ageor stroke severity), the possibility that they are causal israised. Such observations have led some to introduceinterventions that aim to return the physiologicalmeasurement to normal (table 3). However, althoughclose monitoring of patients with acute stroke may bereasonable, caution is needed in application ofinterventions to prevent complications or normalisephysiological measurements. We are often lessimaginative in considering the biologically plausible harmwe might cause by intervening in these ways than infinding a rationale for benefit. If our interventions couldhave adverse effects or are very costly, they shouldprobably be evaluated in randomised trials to establish thebalance between benefit and risk. Few such trials havebeen completed, although several are in progress.Sometimes the abnormal measurement simply indicatesthat the patient has developed a complication, such asfever as a result of infection or venous thromboembolism.Hence, an intervention that simply aims to normalise theabnormality may not be very effective unless theunderlying cause is identified and treated.

The intensity with which patients are monitored forphysiological abnormalities and complications variessubstantially between stroke units. At one extreme, strokeintensive-care units use one-to-one nursing, invasive

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monitoring of blood pressure and intracranial pressure,and aggressive management of abnormal measurements.At the other extreme, patients may have only pulse,temperature, blood pressure, and Glasgow coma scalerecorded. Although monitoring may seem innocuousenough, invasive monitoring has direct adverse effects (eg,infection) and any monitoring could lead to potentiallyharmful interventions (eg, overaggressive blood-pressurereduction). Encouragingly, a small trial has shown that acompromise with non-invasive monitoring, and protocolsfor treating abnormal physiological measurements, canreduce the frequency of early neurological deterioration.101

Stroke units should provide an environment in whichattitudes, knowledge, and everyday practices ensure thateffective interventions, treatment, and prevention aredelivered to all eligible patients, and ideally whereunproven treatments can be properly assessed. Localguidelines and protocols, integrated care pathways, stafftraining, and audit and quality assurance systems areneeded to optimise performance and thus outcomes forpatients.

Conflict of interest statementWe have been and are principal investigators on steering committees anddata-monitoring committees of trials and collaborative groups concernedwith the treatment and prevention of stroke. However, we do not haveand have not had in the past 5 years any departmental funding fromcommercial organisations to do this work. Our department received agrant from Boehringer-Ingelheim, Novartis, and Schering to establish aresearch MR scanner as part of a joint industry/government scheme, intotal less than 5% of the total set-up cost. Sanofi provided a grant of£20 000 to develop a module for a system to audit quality of outpatientstroke services in Scotland and for us to pilot it in Edinburgh. Some of ushave had honoraria to speak at meetings funded by industry, but no morethan £1000, and to advise companies for fees, which in aggregate come tono more than £3000 per person per year. None of us holds any shares inrelevant companies. For more detail please seewww.dcn.ed.ac.uk/members/conflict.htm.

Role of the funding sourceWe are paid by the University of Edinburgh, the Wellcome Trust, and theLothian University Hospitals Trust, and we currently receive researchgrants from the Wellcome Trust, the PPP Foundation, the Chief ScientistOffice of the Scottish Executive, the Stroke Association, Chest, Heart andStroke Scotland, the Department of Health, Novartis, and Boehringer-Ingelheim. These funders did not see this article before publication.

References1 Warlow CP, Dennis MS, van Gijn J, et al. What caused this transient

or persisting ischaemic event? In: Stroke: a practical guide tomanagement. Oxford: Blackwell Science, 2001: 223–300.

2 Albers GW, Caplan LR, Easton DJ, et al. Transient ischemic attack:proposal for a new definition. N Engl J Med 2002; 347: 1713–16.

3 Murray CJL, Lopez AD. The Global Burden of Disease: acomprehensive assessment of mortality and disability from diseases,injuries and risk factors in 1990 and projected to 2020. Boston:Harvard University Press, 1996.

4 Rothwell PM. The high cost of not funding stroke research: acomparison with heart disease and cancer. Lancet 2001; 357:1612–16.

5 Cochrane Controlled Trials Register. In: The Cochrane Library, Issue3, 2003. Oxford: Update Software.

6 Barton S, ed. Clinical evidence, issue 8. London: BMJ PublishingGroup and the American College of Physicians-American Society ofInternal Medicine, 2002. (Updated every 6 months).

7 Scottish Intercollegiate Guidelines Network. http://www.sign.ac.uk/guidelines/index.html. (accessed March 18, 2003).

8 The Intercollegiate Working Party for Stroke. National clinicalguidelines for stroke. London: Royal College of Physicians, 2002.Available at: www.rcplondon.ac.uk (accessed July 27, 2003).

9 American Heart Association. http://www.americanheart.org/presenter.jhtml?identifier=3004586 (accessed Sept 18, 2002).

10 Internet Stroke Center. http://www.strokecenter.org/trials/ (accessedFeb 18, 2003).

11 Sarti C, Rastenyte D, Cepaitis Z, Tuomilehto J. International trendsin mortality from stroke, 1968 to 1994. Stroke 2000; 31: 1588–601.

12 Sudlow CLM, Warlow CP, for the International Stroke Incidence

Collaboration. Comparable studies of the incidence of stroke and itspathological types: results from an international collaboration. Stroke1997; 28: 491–99.

13 Kolominsky-Rabas PL, Sarti C, Heuschmann PU, et al. A prospectivecommunity-based study of stroke in Germany–the Erlangen StrokeProject (ESPro): incidence and case fatality at 1, 3, and 12 months.Stroke 1998; 29: 2501–06.

14 Thrift AG, Dewey HM, Macdonell RAL, McNeil JJ, Donnan GA.Incidence of the major stroke subtypes: initial findings from the NorthEast Melbourne Stroke Incidence Study (NEMESIS). Stroke 2001;32: 1732–38.

15 Vemmos KN, Bots ML, Tsibouris PK, et al. Stroke incidence andcase fatality in southern Greece: the Arcadia stroke registry. Stroke1999; 30: 363–70.

16 Lauria G, Gentile M, Fassetta G, et al. Incidence and prognosis ofstroke in the Belluno province, Italy: first-year results of a community-based study. Stroke 1995; 26: 1787–93.

17 Carolei A, Marini C, Di Napoli M, et al. High stroke incidence in theprospective community-based L’Aquila registry (1994–1998): firstyear’s results. Stroke 1997; 28: 2500–06.

18 Ellekjaer H, Holmen J, Indredavik B, Terent A. Epidemiology ofstroke in Inherred, Norway, 1994–1996: incidence and 30-day case-fatality rate. Stroke 1997; 28: 2180–84.

19 Feigin VL, Lawes CMM, Bennett DA, Anderson CA. Strokeepidemiology: a review of population-based studies of incidence,prevalence, and case-fatality in the late 20th century. Lancet Neurol2003; 2: 43–53.

20 Warlow CP, Dennis MS, van Gijn J, et al. A practical approach to themanagement of stroke patients. In: Stroke: a practical guide tomanagement. Oxford: Blackwell Science, 2001: 414–41.

21 Smadja D, Cabre P, May F, et al. ERMANCIA: Epidemiology ofstroke in Martinique, French West Indies–part I: methodology,incidence and 30-day case fatality rate. Stroke 2001; 32:2741–47.

22 Keir SL, Wardlaw JM, Warlow CP. Stroke epidemiology studies haveunderestimated the frequency of intracerebral haemorrhage: asystematic review of imaging in epidemiological studies. J Neurol2002; 249: 1226–31.

23 Brown RD, Whisnant JP, Sicks JD, O’Fallon WM, Wiebers DO.Stroke incidence, prevalence, and survival: secular trends inRochester, Minnesota, through 1989. Stroke 1996; 27: 373–80.

24 Jorgensen HS, Plesner AM, Hubbe P, Larsen K. Marked increase ofstroke incidence in men between 1972 and 1990 in Frederiksberg,Denmark. Stroke 1992; 23: 1701–04.

25 Bonita R, Broad JD, Beaglehole R. Changes in stroke incidence andcase-fatality in Auckland, New Zealand, 1981–91. Lancet 1993; 342:1470–73.

26 Feigin VL, Wiebers DO, Whisnant P, O’Fallon WM. Strokeincidence and 20-day case-fatality rates in Novosibirsk, Russia, 1982through 1992. Stroke 1995; 26: 924–29.

27 Jamrozik K, Broadhurst RJ, Lai N, Hankey GJ, Burvill PW, Anderson CS. Trends in the incidence, severity, and short-termoutcome of stroke in Perth, Western Australia. Stroke 1999; 30:2105–11.

28 Counsell C, Dennis M, McDowall M, Warlow C. Predicting outcomeafter acute and subacute stroke: development and validation of newprognostic models. Stroke 2002; 33: 1041–47.

29 Prospective Studies Collaboration. Age-specific relevance of usualblood pressure to vascular mortality: a meta-analysis of individualdata for one million adults in 61 prospective studies. Lancet 2002;360: 1903–13.

30 Prospective Studies Collaboration. Cholesterol, diastolic bloodpressure, and stroke: 13 000 strokes in 450 000 people in 45prospective cohorts. Lancet 1995; 346: 1647–53.

31 Eastern Stroke and Coronary Heart Disease Collaborative Group.Blood pressure, cholesterol and stroke in eastern Asia. Lancet 1998;352: 1801–07.

32 Mas J-L. Patent foramen ovale and stroke. Pract Neurol 2003; 3:4–11.

33 Ridker PM. Inflammatory biomarkers, statins, and the risk of stroke: cracking a clinical conundrum. Circulation 2002; 105:2583–85.

34 Perry IJ. Homocysteine and risk of stroke. J Cardiovasc Risk 1999; 4:235–40.

35 Goldstein LB. Novel risk factors for stroke: homocysteine,inflammation, and infection. Curr Atheroscler Rep 2000; 2: 110–14.

36 Hassan A, Markus HS. Genetics and ischaemic stroke. Brain 2000;123: 1784–812.

37 Danesh J, Collins R, Appleby P, Peto R. Association of fibrinogen, C-reactive protein, albumin, or leukocyte count with coronary heartdisease: meta-analyses of prospective studies. JAMA 1998; 279:1477–82.

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38 Danesh J. Coronary heart disease, Helicobacter pylori, dental disease,Chlamydia pneumoniae, and cytomegalovirus: meta-analyses ofprospective studies. Am Heart J 1999; 138: S434–37.

39 Danesh J, Lewington S. Plasma homocysteine and coronary heartdisease: systematic review of published epidemiological studies.J Cardiovasc Risk 1998; 5: 229–32.

40 Keavney B, McKenzie C, Parish S, et al. Large-scale test ofhypothesised associations between the angiotensin-converting-enzymeinsertion/deletion polymorphism and myocardial infarction in about5000 cases and 6000 controls. Lancet 2000; 355: 434–42.

41 Huxley R, Neil A, Collins R. Unravelling the fetal origins hypothesis:is there really an inverse association between birthweight andsubsequent blood pressure? Lancet 2002; 360: 659–65.

42 Ricci S, Celani MG, Righetti E. Clinical methods for diagnosticconfirmation of stroke subtypes. Neuroepidemiology 1993; 13:290–95.

43 Hawkins GC, Bonita R, Broad JB, Anderson N. Inadequacy ofclinical scoring systems to differentiate stroke subtypes in population-based studies. Stroke 1995; 26: 1338–42.

44 Wardlaw JM, Keir SL, Dennis MS. The impact of delays incomputed tomography of the brain on the accuracy of diagnosis and subsequent management in patients with minor stroke. J Neurol Neurosurg Psychiatry 2003; 74: 77–81.

45 Bradley WG. MR appearance of haemorrhage in the brain. Radiology1993; 189: 15–26.

46 Wardlaw JM, Statham PFX. How often is haemosiderin not visible onroutine MRI following traumatic intracerebral haemorrhage?Neuroradiology 2000; 42: 81–84.

47 Wardlaw JM, Lewis SC, Dennis MS, Counsell C, McDowall M. Is visible infarction on computed tomography associated with anadverse prognosis in acute ischaemic stroke? Stroke 1998; 29:1315–19.

48 Warlow CP, Dennis MS, van Gijn J, et al. What pathological type ofstroke is it? In: Stroke: a practical guide to management. Oxford:Blackwell Science, 2001: 151–93.

49 Pereira AC, Doyle VI, Howe FA, Griffiths JR, Brown MM. Thetransient disappearance of cerebral infarction on T2 weighted MRI.Clin Radiol 2000; 55: 725–27.

50 Wardlaw JM, Armitage P, Dennis MS, Lewis S, Marshall I, Sellar R.The use of diffusion-weighted magnetic resonance imaging to identifyinfarctions in patients with minor strokes. J Stroke Cerebrovasc Dis2000; 9: 70–75.

51 Hankey G, Warlow C. Treatment and secondary prevention of stroke:evidence, costs and effects on individuals and populations. Lancet1999; 354: 1457–63.

52 Gubitz G, Sandercock P, Counsell C. Antiplatelet therapy for acuteischaemic stroke (Cochrane Review). In: The Cochrane Library,Issue 1, 2003. Oxford: Update Software.

53 Chen ZM, Sandercock P, Pan HC, et al. Indications for early aspirinuse in acute ischemic stroke a combined analysis of 40 000randomized patients from the Chinese Acute Stroke Trial and theInternational Stroke Trial. Stroke 2000; 31: 1240–49.

54 Coull BM, Williams LS, Goldstein LB, et al. Anticoagulants andantiplatelet agents in acute stroke. Neurology 2002; 59: 13–22.

55 Gubitz G, Counsell C, Sandercock P, Signorini D. Anticoagulants foracute ischaemic stroke (Cochrane Review). In: The Cochrane Library,Issue 1, 2003. Oxford: Update Software.

56 Counsell C, Sandercock P. Low-molecular-weight heparins orheparinoids versus standard unfractionated heparin for acuteischaemic stroke stroke (Cochrane Review). In: The Cochrane Library,Issue 1, 2003. Oxford: Update Software.

57 Scottish Intercollegiate Guidelines Network Publication No 62:Prophylaxis of venous thromboembolism, October 2002.http://www.sign.ac.uk/guidelines/fulltext/62/index.html(accessed July 27, 2003).

58 Wardlaw, JM, del Zoppo G, Yamaguchi T. Thrombolysis for acuteischaemic stroke stroke (Cochrane Review). In: The Cochrane Library,Issue 1, 2003. Oxford: Update Software.

59 Wardlaw JM, Liu M. Thrombolysis (different doses, routes ofadministration and agents) for acute ischaemic stroke stroke(Cochrane Review). In: The Cochrane Library, Issue 1, 2003. Oxford:Update Software.

60 Sandercock P, Berge E, Dennis M, et al. A systematic review of theeffectiveness, cost-effectiveness and barriers to implementation ofthrombolytic and neuroprotective therapy for acute ischaemic strokein the NHS. Health Technol Assess 2002; 6: 35–57.

61 von Kummer R. CT of acute cerebral ischemia. Radiology 2000; 216:611–12.

62 Patel SC, Levine S, Tilley BC, et al. Lack of clinical significance ofearly ischaemic changes on computed tomography in acute stroke.JAMA 2001; 286: 2830–38.

63 Gilligan AK, Markus R, Read SJ, et al. Baseline blood pressure but

not early computed tomography changes predicts major haemorrhagein acute ischaemic stroke. Stroke 2002; 33: 2236–42.

64 Donnan GA, Davis SM. Neuroimaging, the ischaemic penumbra,and selection of patients for acute stroke therapy. Lancet Neurol2002; 1: 417–23.

65 Winkley JM, Adams HP Jr. Potential role of abciximab in ischemiccerebrovascular disease. Am J Cardiol 2000; 85: 47C–51C.

66 Kittusamy PK, Koenigsberg RA, McCormick DJ. Abciximab for thetreatment of acute distal embolization associated with internalcarotid artery angioplasty. Catheter Cardiovasc Interv 2001; 54:221–33.

67 Liu M, Counsell C, Wardlaw JM. Fibrinogen depleting agents foracute ischaemic stroke (Cochrane Review). In: The Cochrane Library,Issue 1, 2003. Oxford: Update Software.

68 Bradford AL. Design of the Intravenous Magnesium Efficacy inAcute Stroke (IMAGES) trial. Curr Control Trials Cardiovasc Med2000; 1: 184–90.

69 Saver JL, Kidwell CS, Hamilton S, et al. The field administration ofstroke therapy: magnesium (FAST-MAG) phase 3 trial. 27thInternational Stroke Conference, 2002.

70 Fernandes HM, Gregson B, Siddique S, Mendelow AD. Surgery inintracerebral hemorrhage: the uncertainty continues. Stroke 2000;31: 2511–16.

71 Warlow CP, Dennis MS, van Gijn J, et al. Preventing recurrentstroke and other serious vascular events. In: Stroke: a practical guideto management. Oxford: Blackwell Science, 2001: 653–722.

72 Johnston SC, Gress DR, Browner WS, Sidney S. Short-termprognosis after emergency department diagnosis of TIA. JAMA2000; 284: 2901–906.

73 Lovett JK, Dennis MS, Sandercock PAG, Bamford JM, Warlow CP,Rothwell PM. High early risk of stroke after a first transientischaemic attack. J Neurol Neurosurg Psychiatry (in press).

74 Antithrombotic Trialists’ Collaboration. Collaborative meta-analysisof randomised trials of antiplatelet therapy for the prevention ofdeath, myocardial infarction, and stroke in high risk patients. BMJ2002; 324: 71–86.

75 Hankey GJ, Sudlow CLM, Dunbabin DW. Thienopyridines oraspirin to prevent stroke and other serious vascular events inpatients at high risk of vascular disease? A systematic review of theevidence from randomized trials. Stroke 2000; 31: 1779–84.

76 The Clopidogrel in Unstable Angina to Prevent Recurrent Events(CURE) Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494–502.

77 Gubitz G, Sandercock P. Stroke prevention: long term oralanticoagulation for people in sinus rhythm. In: Barton S, ed.Clinical evidence, issue 8. London: BMJ Publishing Group and theAmerican College of Physicians–American Society of InternalMedicine, 2002. (Updated every 6 months).

78 Algra A, de Schryver ELLM, van Gijn J, Kappelle LJ, Koudstaal PJ.Oral anticoagulants versus antiplatelet therapy for preventing furthervascular events after transient ischaemic attack or minor stroke ofpresumed arterial origin (Cochrane Review). In: The CochraneLibrary, Issue 1, 2003. Oxford: Update Software.

79 Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotictherapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999; 131: 492–501.

80 Scottish Intercollegiate Guidelines Network Publication No 36:Antithrombotic therapy, March 1999. http://www.sign.ac.uk/guidelines/fulltext/36/index.html (accessed July 27, 2003).

81 Collins R, MacMahon S. Blood pressure, antihypertensive drugtreatment, and the risks of stroke and of coronary heart disease.Br Med Bull 1994; 50: 272–98.

82 PROGRESS Collaborative Group. Randomised trial of aperindopril-based blood-pressure-lowering regimen among 6105individuals with previous stroke or transient ischaemic attack. Lancet2001; 358: 1033–41.

83 Sudlow C. Stroke prevention: blood pressure reduction. In: BartonS, ed. Clinical evidence, issue 8. London: BMJ Publishing Groupand the American College of Physicians–American Society ofInternal Medicine, 2002. (Updated every 6 months).

84 Heart Protection Study Collaborative Group. MRC/BHF HeartProtection Study of cholesterol lowering with simvastatin in 20 536high-risk individuals: a randomised placebo-controlled trial. Lancet2002; 360: 7–22.

85 Rothwell PM, Eliasziw M, Gutnikov SA, et al. Analysis of pooleddata from the randomised controlled trials of endarterectomy forsymptomatic carotid stenosis. Lancet 2003; 361: 107–16.

86 Zweibel WJ. Duplex carotid sonography. In: Zweibel WJ, ed.Introduction to vascular ultrasonography, 3rd edn. Philadelphia: W B Saunders, 1992: 105–32.

87 Rothwell PM, Pendlebury ST, Wardlaw JM, Warlow CP. A critical

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appraisal of the design and reporting of studies of imaging andmeasurement of carotid stenosis. Stroke 2000; 31: 1444–50.

88 Patel SG, Collie D, Wardlaw JM, et al. Outcome, observer reliability,and patient preferences if CTA, MRA, or Doppler ultrasound wereused, individually or together, instead of digital subtractionangiography before carotid endarterectomy. J Neurol NeurosurgPsychiatry 2002; 73: 21–28.

89 The Cochrane Library, Issue 3, 2002. Oxford: Update Software.90 Rothwell PM, Warlow CP, on behalf for the European Carotid

Surgery Trialists’ Collaborative Group. Prediction of benefit fromcarotid endarterectomy in individual patients: a risk-modelling study.Lancet 1999; 353: 2105–10.

91 CAVATAS Investigators. Endovascular versus surgical treatment inpatients with carotid stenosis in the Carotid and VertebralTransluminal Angioplasty Study (CAVATAS): a randomised trial.Lancet 2001; 357: 1729–37.

92 Beral V, Banks E, Reeves G. Evidence from randomised trials on thelong-term effects of hormone replacement therapy. Lancet 2002; 360:942–44.

93 Stroke Unit Trialists’ Collaboration. Organised inpatient (stroke unit)care for stroke (Cochrane Review). In: The Cochrane Library, Issue1, 2003. Oxford: Update Software.

94 Langhorne P, Pollock A in conjunction with the Stroke Unit TrialistsCollaboration. What are the components of effective stroke unit care?Age Ageing 2002; 31: 365–71.

95 Ronning OM, Guldvog B. Should stroke victims routinely receivesupplemental oxygen? Stroke 1999; 30: 2033–37.

96 Scott JF, Robinson GM, French JM, O’Connell JE, Alberti KGMM,Gray CS. Glucose potassium insulin infusions in the treatment ofacute stroke patients with mild to moderate hyperglycaemia. Stroke1999; 30: 793–99.

97 Bassetti C, Aldrich MS. Sleep apnoea in acute cerebrovasculardiseases: final report on 128 patients. Sleep 1999; 22: 217–22.

98 The FOOD Trial Collaboration. Performance of a statistical model topredict stroke outcome in the context of a large simple randomisedcontrolled trial of feeding. Stroke (in press).

99 Burn J, Dennis M, Bamford J, Sandercock P, Wade D, Warlow C.Epileptic seizures after a first-ever stroke: the Oxfordshire CommunityStroke Project. BMJ 1998; 315: 1582–87.

100House A, Dennis MS, Molyneux A, Warlow C, Hawton K.Emotionalism after stroke. BMJ 1989; 298: 991–94.

101Davis M, Hollymann C, McGiven M, Chambers I, Egbuji J, Barer D.Physiological monitoring in acute stroke. Age Ageing 1999;28 (suppl 1): P45.

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Bone-marrow fibrin-ring granuloma

Patrick Blanco, Jean-François Viallard, Marie Parrens, Patrick Mercié, Jean-Luc Pellegrin

Clinical picture

Clinique de Médecine Interne et Maladies Infectieuses (P Blanco MD, J F Viallard MD, J L Pellegrin MD, P Mercié MD), Laboratoired'Anatomopathologie (M Parrens MD), Hôpital Haut-Lévêque, 33604 Pessac Cedex, France

A 74-year-old woman presented with fever, asthenia,anorexia, and weight loss of 4 kg. She had no medicalhistory. On physical examination she had polyadenopathywithout splenomegaly. Results of laboratory investigationswere as follows: white blood cell (WBC) count17·7�109/L (total lymphocyte count 6·7�109/L, with0·93�109/L hyperbasophilic atypical lymphocytes);haemoglobin 121 g/L; platelets 267 000/�L; raised aspar-tate and alanine aminotransferase 50 IU/L (normal 10–35 IU/L) and 79 IU/L (normal 5–40 IU/L),respectively. Analysis of lymphocyte subpopulationsrevealed a low CD4�/CD8� ratio (1·1/1·86). Bone-marrow biopsy specimen contained multiple fibrin-ringgranulomas (figure). Specific serological tests for Epstein-Barr virus detected IgM and IgG anti-early antigen (EA)but no antibodies to Epstein-Barr nuclear antigen(EBNA), indicating a primary infection. Heterophilantibodies were present. Paracetamol resolved clinicalsymptoms within 2 weeks. 6 months later the patient wasasymtomatic. Routine haematological test results werenormal, including the CD4�/CD8� ratio. IgG anti-EBNA antibodies had appeared and IgM anti-EA haddisappeared.


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