ictus complicaciones2011

8/3/2019 Ictus Complicaciones2011

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Review

Lancet Neurol 2011; 10: 35771

Published Online

January 18, 2011

DOI:10.1016/S1474-

4422(10)70313-6

Acute Stroke Programme,

Department of Medicine and

Clinical Geratology, Oxford

Radcliffe NHS Trust, Oxford, UK

(J S Balami MRCP); Nuffi eld

Department of Medicine,

University of Oxford, Oxford,

UK (R-L Chen PhD);Department

of Neuroradiology, BiomedicalResearch Centre, John Radcliffe

Hospital, Oxford, UK

(I Q Grunwald PhD,

Prof A M Buchan FMedSci);and

Acute Vascular Imaging Centre,

Biomedical Research Centre,

University of Oxford, John

Radcliffe Hospital, Oxford, UK

(A M Buchan)

*Contributed equally to this

Review.

Correspondence to:

Prof Alastair M Buchan, Acute

Vascular Imaging Centre,

Biomedical Research Centre,

University of Oxford, JohnRadcliffe Hospital, Oxford

OX3 9DU, UK

[email protected].

ac.uk

Neurological complications of acute ischaemic stroke

Joyce S Balami*, Ruo-Li Chen*, Iris Q Grunwald, Alastair M Buchan

Complications after ischaemic stroke, including both neurological and medical complications, are a major cause ofmorbidity and mortality. Neurological complications, such as brain oedema or haemorrhagic transformation, occurearlier than do medical complications and can affect outcomes with potential serious short-term and long-termconsequences. Some of these complications could be prevented or, when this is not possible, early detection andproper management could be effective in reducing the adverse effects. However, there is little evidence-based data toguide the management of these neurological complications. There is a clear need for improved surveillance andspecific interventions for the prevention, early diagnosis, and proper management of neurological complicationsduring the acute phase of stroke to reduce stroke morbidity and mortality.

IntroductionAdvances in the diagnosis and treatment of acute stroke

have been made over the past two decades, but mortalityafter stroke is still high, with stroke ranked as thesecond most common single cause of death in thedeveloped world after ischaemic heart disease, or thirdif all neoplastic diseases are considered as a group. 1 Aleading cause of death, accounting for 2350% of totaldeaths in patients with ischaemic stroke, is post-strokecomplications. 2 Even if not always life-threatening,these complications can lead to delay in rehabilitation,prolonged hospital stays, poor functional outcomes,and increased costs of care.24 Complications afterischaemic stroke comprise medical and neurologicalcomplications. 2,5,6 Neurological complications include

brain oedema, haemorrhagic transformation, seizuresand epilepsy, recurrent stroke, and delirium (table 1).These complications are less frequent than medicalcomplications5 but occur earlier in the course of strokeprogressionwithin 4872 h of stroke onset rather thanwithin the first few weeks of stroke.6,7,9,16,20 Results fromsome studies have indicated that deaths within the firstfew days of stroke are usually the direct consequence ofbrain damage from neurological complications.21,22Similarly, autopsy series of early stroke fatalities haveindicated that death within the first week after stroke ismainly attributable to the direct effects of stroke, suchas brain oedema with transtentorial herniation.22,23 In astudy of neurological worsening during the acute

phase of ischaemic stroke in 1964 patients, 336% ofpatients deteriorated because of progressive stroke,273% as a result of brain swelling, 113% owing torecurrent ischaemic stroke, and 105% because ofparenchymal haemorrhage. The remaining 173%deteriorated because of pyrexia, hyperglycaemia, andhypertension, which are abnormal physiologicalvariables or medical complications.24

Many reviews have focused on medical complicationsand their management, with little discussion ofneurological complications.3,25,26 Moreover, there are fewevidence-based data to guide the management of theseneurological complications. For example, a predicamentarises in the prevention and effective management ofbrain oedema, which is a leading cause of death.

Treatments aimed at reducing intracranial pressure areof unproven value. Similarly, there is insuffi cient evidence

to lend support to the routine use of antiepileptic drugsfor the primary or secondary prevention of seizures afterischaemic stroke. Additionally, therapeutic dilemmas canarise as to when to use anticoagulation after recurrentstroke in patients with atrial fibrillation and possiblehyperthrombotic states.

In this Review, we focus on major neurological compli-cations with an emphasis mainly on those events thatoccur in the acute phase of ischaemic stroke. We discussneurological complications both in animals and in clinicalsettings. We outline the relevant preventive and manage-ment strategies based on recent evidence and guidelinesand highlight the paucity of evidence for many importantand prevalent neurological complications. Subacute andchronic neurological complications (eg, depression anddementia) and medical complications are beyond thescope of this Review and have not been included.

Brain oedemaClinical featuresBrain oedema is a leading cause of death after stroke,especially within the first week.27Patients with stroke6,24andanimals with cerebral ischaemia28 often have brain oedema.The primary cause of brain oedema is ionic imbalance dueto energy depletion in cerebral ischaemia.29 Two types ofoedemacytotoxic and vasogenic oedemaoccur inpatients with ischaemic stroke. Cytotoxic oedema is

characterised by the translocation of interstitial water intothe intracellular compartment and occurs early, when thebloodbrain barrier is still intact.30 At the late stage ofstroke, the bloodbrain barrier is compromised, causingvasogenic oedema, characterised by fluid movement fromvascular to extravascular spaces.31 Vasogenic oedema leadsto an expansion of brain volume with increased intracranialpressure, herniation, and additional ischaemic injuries.32Differentiation of cytotoxic and vasogenic brain oedema inthe clinical setting is important for diagnostic andtherapeutic purposes because cytotoxic oedema isunresponsive to anti-oedematous pharmacologicaltreatment.33 Recent advances in MRI help to distinguishthe type of oedema. Cytotoxic brain oedema causes areduction in overall diffusivity of water molecules and


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shows high signal intensity on diffusion-weighted MRI34(figure 1A), whereas vasogenic oedema causes increasedwater in brain tissues, which can be shown on conventionalT2-weighted images35 and fluid-attenuated inversionrecovery sequences36 (figure 1B, figure 1C).

The extent of swelling highly depends on the extentand location of the infarcted area37 and the age of thepatients.38 Younger patients are more prone to developingfatal brain oedema or malignant middle cerebral artery(MCA) syndrome than are older patients.38,39 Results fromanimal studies also show that ageing mice havesignificantly less stroke-induced oedema than do young

animals,40 possibly because some cerebral atrophyprotects older people from developing space-occupyingbrain swelling.27

Hemispheric oedemaThe overall risk of cerebral oedema in patients withanterior circulation ischaemic stroke is estimated to be1020%.4143 In patients with major anterior circulationocclusion such as MCA stem occlusion, cerebral oedematends to appear within the first 4 days after stroke onset.44,45Patients with large cerebral infarction, especially whencomplicated by brain oedema, often present in coma46,47(figure 2A and figure 3A). Brain oedema with midlinestructure shift or brainstem compression is a majorcause of mortality.47

Malignant MCA infarction is a condition in which theMCA territory is completely infarcted, with rapidlydeveloping massive swelling, which can cause brainherniation as early as 20 h after symptom onset.27 Thistype of infarction is life-threatening and is one of the mostdevastating neurological complications of ischaemicstroke, occurring in 110% of all supratentorial ischaemicstrokes.27 The overall mortality rate for acute MCAinfarctions caused by cerebral herniation secondary tobrain oedema ranges between 7% and 23%, whereas thatof malignant MCA infarction is estimated to be between40% and 80%,27,48 and up to 80% in untreated patients.27,33

The development of malignant MCA infarction can bepredicted with high sensitivity (91%) and specificity (94%)by the appearance of large hypoattenuation (defined asgreater than two-thirds of the MCA territory) on enhancedCT and large areas of hypoperfusion on CT perfusionimaging.43,49,50 Other predictive imaging findings are alarge diffusion-weighted imaging lesion volume, severeperfusion deficits on perfusion-weighted MRI or singlePET scan within 6 h, and a large area showing an apparentdiffusion coeffi cient decrease within 6 h of stroke.51,52

Cerebral vein and dural sinus thrombosis (CVST) is aninfrequent stroke type but is potentially life-threatening,with mortality ranging from 43% to 83%.53,54 CVSTcauses a wide range of parenchymal changes, includingcytotoxic oedema and substantial vasogenic oedema.

Indredavik

et al7

Navarro

et al8

Hong

et al9

Rocco

et al10

Hung

et al11

Heuschmann

et al12

Cavallini

et al13

Weimar

et al2

Roth

et al14

Grau

et al15

Langhorne

et al16

Johnston

et al6

Pinto

et al17

Davenport

et al18

Kalra

et al19

Dromerick

and Reding5

Study design P, SC P, MC P, MC P, SC P, SC R, MC R, SC P, MC P, SC P, MC P, MC R, MC P, SC P, SC R, SC P, SC

Participants (n) 489 1153 1254 261 346 13440 268 3866 1029 5017 311 279 213 607 245 100

Type of stroke IS, HS IS, HS IS IS, HS IS, HS IS IS IS IS, HS IS IS, HS IS IS IS, HS IS, HS IS, HS

Timing Acute,

subacute

Acute Acute Sub-

acute

Sub-

acute

Acute Acute Acute Sub-

acute

Acute Acute,

subacute

Acute,

subacute

Acute Subacute Sub-

acute

Subacute

Total complication

rate (%)

64 429 242 60 44 544 54 292 75 85 95 41 59 60

Stroke

progression* (%)

184 171 79 112 3 45

Brain oedema (%) 8

Increased ICP (%) 28 76 63

Brain herniation

(%)

3

Hydrocephalus (%) 1 05 SHT (%) 3 03 14

ICH (%) 2 17 4 05

Seizures (%) 20 13 1 17 15 30 14 15 14 3 3 05 4 38 3

Recurrent stroke

(%)

10 49 20 15 25 51 16 43 9 18 09

Delirium or

confusion (%)

30 36 5

Consciousness

disturbance (%)

158 5

=not reported. R=retrospective. P=prospective. IS=ischaemic stroke. HS=haemorrhagic stroke. SC=single centre. MC=multicentre. ICP=intracranial pressure. SHT=symptomatic haemorrhagic transformation.

ICH=intracerebral haemorrhage. *Stroke progression refers to early neurological deterioration in the acute phase of stroke associated with poor prognosis.

Table 1: Clinical studies with reported frequencies of neurological complications after stroke


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Stupor or coma is reported in 1519% of patients with

CVST, especially in patients with bilateral thalamicinvolvement.54 Transtentorial herniation attributable tomultiple lesions, diffuse oedema, and focal mass effect isthe most frequent cause of death.54 The term malignantCVST describes a subset of patients with rapid deteriorationfrom severe CVST with supratentorial parenchymal lesionsand signs of transtentorial herniation and is reported tooccur in about 5% of cases.55 Signs of malignant CVSTmight be present at onset or in the first 48 h in about 25%of patients, but these signs usually occur after a few days ofundiagnosed headache. The deterioration can be extremelyrapid, occurring as early as 22 h after symptom onset.Frequent seizures, the presence of large, haemorrhagicparenchymal lesions, and a rapid increase in lesion volume

can be indicative of a malignant course.55

Cerebellar oedemaCerebellar oedema is a common complication in 1754%of patients with cerebellar infarction and can inducebrainstem compression, descending (transforaminal) orascending (transtentorial) herniation, and obstructivehydrocephalus.5658 Cerebellar oedema usually peaks onthe third day after the infarction, although it can occurany time after ischaemia.58 The posterior fossa provideslittle space for compensation of mass effect, and life-threatening brainstem compression can develop rapidly.Gaze palsy and a progressive decline in level ofconsciousness are common clinical manifestations.56Additionally, rapid deterioration from cerebellar oedemacan be associated with sudden apnoea from brainstemcompression and cardiac arrhythmias. Malignantcerebellar infarction describes a subset of patients withrapid deterioration from infarct swelling.5860 Neuro-imaging can be used to detect severe oedema formationbefore transforaminal or transtentorial herniation occurs58(figure 2B). CT scans can be used to show displacementof the fourth ventricle, obstructive hydrocephalus, andobliteration of the basal cisterns.56,61 However, initial CTscans are normal in up to 25% of patients who thendevelop mass effect.58 Coma or loss of consciousness iscommonly associated with brainstem syndromes such as

top-of-the-basilar syndrome62 and locked-in syndrome.63Hiccoughs can be associated with lateral medullary

infarction (Wallenbergs syndrome), after lesions in thepontomedullary area of the brainstem or infarction in theterritory of the posterior inferior cerebellar artery, andcan cause distress, exhaustion, aspiration pneumonia,and respiratory distress.64,65 Intractable hiccoughs mightlead to the development of irregularities of the respiratoryrhythm culminating in respiratory arrest.65

ManagementThe initial general management of increased intracranialpressure after acute ischaemic stroke includes elevationof the head end of the bedto a 2030 angle in an attemptto improve venous drainage. Additionally, factors that

increase intracranial pressure such as hypoxia,hypercapnia, hyperthermia, hyperglycaemia, andantihypertensive drugs, particularly those that can causecerebral vasodilatation, should be avoided.59

Hemicraniectomy is recommended in selected patientswith substantial brain ischaemic swelling and life-threatening brain shifts.59,60 The underlying principle ofremoving part of the cranium is to create space for theexpanding brain so as to prevent secondary damage tovital brain tissue and to improve collateral perfusion.66

Figure 1: MRI showing c ytotoxic and vasogenic brain oedema after cerebellar infarction (arrows)

(A) Diffusion-weighted MRI showing cytotoxic oedema in the left cerebellum. (B) Axial fluid-attenuated inversion

recovery image showing vasogenic oedema that matches the DWI lesion. (C) T2-weighted MRI showing vasogenic

oedema 2 days after stroke onset.

Figure 3: Brain samples showing cerebral infarction and haemorrhagic transformation

Slices of brain from autopsy showing (A) an area of infarction involving the middle cerebral artery territory (arrow)

and (B) an area of haemorrhagic transformation in the cerebral hemisphere (from a different patient).

Figure 2: CT scans showing cerebral and cerebellar oedema after acute

ischaemic infarct

(A) CT scan showing cerebral oedema (green arrow) with compression of the left

ventricle (red arrow) after infarct of the left middle cerebral artery territory.

(B) CT scan showing posterior circulation stroke (left-sided posterior inferior

cerebellar artery infarct) with involvement of the pons 10 h after onset of stroke

(green arrows).

B CA

BA

BA


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Similarly, decompressive surgery can improve corticalcollateral vein drainage, thus preventing the extension ofthrombosis and possibly favouring the diffusion ofheparin in CVST.55 Table 2 summarises both medicaland surgical management of brain oedema afterischaemic stroke.

Haemorrhagic transformationClinical features

Haemorrhagic transformation of brain infarction is acommon and potentially serious complication of acuteischaemic stroke occurring in 3040% of clinical cases.79

The main causes of haemorrhagic conversion are theloss of microvascular integrity and disruption ofneurovascular homoeostasis.80 The mechanisms for thedisruption are multifactorial, and these factors caninteract with each other. These factors have beenidentified as treatment with alteplase, aquaporin, matrixmetalloproteinase, inflammation, vascular endothelialgrowth factor, nitric oxide synthase, and free radicals. 30The frequency of symptomatic haemorrhagictransformation is higher in patients treated withintravenous alteplase (6%), mechanical embolectomy,and intra-arterial fibrinolytics (7%) than in those

managed with supportive care (06%).8183 Althoughthrombolysis with alteplase increases the risk ofhaemorrhage, which remains the most fearedcomplication, 100 patients need to be treated withalteplase for one significant adverse outcome to occur.41In addition to thrombolytic drugs, the use of otherantithrombotics, especially anticoagulants, can increasethe likelihood of serious haemorrhagic transformationafter ischaemic stroke.84,85 The early use of aspirin could

be associated with a small increase in the risk of clinicallydetectable haemorrhage. However, in the InternationalStroke Trial (IST),86 aspirin did not have a significanteffect on the risk of haemorrhagic transformationcompared with prophylactic use of medium-doseheparin, which significantly increased the risk ofhaemorrhagic transformation during the first few weeksafter ischaemic stroke.Other risk factors for thrombolysis-related intracerebral haemorrhage include age olderthan 65 years, severe stroke, high glucose concentrationsin the serum, and signs of mass effect on pre-treatmentimaging.87 Elderly patients with stroke are more likely todevelop haemorrhagic transformation owing to factorssuch as impaired rate of alteplase clearance, higherfrequency of transformation in cardioembolic than

Description Level of evidence

Medical

General Measures should be taken to reduce risk of oedema, and patients should be closely monitored for signs of neurological worsening during the first

few days after ischaemic stroke59Level 1B

Osmotherapy Osmotherapy using glycerol, mannitol, corticosteroids, barbiturates, or hyperosmolar saline solutions are recommended for treatment of

deteriorating patients with brain oedema after large cerebral infarction, although these measures are unproven59

Osmotic substances might be harmful in venous outflow obstruction because they are not quickly eliminated from the intracerebral circulation67

Level 3C

Hypothermia Moderate hypothermia between 32C and 34C might improve clinical outcome;68 in a small RCT (n=25), mild hypothermia (35C) in addition to

decompressive surgery led to a better clinical outcome than did decompressive surgery alone69

No recommendation is given about hypothermic therapy in patients with space-occupying infarction60

Level 3C

Anticoagulation Routine use of anticoagulation for improving neurological outcome in arterial ischaemic stroke has not been proven and is not recommended59

Intravenous anticoagulation with heparin or subcutaneous anticoagulation with low-molecular-weight heparin followed by oral anticoagulation is the

first-line treatment for symptomatic CVST70

Endovascular chemical thrombolysis or mechanical thrombectomy might be needed when systemic anticoagulation therapy fails or is considered

to be high risk in patients with CVST 71

Management of isolated intracranial hypertension owing to CVST might involve a lumbar puncture to drain CSF before starting heparin when patients

develop papilloedema that might threaten visual acuity; this event is usually followed by a rapid improvement of headache and vision deficits 67

Level 3C

Surgical

Decompressive surgery If done early, decompressive hemicraniectomy (


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atherosclerotic infarcts, and possible age-associatedmicroangiopathy (either cerebral amyloid angiopathy orhypertensive microangiopathy) and leukoaraiosis.88

Haemorrhagic venous infarct is common in CVST,occurring in about 3040% of patients.54Haemorrhage incerebral venous thrombosis might be precipitated bycontinued arterial perfusion in areas of cell death, as inreperfusion in arterial ischaemia. Increased venouspressure beyond the limit of the venous wall is also alikely mechanism.89

Intracerebral haemorrhage ranges from small

asymptomatic petechiae to large haematoma with possiblepressure effects (figure 3B). On the basis of radiologicalappearance or clinical measurements, haemorrhagictransformation can be graded by use of either the NationalInstitute of Neurological Disorders and Stroke (NINDS)90or European Cooperative Acute Stroke Study (ECASS)91classifications. ECASS classifies haemorrhagic trans-formation into haemorrhagic infarction and parenchymalhaemorrhages, with each class further divided into twotypes (figure 4). H1-1 is defined as small petechiae alongthe margins of the infarcted area; HI-2 as confluentpetechiae within the infarcted area, but with no masseffect; PH-1 as haematoma in less than 30% of the infarctedarea with mild mass effect; and PH-2 as haematoma inmore than 30% of the infarcted area with a notable mass

effect.91 The NINDS system classifies haemorrhagictransformation into two types: haemorrhagic cerebralinfarction, defined as CT findings of acute infarction withpunctate or variable hypodensity and hyperdensity, with anindistinct border within the vascular territory; and intra-cerebral haematoma, defined as CT findings of a typicalhomogeneous, hyperdense lesion with a sharp border withor without oedema or mass effect within the brain.90

Haemorrhagic transformation expands brain oedemaand leads to displacement and disruption of brainstructures, increases intracranial pressure, induces

apoptotic neuronal and glial cell death,92 and is associatedwith extremely high rates of mortality. In patients withcerebellar ischaemia (figure 4), there is also a notablyincreased risk of deterioration from mass effect.58Similarly, haemorrhagic venous infarct in CVST can leadto death from cerebral herniation.70

ManagementThere is no intervention available for reducing the risk ofhaemorrhagic transformation, although careful selectionof suitable patients for thrombolytic therapy could reducethis complication. Antithrombotic drugs are notrecommended for use in the first 24 h after thrombolytictreatment.59 Management of patients with haemorrhagictransformation depends on the amount of bleeding and

Figure 4: CT and MRI scans showing cerebral and cerebellar haemorrhagic transformation according to the ECASS classification

(AE) Cerebral haemorrhagic transformation. CT images showing (A) small petechiae (ECASS91 H1-1), (B) confluent petechiae (H1-2), (C) haematoma in 30% of the infarcted area with a notable mass effect (PH-2). (E) MRI scan shows T2*-weighted

image of haemosiderin within the infarcted area (PH-1, haematoma in


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associated symptoms, which might require neurosurgical

clot evacuation in deteriorating patients.The decision as to whether or when to restart anti-thrombotic therapy after haemorrhagic transformationdepends on the risk of subsequent arterial or venousthromboembolism, the risk of recurrent intracerebralhaemorrhage, and the clinical state of the patient.Antiplatelet drugs might be a better and safer choice thanwarfarin for patients with a relatively lower risk ofcerebral infarction (eg, patients with non-valvular atrialfibrillation) but with a higher risk of rebleeding (eg,elderly patients with lobar intracerebral haemorrhage orpossible amyloid angiopathy); conversely, in patientswith a very high risk of thromboembolism in whomrestarting warfarin is likely to be beneficial, warfarin

therapy can be restarted 710 days after onset of theoriginal intracerebral haemorrhage.93

In patients with haemorrhagic venous infarct causedby CVST, the risk of heparin-induced intracerebralhaemorrhage needs to be weighed against the risk ofhaemorrhage caused by additional thrombotic venousocclusion. However, no new or enlarging haemorrhagewas reported in 40 patients treated with heparin in aCochrane review of two clinical trials.9496 Furthermore,treatment with an anticoagulant was safe and associatedwith a reduced risk of death or dependency.94 Table 3

summarises both medical and surgical management of

haemorrhagic transformation after ischaemic stroke.

Seizures and epilepsyClinical featuresSeizures can occur soon after the onset of ischaemicstroke or can be delayed.97 Early seizures are usuallydefined as those that occur within 1 or 2 weeks afterstroke and late seizures as those that occur after that.97,98The reported frequency of early seizures after ischaemicstroke ranges from 2% to 23% and that of late seizuresis between 3% and 67%, depending on the study design,sample sizes, and length of follow-up.9799

Epilepsy

(recurrent seizures) develops in only 254% ofpatients.98 Although early seizures after stroke are

thought to result from cellular biochemical dysfunctionleading to electrically excitable tissue, late-onset seizuresare thought to be caused by gliosis and the developmentof meningocerebral cicatrices.94Several risk factors havebeen identified, such as large cortical infarcts,involvement of multiple sites, embolic stroke, strokeseverity,98,100 size of the infarct, decreased consciousness,and haemodynamic and metabolic disturbance.100Seizures occur more often in patients with cranial sinusthrombosis than in patients with arterial stroke andmight be the initial form of presentation in CVST.54In

Level of evidence

Asymptomatic haemorrhagic transformationGeneral

No specific intervention is recommended for the management of ischaemic stroke patients with asymptomatic haemorrhagic

transformation59Level 2BC

Symptomatic haemorrhagic transformation

Medical

Initial monitoring and management of patients should take place in an intensive care unit93 Level 1B

For patients with haemorrhagic transformation secondary to thrombolytic therapy, treatment with infusion of platelets and

cryoprecipitate that contains factor VIII to rapidly correct the systemic fibrinolytic state created by altepl ase is recommended93Level 2BC

Protamine sulfate therapy is recommended to reverse heparin-induced intracerebral haemorrhage93 Level 1B

For patients with warfarin-associated intracerebral haemorrhage, intravenous vitamin K to reverse the effects of warfarin and treatment

to replace clotting factors is recommended93Level 1B

Full-dose anticoagulation (initially full-dose heparin and then warfarin) is recommended in patients with haemorrhagic venous infarct

owing to CVST70Level 3C

Surgical

For patients presenting with lobar clots >30 mL and within 1 cm of the surface, evacuation of supratentorial intracerebral haemorrhage

by standard craniotomy might be considered93Level 2BB

For patients with cerebellar haemorrhage >3 cm who are deteriorating neurologically or who have brainstem compression and/or

hydrocephalus from ventricular obstruction, surgical removal of the haemorrhage as soon as possible is recommended93Level 1B

Antithrombotic therapy after haemorrhagic transformation

General

The decision to restart antithrombotic therapy after haemorrhagic transformation depends on the risk of subsequent arterial or venous

thromboembolism, the risk of recurrent intracerebral haemorrhage, and the clinical state of the patient

Anticoagulation should be considered in patients with a very high risk of thromboembolism or when there are definite indications for

these drugs93Level 2BB

The use of long-term anticoagulation for treatment of non-valvular atrial fibrillation in patients with high risk of rebleeding should be

avoided93Level 2AB

=not applicable. The level of evidence is according to the Oxford Centre for Evidence-based Medicine Level of Evidence.78

Table 3: Clinical management of haemorrhagic transformation after ischaemic stroke


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one study,101 nearly 40% of patients with CVST had

seizures at presentation and an additional 7% of patientswith CVST had seizures within 2 weeks of diagnosis.Non-convulsive seizures, which are diffi cult to detect

clinically because electroencephalography is needed fordiagnosis, might account for deteriorating function insome cases.102 Patients with early-onset seizures have arecurrence rate of 16%, whereas patients with late-onsetseizures have a recurrence rate of more than 50%. Thefrequency of recurrent seizures is related to the infarctand associated neuronal death.103 Recurrence of late-onset seizures or post-stroke epilepsy increases thedisability of patients with stroke and can promote theoccurrence of vascular cognitive impairment.104,105 Theevidence of an effect of post-stroke seizures on stroke

mortality is conflicting. In one study of 1220 patients, 106the overall in-hospital mortality rate in patients whodeveloped early seizures (within 48 h) after stroke was379% compared with 144% in patients withoutseizures. Conversely, in two other studies, early seizureswere not associated with worse neurological deficits107or increased in-hospital mortality, but were associatedwith better outcome in terms of Scandinavian strokescale scores.108 The authors postulated that seizureswere a manifestation of a large ischaemic penumbrathat contributed to better recovery.

ManagementBy contrast with intracerebral or subarachnoidhaemorrhage, there is no definitive evidence or clearguidelines for when to initiate anticonvulsant therapy,for the choice of therapy, or for duration of therapy inpatients with ischaemic stroke. The optimal timing andtype of antiepileptic treatment for patients with post-stroke seizures and epilepsy are still under debate. Nocontrolled trials have yet been done to assess the effi cacyof specific antiepileptic drugs in stroke-relatedseizures.97 Thus, the choice of an anticonvulsant drugshould be guided by the individual characteristics ofeach patient, including medical comorbidities andconcurrent medications.97

It is common practice to treat recurrent early seizures

with short-term antiepileptic drug treatment for about36 months, whereas late seizures require long-termconventional therapy. However, no study has been doneto assess the advantages and disadvantages of long-termand short-term therapy.109 In a retrospective study105 thatspecifically examined the risk factors for developingepilepsy, long-term antiepileptic use was not needed toprevent recurrence of early seizures in comparison tolate-onset seizures. In one uncontrolled study110 ofgabapentin monotherapy in patients with a first, latepost-stroke seizure, gabapentin was associated with 80%seizure remission after 30 months.

In early-onset seizures and status epilepticus,intravenous benzodiazepines are the first choice,eventually followed by phenytoin, sodium valproate, or

carbamazepine.100 However, most first-generation

antiepileptic drugs, particularly phenytoin, might not bethe best choicein patients with stroke because of theirsuboptimal pharmacokinetic profile and interaction withanticoagulants or salicylates, the possibility of poortolerance by patients, and the likely detrimental effectonbone health and functional recovery.97,111 Similarly, resultsfrom clinical studies have indicated that most antiepilepticdrugs impair cognition in elderly patients.97,105 Theseside-effects are reduced with the new-generation anti-epileptic drugs, such as lamotrigine, gabapentin, andlevetiracetam. 97 Hence, lamotrigineor gabapentin mightbe appropriate first-line treatments for post-strokeseizures and epilepsy in elderly patients orin youngerpatients who need anticoagulants, and carbamazepine

for patients with no bone health problems and who donot need anticoagulation.97There is insuffi cient evidencefor prophylactic use of antiepileptic drugs to preventseizures after stroke. Prophylactic treatment withanticonvulsants in patients with recent stroke who havenot had seizures is not recommended.59

Recurrent strokeClinical featuresPatients with acute ischaemic stroke are at a high risk ofstroke recurrence in the first week, although this riskdeclines over time.112,113 The early risk of recurrence isabout 10% at 1 week, between 2% and 4% at 1 month, andabout 5% yearly thereafter.114,115

The risk of recurrent

stroke can vary substantially among patients according tothe underlying pathological changes, lifestyles factors,and comorbidities.The majorrisk factors for recurrentstroke include old age,116 previous stroke,117 diabetesmellitus,116 hypertension, atrial fibrillation, cardiacdiseases,118 smoking,116,118 and carotid stenosis.119 Data fromsome studies have indicated that patients with largeartery atherosclerosis have the highest risk of earlyclinical recurrent stroke113 compared with otheraetiological subgroups.120 Transcranial doppler can beused to detect microembolic signals and can be usefulfor identification of patients who are at risk of earlyrecurrent stroke.121 The prognostic score (recurrence risk

estimator at 90 days [RRE-90 score]), which integratesclinical and imaging information to predict early risk ofrecurrence after ischaemic stroke, could have thepotential to improve stroke management algorithms andclinical practice in acute stroke care.122 Contrary to earlierassumptions that the risk of recurrent stroke is lower forposterior circulation than for anterior circulation, resultsfrom a meta-analysis suggest that the risk is also high forposterior circulation strokes.123 In a prospective study,124the presence of vertebrobasilar stenosis was associatedwith a greatly increased risk of recurrent stroke, as highas 33% in the first month after an initial event. CTangiography and contrast-enhanced magnetic resonanceangiography have a high sensitivity for detection ofvertebrobasilar stenosis and are more sensitive than


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ultrasound, which does not allow visualisation of the

whole vertebral artery.

125

Early recurrent ischaemia is highly associated withincreased dependency and with early and late mortality,126with an increasing risk of severe disability or death witheach additional recurrent stroke.112 Recurrent strokecaused early clinical deterioration in 113% of1964 patients with stroke24and 45% of 8291 patients withtransient ischaemic stroke or minor stroke.126 Severalobservational studies in human beings have investigatedwhether ischaemic preconditioning occurs after transientischaemic stroke.127129 However, this assessment is verydiffi cult, because of confounding factors, such as smallsample size, high rate of recanalisation, and lowoccurrence of cardioembolic infarct in patients with

transient ischaemic stroke.127 Furthermore, whetherdifferences in underlying pathophysiology and treatmentof those with earlier transient ischaemic stroke couldaccount for differences in outcome of subsequent strokesin these studies is unknown.128

One approach to study this factor is to use animalmodels. Some animals have an initial, mild transientstroke, followed by either a second moderate stroke orglobal ischaemia.130,131 The short initial transient strokehad dual effects on the histopathological consequencesof a second ischaemic insult. Proximal to the occlusion,there was enhanced injury, whereas there was evidenceof neuroprotection more distal to the occlusion.131

ManagementThe early increased risk of recurrent stroke justifies theneed for early secondary prevention. Therefore,identification of the cause and treatment of the strokewhen possible is imperative. There is good evidence thatthe correction of abnormal physiological variables afterstroke and early mobilisation (when clinical conditionpermits) improve clinical outcome and reduce the risk ofstroke recurrence.59 At least 95% of recurrent strokesmight be prevented through a comprehensive andmultifactorial approach involving the use of antiplatelettherapy, reduction of elevated cholesterol, treatment ofhypertension, blood sugar control, anticoagulation for

atrial fibrillation, carotid endarterectomy, and lifestylechanges.132 However, blood pressure management in thesetting of acute stroke is still controversial but hopefullysome results from ongoing trials (Effi cacy of Nitric Oxidein Stroke [ENOS]133 and Scandinavian Candesartan AcuteStroke Trial [SCAST])134 might provide answers to thepredicament about management of blood pressure inacute stroke.

Surgical and endovascular interventions are optionsfor the treatment of patients with ischaemic stroke andsymptomatic atherosclerotic narrowing of largeextracranial or intracranial arteries.135,136 The man-agement of symptomatic intracranial atheroscleroticdisease, unlike extracranial stenosis, is controversial.Results from the ongoing trial on the use of the

self-expandable Wingspan stent (Boston Scientific, CA,

USA) for the treatment of intracranial atheroscleroticdisease (Stenting versus Aggressive MedicalManagement for Preventing Recurrent Stroke inIntracranial Stenosis [SAMMPRIS]137) and the VitesseIntracranial Stent Study for Ischemic Therapy (VISSIT)trial138 using a balloon-expandable stent (Pharos VitesseMircus Endovascular Corporation, CA, USA) mighthelp to provide an evidence-based managementregimen for patients. Table 4 summarises some of themedical and surgical management approaches for theprevention of recurrent stroke.

DeliriumClinical features

Delirium is an acute transient disturbance ofconsciousness and a change in cognition with fluctuatingintensity.156 Delirium is a common problem in the acutestroke setting, with prevalence estimates ranging from13% to 48%.157160 In some studies, delirium has beenreported in up to half of patients, especially in the firstweek after ischaemic stroke.16,160 The cause of stroke-related delirium is poorly understood,161 but changes inneurotransmitter concentrations (eg, acetylcholine anddopamine,161163 serotonin, norepinephrine, and GABA),a non-specific reaction to stress, and activation of thehypothalamicpituitaryadrenal axis might have arole.25,156 Hypoperfusion in the frontal, parietal, andpontine regions, as indicated by single photon emissionCT scans in patients with delirium and acute braininjury, might have an important role in the onset ofdelirium post-stroke.164 Furthermore, in one study,157there was an association between delirium andhypercortisolism in acute stroke; in previous acuteconfusional states, pre-existing cognitive impairment,158,160poorpre-stroke vision,157 sleep apnoea, earlier treatmentwith anticholinergic drugs, old age,156,158 severe stroke,total anterior circulation infarction,158,160 left-sided brainlesions,157 lesions in the thalamus and caudate nucleus,163cardioembolic stroke, intracerebral haemorrhages,158

dysphagia on admission, neglect, and metabolic orinfectious disorders160 have all been identified as

independent risk factors for the development of post-stroke delirium. Delirium after stroke prolongs hospitalstay and increases risk of dementia and admission toan institution.156,159,160

ManagementRecommendations about treatment of delirium afterstroke are usually similar to those for the management ofdelirium in patients with other diseases, because thereare no trials of delirium specifically in acute stroke. In aclinical trial of 853 patients aged 70 years or older admittedto general medical wards, a multicomponent interventiontargeting cognitive impairment, sleep deprivation,immobility, visual and hearing impairment, anddehydration reduced the occurrence of delirium from


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15% in the control group to 99% in the intervention

group. Although the intervention reduced the duration ofthe delirious state, there was no effect on the severity ofdelirium once it occurred, or on recurrence rates.165Haloperidol is the drug of choice if sedation is needed,although the evidence base for use of this drug is weak.166

Central post-stroke pain

Clinical featuresCentral post-stroke pain, also known as Dejerine-Roussysyndrome or thalamic pain syndrome, occurs after infarctsof the ventroposterolateral thalamus,167,168 and aftersubcortical, capsular, lower brainstem infarcts,168,169 lateral

Level of evidence

Medical

Antiplatelet drugs

Antiplatelet drugs are effective in secondary stroke prevention after ischaemic stroke and TIA with an overall risk reduction estimated at about 2025%139

In a pooled analysis140 of the two largest trials of acute aspirin use (the International Stroke Trial86 and the Chinese Acute Stroke Trial141), aspirin reduced recurrent

ischaemic stroke by seven per 1000 treated (p3) between active treatment (labetalol or lisinopril) and

placebo at 2 weeks (61% with active treatment, 59% with placebo)

Similarly, there was no significant difference between active treatment (labetalol or lisinopril) or placebo in early neurological deterioration (NIHSS score of 4 points at 72 h:

6% with active treatment vs 5% with placebo); however, there was a borderline decrease in mortality at 3 months (10% with active treatment vs 20% with placebo)143

Level 3C

Statins

Data from the SPARCL trial indicated that treatment with atorvastatin reduced the risk of recurrent stroke (16% RRR) in patients with recent stroke or TIA but no

history of heart disease144Level 1B

Anticoagulation

The routine use of anticoagulation for preventing early recurrent stroke in patients with arterial ischaemic stroke has not been proven and is not recommended59

Results from the European Atrial Fibrillation trial indicate that oral anticoagulation prevents recurrent stroke in patients with atrial fibrillation;145 there was a 68%

RRR for a recurrent stroke in patients treated with warfarin vs only 19% for aspirin

Level 1A

A Cochrane analysis concluded that oral anticoagulation is more effective than was aspirin for the prevention of vascular events (odds ratio 067; 95% CI 050091)or recurrent stroke (odds ratio 049; 95% CI 033072);146 risk of major bleeding complication, but not risk of intracranial bleeding, was significantly increased Level 1A

In the WASID trial, warfarin was associated with significantly higher rates of adverse events and provided no benefits over aspirin against stroke and vascular death in

patients with symptomatic stenosis of a major intracranial artery, which suggests that aspirin should be used in preference to warfarin for patients with intracranial

arterial stenosis147

Level 1A

Glucose regulation

On the basis of subanalysis of the results of three randomised trials (GIST-UK, THIS, and GRASP) and additional studies, aggressive glucose regulation might be

beneficial in hyperglycaemic patients with diabetes who have moderate to severe stroke 148

Hyperglycaemia (>140 mg/dL) should be treated with insulin in patients with acute ischaemic stroke59 Level 2C

For patients with type 2 diabetes who do not need insulin after stroke, individualised oral antidiabetic therapy is recommended60 Level 3B

Surgical

Carotid endarterectomy

Carotid endarterectomy is the best-studied surgical intervention for symptomatic carotid stenosis, and data from two large trials indicate that early intervention

reduces recurrent stroke risk149,150

The benefit is much greater if patients are operated on within the first 2 weeks after the initial event151

Level 1A

Carotid artery balloon angioplasty and stenting

Owing to a high mortality, carotid angioplasty and stenting are typically reserved for patients who have a contraindication to carotid e ndarterectomy or who have

re-stenosis after carotid endarterectomy152Level 2B

Extracranial/intracranial bypass

Extracranial/intracranial bypass is being assessed in the Carotid Occlusion Surgery Study for use in patients with occlusion of the internal carotid artery who cannot be

treated with carotid endarterectomy or endovascular interventions153

Vertebral angioplasty and stenting

Vertebral angioplasty and stenting might offer a potential treatment for patients with vertebrobasilar stenosis;154 however, results from the only published randomised

trial of angioplasty and stenting for vertebral artery disease (CAVATAS) have not shown a benefit of endovascular treatment of vertebral artery stenosis, but this was

based on only a small number of patients155

Level 3C

The level of evidence is according to the Oxford Centre for Evidence-based Medicine Level of Evidence.78 NIHSS=National Institutes of Health stroke scale. RRR=relative risk reduction. TIA=transient ischaemic

attack. CHHIPS=Controlling Hypertension and Hypotension Immediately Post Stroke. SPARCL=Stroke Prevention by Aggressive Reduction in Cholesterol Levels. WASID=WarfarinAspirin Symptomatic

Intracranial Disease. The GIST-UK=Glucose Insulin in StrokeUK. THIS=Treatment of Hyperglycaemia in Ischaemic Stroke. GRASP=Glucose Regulations in Acute Stroke Patients. CAVATAS=Carotid and Vertebral

Artery Transluminal Angioplasty Study.

Table 4: Clinical management for the prevention of recurrent stroke


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medullary infarcts (Wallenbergs syndrome),170 andanterior spinal artery syndrome.171 The infarcts arecharacterised by involvement of the spinothalamic systemanywhere in its course with sparing of the lemniscalpathways, as indicated by the normal somatosensory-evoked potentials in patients with central post-strokepain.167,170 The prevalence of central post-stroke pain isestimated to be between 1% and 12% in all patients withstroke,7,169,172 whereas about 18% of patients with asomatosensory disturbance develop central post-strokepain.169 The onset time for symptoms to develop is variable,ranging from days to years, but symptoms usually occurseveral months later.172 In one study of 180 patients,173 painonset occurred within the first week after stroke in 36% ofpatients. Central post-stroke pain can interfere withsleep169,172 and can compromise rehabilitation.168

ManagementDifferentiation between central post-stroke pain andother types of post-stroke pain is important becausedifferent treatment strategies might be needed. A new

grading system for central post-stroke pain was proposedto distinguish patients with central post-stroke pain frompatients with peripheral pain.172 The new proposedgrading system requires the presence of pain with adistinct convincing distribution, an association betweenhistory and relevant lesion, clinical examinationsuggestive of negative or positive sensory signs withinthe area, and confirmation by diagnostic tests (eg, CT orMRI) for the presence of a relevant disease or lesionaffecting the somatosensory system.174

Despite many guidelines for the treatment ofneuropathic pain, there are few guidelines for thetreatment of central post-stroke pain. Amitriptyline andlamotrigine are recommended as first-line drugs andmexiletine, fluvoxamine, and gabapentin as second-line

drugs.175,176 Lidocaine and propofol are recommended for

short-term pain relief in patients with central post-strokepain.175 Table 5 summarises the recommended drugtherapy for central post-stroke pain.

HeadacheClinical featuresHeadache is a common accompaniment of acute ischaemicstroke, occurring before (sentinel headache; 4360%),concurrently (onset headache; 2530%), or after (late-onsetheadache; 1427%) focal neurological signs.177,178 TheInternational Headache Society has established criteria toidentify headache associated with stroke. These criteriainclude requirements for onset of a new type of headache(ie, not an exacerbation of a pre-existing type of headache)

and a headache that occurs simultaneously or in very closetemporal relation with the onset of other neurologicalsigns.179 Ischaemic stroke can cause a migraine syndromein patients who previously did not have a history ofmigraine or can precipitate a migraine attack in patientswho are prone to migraine. Similarly, patients who areaffected with migraine after stroke might continue to haverecurrent attacks of migraine.180 Headache after acutestroke is usually severe and generally starts on the first dayof stroke, lasts about 38 days, and is most frequentlycontinuous and of pressure-type in nature.181 Headachesare more common after major strokes177,182 and significantlymore frequent in patients with vertebrobasilar territoryischaemia than in patients with anterior circulationstroke,183 probably because vessels in the posteriorcirculation are more densely innervated by nociceptiveafferents than are those in the anterior circulation.177 Mostaspects of onset headache are still debated and there is noprecise definition, although this type of headache mightbe an indication of the initial vascular occlusion andresultant ischaemia.183 In one study,184onset headache wasa strong predictor of early neurological deterioration inacute stroke (sensitivity 56%, specificity 99%, positivepredictive value 98%). Delayed headache might beattributable to various factors, including oedema,intracranial hypertension, haemorrhagic transformation,delayed effects of products of thrombosis and ischaemia,

or delayed disturbance to the function of thetrigeminovascular system.183,184 Headache can also besecondary to treatments (eg, dipyridamole) used forsecondary stroke prevention.135

ManagementThere are no specific studies that have investigateddefinite treatments and their effects in patients withheadache at stroke onset or those with delayed-onsetheadache. Post-stroke headache is usually mild and oftenresolves spontaneously or might respond to simpleanalgesics such as paracetamol, but opiates should beavoided because they might mask the clinical picture andcan have possible adverse effects such as respiratorydepression and hypotension.185

Level of evidence

Antidepressants

Tricyclic antidepressants are first-line drugs for neuropathic pain with demonstrable

beneficial effect176

Amitriptyline is effective, safe, and well tolerated compared with placebo Level 2B

Fluvoxamine is effective175 Level 2B

Anticonvulsants

Lamotrigine is moderately effective and well tolerated175,176 Level 1B

Gabapentin is well tolerated but not effective173 Level 3C

Opiates

Both morphine and naloxone are ineffective and often cause side-effects175 Level 2B

Anaesthetics

Anaesthetics are effective for a short period

Lidocaine is effective173 Level 2B

Propofol and pentothal are effective173

Level 3CMexiletine is not effective and causes several side-effects173 Level 3C

The level of evidence is according to the Oxford Centre for Evidence-based Medicine Level of Evidence.78

Table 5: Clinical management of central post-stroke pain


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Sleep disorders

Clinical featuresSleep disorders are frequent in the initial stages afterstroke. Sleep disorders in the form of increased sleepneeds (hypersomnia), excessive daytime sleepiness, orinsomnia are present in about 1050% of patients withstroke.186,187 Persistent, severe sleep-wake disturbances aresuggestive of bilateral paramedian thalamic, left-sidedthalamic or brainstem infarcts, and large hemisphericstroke with mass effect.186,187 Sleepiness can also be part ofa terminal brainstem syndrome.188 Other possibleassociations or precipitating factors include depression,anxiety, sleep-disordered breathing, drugs, post-strokepain, medical complications (urinary or respiratoryinfections, nocturia, dysphagia), and environmental

factors such as noise and light.186 Sleepiness can becaused by interruption of the arousal systems at the levelof the mesencephalic reticular formation fromischaemia.188 As the generation and consolidation of non-rapid eye movement sleep involves sleep spindles, a basiccausative mechanism of sleep-wake disturbances mightbe indicated by changes in spindle activity.186 Althoughsleep disturbance is not life-threatening, an earlyreduction in sleep stage 2 after stroke has been associatedwith a poor prognosis188 and this disturbance mightnegatively affect rehabilitation and functional outcome.186

ManagementPost-stroke sleep-wake disturbance management is achallenging therapeutic goal. There are no systematicstudies or guidelines on the treatment of sleep disordersafter stroke. Precipitating factors such as medicalcomplications should be addressed first. Mianserin isbeneficial in the early treatment of post-stroke insomnia.186Bromocriptine, modafinil, and methylphenidate canimprove sleep behaviour in post-stroke hypersomnia.186,187

Treatment of associated depression with antidepressantscan improve post-stroke sleeping problems and might bepreferable for long-term management of post-strokeinsomnia.186 Non-pharmacological management shouldinclude avoidance of precipitating factors.186

Sleep-disordered breathingClinical featuresSleep-disordered breathing in patients presenting withobstructive, central, or mixed apnoeas is common afterstroke, occurring in about 5072% of patients, and isboth a risk factor and a consequence of stroke.186,187,189 Themost common form of sleep-disordered breathing isobstructive sleep apnoea, which is caused by cessation ofnasal flow because of collapse of the upper airway.186,187

Sleep-disordered breathing might lead to early neuro-logical worsening, thus affecting stroke rehabilitationand leading to poor outcome.186 This breathing disorderis an independent prognostic factor for increasedmortality after a first episode of stroke190 and for increasedrisk of stroke recurrence.186

ManagementSleep-disordered breathing can improve spontaneouslyafter stroke, but might need treatment. Despite theconflicting evidence on the use of continuous positiveairway pressure breathing in patients with stroke whohave sleep-disordered breathing,189 these patients, andthose with obstructive sleep apnoea in particular, shouldbe treated with continuous positive airway pressurebreathing.60

ConclusionsNeurological complications occur early after ischaemicstroke onset, and can lead to death within the first fewdays of stroke. The webappendix lists other neurologicalcomplications of acute ischaemic stroke. Improveddetection and management of neurological compli-cations in the acute phase after stroke could savepatients lives and help to reduce the burden of stroke.Therefore, we believe that attempts to prevent and treatneurological complications after ischaemic strokeshould be made swiftly and aggressively. Until enoughevidence is available from more research, some ofthe recommendations will be based on empirical orrestricted anecdotal information rather than being

evidence based. We believe that there is a clear need forfurther research on the prevention and treatment ofneurological complications in acute ischaemic stroke toimprove the level of evidence of current guidelines andrecommendations.

Contributors

JSB did the clinical literature search and wrote the paper, R-LC did thelaboratory literature search and drafted the paper, IQG contributed

images and reviewed the manuscript, and AMB reviewed and madecritical revisions of this paper.

Conflicts of interest

We declare that we have no conflicts of interest.

Acknowledgments

We are grateful for funding received from the Dunhill Medical Trust, the

Biomedical Research Centre, the National Institute for Health Research,the Fondation Leducq, and the Oxford Radcliffe NHS Trust, UK.

Search strategy and selection criteria

Relevant evidence for this Review was identified through

searches of PubMed and the Cochrane Library, and by

searching and cross-referencing the reference lists and main

journal contents pages. Search terms included stroke,

cerebrovascular accident, isch(a)emic stroke, cerebral

isch(a)emia, complications, neurological complications,

management, treatment, and outcome. The search

included both human and animal studies, and was limited to

studies published in English before November, 2010. The final

reference list was selected on the basis of relevance to the

topics covered in the Review. Guidelines for the management

of acute ischaemic and intracerebral haemorrhage by the

American Heart Association and American Stroke Association

and the European Stroke Organisation were also reviewed.

See Online for webappendix


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Figure 3 was provided by Margaret Esiri (Department of ClinicalNeurology and Neuropathology, Oxford Radcliffe NHS Trust, UK).

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