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Consensus Paper

Cerebrovasc Dis 2008;25:457507 Received: February 19, 2008


Accepted: March 27, 2008
DOI: 10.1159/000131083
Published online: May 6, 2008

Guidelines for Management of Ischaemic


Stroke and Transient Ischaemic Attack 2008
The European Stroke Organisation (ESO) Executive Committee and the
ESO Writing Committee

Key Words Foreword


Stroke prevention Educational measures Stroke Unit
Imaging Acute treatment Rehabilitation This article represents the update of the European
Stroke Initiative (EUSI) Recommendations for Stroke
Management, which were first published in this journal
Abstract in 2000 [1, 2], and subsequently translated into a number
This article represents the update of the European Stroke Ini- of languages including Spanish, Portuguese, Italian, Ger-
tiative Recommendations for Stroke Management. These man, Greek, Turkish, Lithuanian, Polish, Russian and
guidelines cover both ischaemic stroke and transient isch- Mandarin Chinese. The first update of the recommenda-
aemic attacks, which are now considered to be a single en- tions was published in 2003 [2]. In 2006, the EUSI decid-
tity. The article covers referral and emergency management, ed that a larger group of authors should prepare the next
Stroke Unit service, diagnostics, primary and secondary pre- update. In the meantime, a new European Stroke Society,
vention, general stroke treatment, specific treatment includ- the European Stroke Organisation (ESO), was established
ing acute management, management of complications, and and took over the task of updating the guidelines. Ac-
rehabilitation. cordingly, the new recommendations have been prepared
by members of both the former EUSI Recommendations
Writing Committee and the ESO (see appendix). The
Copyright 2008 S. Karger AG, Basel / Translation is only granted with members of the Writing Group met in Heidelberg, Ger-
permission from the publisher and ESO, please contact p.roth@karger.ch many for 3 days in December 2007 to finalize the new

The ESO Writing Committee: Peter A. Ringleb, Heidelberg, Ger- Hugh S. Markus, London, UK; Jean-Louis Mas, Paris, France; Hein-
many; Marie-Germaine Bousser, Paris, France; Gary Ford, Newcas- rich P. Mattle, Bern, Switzerland; Keith Muir, Glasgow, UK; Bo Norr-
tle, UK; Philip Bath, Nottingham, UK; Michael Brainin, Krems, Aus- ving, Lund, Sweden; Victor Obach, Barcelona, Spain; Stefano Paoluc-
tria; Valeria Caso, Perugia, Italy; lvaro Cervera, Barcelona, Spain; ci, Rome, Italy; E. Bernd Ringelstein, Mnster, Germany; Peter D.
Angel Chamorro, Barcelona, Spain; Charlotte Cordonnier, Lille, Schellinger, Erlangen, Germany; Juhani Sivenius, Kuopio, Finland;
France; Lszl Csiba, Debrecen, Hungary; Antoni Davalos, Barce- Veronika Skvortsova, Moscow, Russia; Katharina Stibrant Sunner-
lona, Spain; Hans-Christoph Diener, Essen, Germany; Jos Ferro, hagen, Gteborg, Sweden; Lars Thomassen, Bergen, Norway; Danilo
Lisbon, Portugal; Werner Hacke, Heidelberg, Germany; Michael Toni, Rome, Italy; Rdiger von Kummer, Dresden, Germany; Nils Gun-
Hennerici, Mannheim, Germany; Markku Kaste, Helsinki, Finland; nar Wahlgren, Stockholm, Sweden; Marion F. Walker, Nottingham,
Peter Langhorne, Glasgow, UK; Kennedy Lees, Glasgow, UK; Di- UK; Joanna Wardlaw, Edinburgh, UK.
dier Leys, Lille, France; Jan Lodder, Maastricht, The Netherlands;

2008 S. Karger AG, Basel Werner Hacke, MD, PhD


10159770/08/02550457$24.50/0 Department of Neurology, University of Heidelberg, Im Neuenheimer Feld 400
Fax +41 61 306 12 34 DE69120 Heidelberg (Germany)
E-Mail karger@karger.ch Accessible online at: Tel. +49 6221 568 210, Fax +49 6221 565 348
www.karger.com www.karger.com/ced E-Mail werner_hacke@med.uni-heidelberg.de

www.belimantil.info
Table 1. Classification of evidence for diagnostic and for therapeutic measures (from Brainin et al. [582])

Evidence classification scheme for a diagnostic measure Evidence classification scheme for a therapeutic intervention

Class I A prospective study in a broad spectrum of persons An adequately powered, prospective, randomized, controlled clin-
with the suspected condition, using a gold standard ical trial with masked outcome assessment in a representative pop-
for case definition, where the test is applied in a blind- ulation or an adequately powered systematic review of prospective
ed evaluation, and enabling the assessment of appro- randomized controlled clinical trials with masked outcome assess-
priate tests of diagnostic accuracy ment in representative populations. The following are required:
a randomization concealment
b primary outcome(s) is/are clearly defined
c exclusion/inclusion criteria are clearly defined
d adequate accounting for dropouts and crossovers with num-
bers sufficiently low to have a minimal potential for bias
e relevant baseline characteristics are presented and substan-
tially equivalent among treatment groups or there is appropri-
ate statistical adjustment for differences
Class II A prospective study of a narrow spectrum of persons Prospective matched-group cohort study in a representative popu-
with the suspected condition, or a well-designed retro- lation with masked outcome assessment that meets ae above or a
spective study of a broad spectrum of persons with an randomized, controlled trial in a representative population that
established condition (by gold standard) compared to lacks one criterion ae
a broad spectrum of controls, where test is applied in a
blinded evaluation, and enabling the assessment of
appropriate tests of diagnostic accuracy
Class III Evidence provided by a retrospective study where All other controlled trials (including well-defined natural history
either persons with the established condition or con- controls or patients serving as own controls) in a representative
trols are of a narrow spectrum, and where test is applied population, where outcome assessment is independent of patient
in a blinded evaluation treatment
Class IV Evidence from uncontrolled studies, case series, case Evidence from uncontrolled studies, case series, case reports, or
reports, or expert opinion expert opinion

recommendations. The members of the Writing Com- ment, specific treatment including acute management,
mittee were assigned to six groups covering different top- management of complications, and rehabilitation.
ics. Each group was co-chaired by two colleagues, and Changes in the guidelines necessitated by new evi-
included up to five further experts. In order to avoid bias dence will be continuously incorporated in the on-line
or conflict of interest, none of the chairs had major in- version that can be found on the ESO website (www.eso-
volvement in clinical trials or studies discussed in their stroke.org). The reader is advised to check the online ver-
respective group. sion when making important treatment decisions.
These guidelines cover both ischaemic stroke and
transient ischaemic attacks (TIAs), which are now con-
sidered to be a single entity. If recommendations differ for Introduction
the two conditions, this will be explicitly mentioned; oth-
erwise the recommendations are valid for both condi- Stroke is one of the leading causes of morbidity and
tions. Separate guidelines exist or are being prepared for mortality worldwide [4]. Large differences in incidence,
intracerebral haemorrhage [3] and subarachnoid haem- prevalence and mortality have been noted between East-
orrhage. The classes of evidence and levels of recommen- ern and Western Europe. This has been attributed to dif-
dations used in these guidelines are defined according to ferences in risk factors, with higher levels of hypertension
the criteria of the European Federation of Neurological and other risk factors resulting in more severe stroke in
Societies (table 1, 2). The article covers referral and emer- Eastern Europe [5]. Notable regional variations have also
gency management, Stroke Unit service, diagnostics, pri- been found within Western Europe. Stroke is the most
mary and secondary prevention, general stroke treat- important cause of morbidity and long-term disability in

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Europe, and demographic changes will result in an in- Table 2. Definitions for levels of recommendation (from Brainin
crease in both incidence and prevalence. It is also the sec- et al. [582])
ond most common cause of dementia, the most frequent
Level A Established as useful/predictive or not useful/predic-
cause of epilepsy in the elderly, and a frequent cause of tive for a diagnostic measure or established as effec-
depression [6, 7]. tive, ineffective or harmful for a therapeutic interven-
Many guidelines and recommendations for stroke man- tion; requires at least one convincing Class I study or
agement or specific aspects of stroke care have been pub- at least two consistent, convincing Class II studies
lished during the last decade [2, 818]. Most recently, the Level B Established as useful/predictive or not useful/predic-
updated Helsingborg Declaration focused on standards of tive for a diagnostic measure or established as effec-
stroke care and research needs in Europe [19]. In the fu- tive, ineffective or harmful for a therapeutic inter-
vention; requires at least one convincing Class II
ture, the global harmonization of stroke guidelines will be
study or overwhelming Class III evidence
the focus of the World Stroke Organisation, supported by
the ESO and other national and regional stroke societies. Level C Established as useful/predictive or not useful/predic-
tive for a diagnostic measure or established as effec-
tive, ineffective or harmful for a therapeutic inter-
vention; requires at least two Class III studies
Public Awareness and Education
GCP points Recommended best practice based on the experience
of the guideline development group. Usually based
Recommendations on Class IV evidence indicating large clinical uncer-
Educational programmes to increase awareness of stroke at tainty, such GCP points can be useful for health
the population level are recommended (Class II, Level B) workers
Educational programmes to increase stroke awareness among
professionals (paramedics/emergency physicians) are recom-
mended (Class II, Level B)

The time is brain concept means that treatment of severity, but also denial of the disease and the hope that
stroke should be considered as an emergency. Thus, symptoms would resolve. This suggests that educating
avoiding delay should be the major aim in the prehospital the population to recognize stroke symptoms, and chang-
phase of acute stroke care. This has far-reaching implica- ing peoples attitudes to acute stroke, may reduce the de-
tions in terms of recognition of signs and symptoms of lay from stroke onset to emergency medical service (EMS)
stroke by the patient or by relatives or bystanders, the na- involvement.
ture of first medical contact, and the means of transpor- Medical attention is rarely sought by the patient: in
tation to hospital. many cases contact is initially made by a family member
Delays during acute stroke management have been [2830]. Information and educational initiatives should
identified at different levels [20]: therefore be directed both to persons at high risk of stroke
at the population level, due to failure to recognize the and also to those around them.
symptoms of stroke and contact emergency services Stroke awareness depends on demographic and socio-
at the level of the emergency services and emergency cultural factors, and on personal medical knowledge.
physicians, due to a failure to prioritize transport of Knowledge of stroke warning signs varies considerably,
stroke patients depending on the symptoms, and is dependent on the
at the hospital level, due to delays in neuroimaging and way questions are asked (e.g. open-ended or multiple-
inefficient in-hospital care. choice questions [31, 32]).
A large amount of time is lost outside the hospital [21]: While most people agree that stroke is an emergency,
for stroke patients at a Portuguese university hospital this and that they would seek medical help immediately, in
accounted for 82% of the delay in treatment [22]. Studies reality only up to 50% call EMS. In many cases, the first
that identify demographic, social, cultural, behavioural contact is with a family member or with a general practi-
and clinical factors associated with longer prehospital time tioner; in some studies between 45% and 48% of patients
may provide targets for educational campaigns [23, 24]. were referred via a general practitioner [29, 3336].
The interval from symptom onset to first call for med- Most studies show that only approximately 3350%
ical help is the predominant part of prehospital delay [25 of patients recognize their own symptoms as stroke.
28]. Major reasons for delayed contact include lack of There are considerable discrepancies between theoretical
awareness of stroke symptoms and recognition of their knowledge of stroke and the reaction in case of an acute

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stroke. Some studies have shown that patients with better Referral and Patient Transfer
knowledge of stroke symptoms do not always arrive ear-
lier at hospital. Recommendations
The most frequently used sources of stroke informa- Immediate EMS contact and priority EMS dispatch are rec-
ommended (Class II, Level B)
tion are mass media [3739], and friends and relatives Priority transport with advance notification to the receiving
who have knowledge of stroke: only rarely is information hospital (outside and inside hospital) is recommended (Class
derived from general practitioners or books [4044]. The III, Level B)
sources accessed vary with age: older people more often It is recommended that suspected stroke victims should be
obtain information from health campaigns or their gen- transported without delay to the nearest medical centre with
a stroke unit that can provide ultra-early treatment (Class III,
eral practitioner, whereas younger people gain more in- Level B)
formation from TV [3840]. It is recommended that dispatchers and ambulance personnel
Interventional studies have measured the effect of ed- be trained to recognise stroke using simple instruments such
ucation on stroke knowledge. Eight non-randomized as the Face-Arm-Speech Test (Class IV, Good Clinical Prac-
studies measured the impact of educational measures on tice GCP)
Immediate emergency room triage, clinical, laboratory and
prehospital time delay or thrombolysis use [4552]. In six imaging evaluation, accurate diagnosis, therapeutic decision
studies, the intervention was a combined educational and administration of appropriate treatments at the receiving
programme directed at the public, paramedics and health hospital are recommended (Class III, Level B)
professionals, while in two studies education was direct- It is recommended that in remote or rural areas helicopter
ed only to the population. Only the TLL Temple Founda- transfer should be considered in order to improve access to
treatment (Class III, Level C)
tion Stroke Project included a concurrent control group It is recommended that in remote or rural areas telemedicine
[50, 51]. All studies had a pre-post design. Thrombolysis should be considered in order to improve access to treatment
usage increased after education in the intervention group (Class II, Level B)
of the TLL study, but only for up to 6 months after inter- It is recommended that patients with suspected TIA be re-
vention ended [51]. This suggests that public education ferred without delay to a TIA clinic or to a medical centre with
a stroke unit that can provide expert evaluation and immedi-
has to be maintained to sustain stroke awareness in the ate treatment (Class III, Level B)
population.
Education should also be directed to paramedics and
emergency department (ED) staff to improve the accu- Successful care of the acute stroke victim begins with
racy of stroke identification and speed up transfer to the the recognition by both the public and health profession-
hospital [53]. Education of paramedics increases stroke als [56] that stroke is an emergency, like acute myocar-
knowledge, clinical and communication skills and de- dial infarction (MI) or trauma. However, in practice the
creases prehospital delays [54]. majority of ischaemic stroke patients do not receive re-
Educating medical students in basic stroke knowledge combinant tissue plasminogen activator (rtPA) because
during their first year at medical school has been shown they do not reach the hospital soon enough [22, 36, 57,
to be associated with a high degree of knowledge reten- 58]. Emergency care of the acute stroke victim depends
tion [55]. The value of postgraduate training is univer- on a four-step chain:
sally acknowledged, but training programmes for stroke rapid recognition of, and reaction to, stroke signs and
specialists are still heterogeneous throughout Europe. To TIAs
overcome such heterogeneity and to increase the number immediate EMS contact and priority EMS dispatch
of specialists available for stroke care, some countries priority transport with notification of the receiving
(e.g. France, UK) have developed and implemented na- hospital
tional curricula. In contrast, other countries rely on immediate emergency room triage, clinical, laborato-
training specialization within neurology training pro- ry and imaging evaluation, accurate diagnosis, and
grammes. With a view towards harmonization of train- administration of appropriate treatments at the re-
ing, a European Masters Programme for Stroke Medi- ceiving hospital.
cine (http://www.donau-uni.ac.at/en/studium/stroke- Once stroke symptoms are suspected, patients or their
medicine/index.php), and annual Stroke Summer proxies should call EMS. The EMS system should have an
Schools (http://www.eso-stroke.org), have been estab- electronic validated algorithm of questions to diagnose
lished. stroke during the phone interview [33, 59]. The ambu-
lance dispatchers and paramedics should be able to di-

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agnose stroke using simple instruments such as the helicopter transfer of patients with suspected acute isch-
Face-Arm-Speech Test [60]. They should also be able to aemic stroke for potential thrombolysis is cost-effective
identify and provide appropriate help for patients who [71].
need urgent care because of early complications or co- Telemedicine using a bidirectional video-conferenc-
morbidities of stroke, such as impaired consciousness, ing equipment to provide health services or assist health
seizures, vomiting, or haemodynamic instability. care personnel at distant sites is a feasible, valid and reli-
Suspected stroke victims should be transported with- able means of facilitating thrombolysis delivery to pa-
out delay to the nearest medical centre with a stroke unit tients in distant or rural hospitals, where timely air or
that can provide ultra-early treatment. Patients with on- ground transportation is not feasible. The quality of treat-
set of stroke symptoms within 3 h should be given prior- ment, complication rates, and short- and long-term out-
ity in evaluation and transportation [20]. In each com- comes are similar for acute stroke patients treated with
munity, a network of stroke units or, if stroke units are rtPA via a telemedicine consultation at local hospitals
not yet available, a network of medical centres providing and those treated in academic centres [7281].
organized acute stroke care should be implemented and Activation of the stroke code as a special infrastruc-
publicized to the general population, health professionals ture with immediate calling of a stroke neurologist at a
and the emergency transport systems [61, 62]. stroke unit and priority transfer of the patients to this
If a doctor receives a call or consultation from a patient centre is effective in increasing the percentage of patients
with suspected stroke, he or she should recommend or treated with thrombolysis, and also in shortening pre-
arrange transportation, preferably through the EMS sys- hospital delays [82, 83].
tem, to the nearest hospital with a stroke unit providing Recent community and hospital-based studies dem-
organized acute stroke care and ultra-early treatment. onstrated a high risk of stroke immediately after a TIA [6,
Ambulance dispatchers should inform the stroke unit 84]. Observational studies showed that urgent evaluation
and describe the patients clinical status. Proxies who can at a TIA clinic and immediate initiation of treatment re-
describe symptom onset or the patients medical history duces stroke risk after TIA [85, 86]. This underlines the
should accompany the patient. need for urgent referral of TIA for expert evaluation and
Few intervention studies have examined the impact of immediate treatment.
decreasing the delay from symptom onset to arrival at the
hospital and making ultra-early treatment accessible for
a larger proportion of patients. Most such studies have Emergency Management
used a before-and-after intervention design, were neither
randomized nor masked with respect to intervention or Recommendations
evaluation of outcome, and lacked concurrent controls Organisation of pre-hospital and in-hospital pathways and
systems for acute stroke patients is recommended (Class III,
[23, 53]. The types of interventions included education
Level C)
and training programmes, helicopter transfer, telemedi- Ancillary tests, as outlined in table 3, are recommended
cine and reorganisation of pre-hospital and in-hospital (Class IV, GCP)
protocols for acute stroke patients.
Direct presentation to the ED via ambulance or EMS
transportation is the fastest way of referral [28, 53, 63 In-hospital delay may account for 16% of total time
65]. Helicopter transport can reduce the time between lost between stroke onset and computed tomography
referral and hospital arrival [66, 67], and also promotes (CT) [22]. Reasons for in-hospital delays are:
access to thrombolytic therapy in remote and rural areas a failure to identify stroke as an emergency
[68]. In mixed rural and urban areas, air and ground dis- inefficient in-hospital transport
tances can be compared using simple rules [69]. No stud- delayed medical assessment
ies have compared air and ground transport specifically delay in imaging
in stroke patients. In one study, predominantly in trauma uncertainty in administering thrombolysis [20, 21,
patients, ground ambulances provided shorter arrival 24].
times at distances less than 10 miles (H16 km) from the Stroke care pathways may allow care to be organized
hospital; even with only short delays in despatching air more effectively, although a meta-analysis [87] did not
transport, air was faster only for distances longer than 45 support their routine implementation. Such pathways
miles (H72 km) [70]. One economic study showed that may reduce delays in door-to-medical department time,

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Table 3. Emergency diagnostic tests in acute stroke patients and were less dependent on discharge [101, 102]. How-
ever, this might not be true for other countries like the
In all patients UK, where most stroke physicians are not neurologists,
1 Brain imaging: CT or MRI
2 ECG but are still highly skilled in management of patients with
3 Laboratory tests TIA and stroke.
Complete blood count and platelet count, Reorganisation of stroke wards can help to avoid bot-
prothrombin time or INR, partial thromboplastin time tlenecks and unnecessary in-hospital transport. Brain
Serum electrolytes, blood glucose imaging facilities should be relocated in or next to the
C-reactive protein or sedimentation rate
Hepatic and renal chemical analysis stroke unit or the ED, and stroke patients should have
priority access [90]. Neuroradiologists should be notified
When indicated
as early as possible [90]. In a Finnish study, in-hospital
4 Extracranial and transcranial Duplex/Doppler ultrasound
5 MRA or CTA delays were decreased considerably by moving the CT
6 Diffusion and perfusion MR or perfusion CT scanner close to the ED and by implementing a pre-noti-
7 Echocardiography (transthoracic and/or transoesophageal) fying system [95]. Thrombolysis should be started in the
8 Chest X-ray CT room or in the vicinity of the scanner. Finally, an ar-
9 Pulse oximetry and arterial blood gas analysis
teriography suite should be readily accessible if endovas-
10 Lumbar puncture
11 EEG cular treatment is required.
12 Toxicology screen Written care protocols for acute stroke patients should
be available; centres using such protocols were found to
have higher thrombolysis rates [93]. Implementing a con-
tinuous quality improvement scheme can also diminish
door-to-imaging time [88, 89], door-to-needle time [89] in-hospital delays [81, 103]. Benchmarks should be de-
and, where appropriate, door-to-arteriography time. fined and measured for individual institutions, and have
Acute stroke care has to integrate EMS, ED staff and recently been developed for regional networks and coun-
stroke care specialists. Communication and collabora- tries. As a minimum requirement, door-to-imaging and
tion between EMS, ED staff, radiologists, clinical labora- door-to-treatment times should be monitored.
tories and neurologists are important for rapid delivery While only a minority of stroke patients present in an
of treatment [9092]. Integrating EMS and ED staff was immediately life-threatening condition, many have sig-
found to increase the use of thrombolysis [93]. Hospitals nificant physiological abnormalities or comorbidities.
where patients are not delivered directly to a stroke unit Symptoms and signs which may predict later compli-
should implement a system allowing the ED to pre-notify cations such as space-occupying infarction, bleeding, or
the acute stroke team as soon as possible. Routinely in- recurrent stroke, and medical conditions such as hyper-
forming ED physicians or stroke physicians during trans- tensive crisis, co-existing MI, aspiration pneumonia, or
port has been shown to be associated with reduced in- cardiac and renal failure, must be recognized early. Stroke
hospital delay [82, 9496], increased use of thrombolysis severity should be assessed by trained staff using the Na-
[93, 94], decreased length of hospital stay [96] and de- tional Institutes of Health Stroke Scale (NIHSS) [104].
creased in-hospital mortality [93]. Initial examination should include:
A stroke recognition instrument with high diagnostic observation of breathing and pulmonary function
accuracy is necessary for rapid triage [97]; stroke mimics early signs of dysphagia, preferably with a validated
like migraine and seizure might be a problem [98, 99]. assessment form [105]
Stroke recognition instruments such as Face-Arm-Speech evaluation of concomitant heart disease
Test and Recognition of Stroke in the Emergency Room assessment of blood pressure (BP) and heart rate
(ROSIER) can assist the correct recognition of stroke by determination of arterial oxygen saturation using in-
ED personnel [60, 98, 100]. frared pulse oximetry if available.
A neurologist or stroke physician should be involved Simultaneously, blood samples for clinical chemistry,
in the acute care of stroke patients and available in the glucose, coagulation and haematology studies should be
ED [99]. Comparing neurologist care to non-neurologist drawn, and a venous line inserted. The examination
care, two studies in the USA found that neurologists per- should be supplemented by a medical history that includes
form more extensive and costly testing, but that their pa- risk factors for stroke and cardiac disease, medications,
tients had lower in-hospital and 90-day mortality rates conditions that may predispose to bleeding complications,

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and markers for stroke mimics. A history of drug abuse, Table 4. Recommended requirements for centres managing acute
oral contraceptive use, infection, trauma or migraine may stroke patients
give important clues, particularly in young patients.
Primary stroke centre Comprehensive stroke centre

Availability of 24-hour CT scan- MRI/MRA/CTA


Stroke Services and Stroke Units ning
Established stroke treatment Transoesophageal echocardi-
Recommendations guidelines and operational proce- ography
It is recommended that all stroke patients should be treated dures, including intravenous
in a stroke unit (Class I, Level A) rtPA protocols 24/7
It is recommended that healthcare systems ensure that acute
stroke patients have access to high-technology medical and Close co-operation of neurolo- Cerebral angiography
surgical stroke care when required (Class III, Level B) gists, internists and rehabilitation
The development of clinical networks, including telemedi- experts
cine, is recommended to expand access to high-technology Specially trained nursing person- Transcranial Doppler sonogra-
specialist stroke care (Class II, Level B) nel phy
Early multidisciplinary stroke Extracranial and intracranial
unit rehabilitation including colour-coded duplex sonogra-
speech therapy, occupational phy
Providing Stroke Services therapy and physical therapy
Neurosonological investigations Specialized neuroradiological,
All acute stroke patients require specialist multidisci-
within 24 h (extracranial Doppler neurosurgical and vascular
plinary care delivered in a stroke unit, and selected pa- sonography) surgical consultation (includ-
tients will require additional high-technology interven- ing telemedicine networks)
tions. Health services need to establish the infrastructure Transthoracic echocardiography Carotid surgery
to deliver these interventions to all patients who require
them: the only reason for excluding patients from stroke Laboratory examinations (in- Angioplasty and stenting
cluding coagulation parameters)
units is if their condition does not warrant active man-
agement. Recent consensus documents [11, 106] have de- Monitoring of blood pressure, Automated monitoring of
ECG, oxygen saturation, blood pulse oximetry, blood pressure
fined the roles of primary and comprehensive stroke cen- glucose, body temperature
tres (table 4).
Primary stroke centres are defined as centres with the Automated ECG monitoring at Established network of reha-
bedside bilitation facilities to provide
necessary staffing, infrastructure, expertise and pro- a continuous process of care,
grammes to provide appropriate diagnosis and treatment including collaboration with
for most stroke patients. Some patients with rare disor- outside rehabilitation centre
ders, complex stroke, or multi-organ disease may need
more specialized care and resources that are not available
in primary stroke centres.
Comprehensive stroke centres are defined as centres
that provide both appropriate diagnosis and treatment Stroke Unit Care
for most stroke patients, and also high-technology medi-
cal and surgical care (new diagnostic and rehabilitation An updated systematic review has confirmed signifi-
methods, specialized tests, automatic monitoring of mul- cant reductions in death (3% absolute reduction), depen-
tiple physiological parameters, interventional radiology, dency (5% increase in independent survivors) and the
vascular surgery, neurosurgery). need for institutional care (2% reduction) for patients
The organisation of clinical networks using telemedi- treated in a stroke unit, compared with those treated in
cine is recommended to facilitate treatment options not general wards. All types of patients, irrespective of gen-
previously available at remote hospitals. Administration der, age, stroke subtype and stroke severity, appear to
of rtPA during telemedicine consultations is feasible and benefit from treatment in stroke units [61, 109]. These
safe [107]. Clinical networks using telemedicine systems results have been confirmed in large observational stud-
achieve increased use of rtPA [80, 108] and better stroke ies of routine practice [110112]. Although stroke unit
care and clinical outcomes [80]. care is more costly than treatment on general neurologi-

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cal or medical wards, it reduces post-acute inpatient care If MRI is used, the inclusion of diffusion-weighted imaging
costs [113, 114] and is cost-effective [115118]. (DWI) and T2*-weighted gradient echo sequences is recom-
A stroke unit consists of a discrete area of a hospital mended (Class II, Level A)
In patients with TIA, minor stroke or early spontaneous re-
ward that exclusively or nearly exclusively takes care of covery, immediate diagnostic work-up, including urgent vas-
stroke patients and is staffed by a specialist multidisci- cular imaging (ultrasound, CT angiography, or MR angiog-
plinary team [61]. The core disciplines of the team are raphy), is recommended (Class I, Level A)
medicine, nursing, physiotherapy, occupational therapy
(OT), speech and language therapy (SLT) and social work Imaging of the brain and supplying vessels is crucial
[119]. The multidisciplinary team should work in a coor- in the assessment of patients with stroke and TIA. Brain
dinated way through regular meetings to plan patient imaging distinguishes ischaemic stroke from intracrani-
care. Programmes of regular staff education and training al haemorrhage and stroke mimics, and identifies the
should be provided [119]. The typical components of type and often also the cause of stroke; it may also help
stroke unit care in stroke unit trials [119] were: to differentiate irreversibly damaged tissue from areas
medical assessment and diagnosis, including imaging that may recover, thus guiding emergency and subse-
(CT, magnetic resonance imaging, MRI), and early as- quent treatment, and may help to predict outcome. Vas-
sessment of nursing and therapy needs cular imaging may identify the site and cause of arterial
early management, consisting of early mobilization, obstruction, and identifies patients at high risk of stroke
prevention of complications, and treatment of hypox- recurrence.
ia, hyperglycaemia, pyrexia and dehydration
ongoing rehabilitation, involving coordinated multi- General Principles
disciplinary team care, and early assessment of needs Stroke victims should have clear priority over other
after discharge. patients for brain imaging, because time is crucial. In
Both acute and comprehensive stroke units admit pa- patients with suspected TIA or stroke, general and neu-
tients acutely and continue treatment for several days. rological examination followed by diagnostic brain im-
Rehabilitation stroke units admit patients after 12 weeks aging must be performed immediately on arrival at the
and continue treatment and rehabilitation for several hospital so that treatment can be started promptly. In-
weeks if necessary. Most of the evidence for effectiveness vestigation of TIA is equally urgent because up to 10% of
comes from trials of comprehensive stroke units and re- these patients will suffer stroke within the next 48 h. Im-
habilitation stroke units [61, 120]. Mobile stroke teams, mediate access to imaging is facilitated by pre-hospital
which offer stroke care and treatment in a number of notification and good communication with the imaging
wards, probably do not influence important outcomes facility: stroke services should work closely with the im-
and cannot be recommended [121]. Such teams have usu- aging department to plan the best use of resources.
ally been established in hospitals where stroke units were Diagnostic imaging must be sensitive and specific in
not available. detecting stroke pathology, particularly in the early phase
The stroke unit should be of sufficient size to provide of stroke. It should provide reliable images, and should be
specialist multidisciplinary care for the whole duration of technically feasible in acute stroke patients. Rapid, fo-
hospital admission. Smaller hospitals may achieve this cused neurological assessment is helpful to determine
with a single comprehensive unit, but larger hospitals which imaging technique should be used. Imaging tests
may require a pathway of care incorporating separate should take into account the patients condition [122]; for
acute and rehabilitation units. example, up to 45% of patients with severe stroke may not
tolerate MR examination because of their medical condi-
tion and contraindications [123125].
Diagnostics
Imaging in Patients with Acute Stroke
Diagnostic Imaging Patients admitted within 3 h of stroke onset may be
candidates for intravenous thrombolysis [126]; CT is usu-
Recommendations ally sufficient to guide routine thrombolysis. Patients ar-
In patients with suspected TIA or stroke, urgent cranial CT riving later may be candidates for trials testing extended
(Class I), or alternatively MRI (Class II), is recommended time windows for thrombolysis or other experimental re-
(Level A) perfusion strategies.

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Plain CT is widely available, reliably identifies most mon aetiologies, or in whom a stroke mimic is suspected
stroke mimics, and distinguishes acute ischaemic from but not clarified on CT. If arterial dissection is suspected,
haemorrhagic stroke within the first 57 days [127129]. MRI of the neck with fat-suppressed T1-weighted se-
Immediate CT scanning is the most cost-effective strat- quences is required to detect intramural haematoma.
egy for imaging acute stroke patients [130], but is not sen- MRI is less suited for agitated patients or for those who
sitive for old haemorrhage. Overall, CT is less sensi- may vomit and aspirate. If necessary, emergency life sup-
tive than MRI, but equally specific, for early ischaemic port should be continued while the patient is being im-
changes [131]. Two thirds of patients with moderate to aged, as patients (especially those with severe stroke) may
severe stroke have visible ischaemic changes within the become hypoxic while supine during imaging [125]. The
first few hours [131135], but no more than 50% of pa- risk of aspiration is increased in the substantial propor-
tients with minor stroke have a visible relevant ischaemic tion of patients who are unable to protect their airway.
lesion on CT, especially within the first few hours of Perfusion imaging with CT or MRI and angiography
stroke [136]. Training in identification of early ischaemic may be used in selected patients with ischaemic stroke
changes on CT [135, 137, 138], and the use of scoring sys- (e.g. unclear time window, late admission) to aid the deci-
tems [134], improve detection of early ischaemic chang- sion on whether to use thrombolysis, although there is no
es. clear evidence that patients with particular perfusion
Early CT changes in ischaemic stroke include decreas- patterns are more or less likely to benefit from throm-
es in tissue X-ray attenuation, tissue swelling with efface- bolysis [150153]. Selected patients with intracranial ar-
ment of cerebrospinal fluid spaces, and arterial hyperat- terial occlusion may be candidates for intra-arterial
tenuation, which indicates the presence of intraluminal thrombolysis, although there is only limited evidence to
thrombus with high specificity [139]. CT is highly spe- support this [154, 155]. Patients with combined obstruc-
cific for the early identification of ischaemic brain dam- tions of the internal carotid artery (ICA) and MCA have
age [132, 140, 141]. The presence of early signs of isch- less chance of recovering with intravenous thrombolysis
aemia on CT should not exclude patients from throm- than patients with isolated MCA obstructions [156]. In
bolysis within the first 3 h, though patients with a patients with MCA trunk occlusions, the frequency of
hypoattenuating ischaemic lesion which exceeds one severe extracranial occlusive disease in the carotid distri-
third of the middle cerebral artery (MCA) territory may bution is high [157, 158].
benefit less from thrombolysis [126, 134, 135, 142, 143]. Mismatch between the volume of brain tissue with
Some centres prefer to use MRI as first-line routine critical hypoperfusion (which can recover after reperfu-
investigation for acute stroke. MRI with DWI has the ad- sion) and the volume of infarcted tissue (which does not
vantage of higher sensitivity for early ischaemic changes recover even with reperfusion) can be detected with MR
than CT [131]. This higher sensitivity is particularly use- diffusion/perfusion imaging with moderate reliability
ful in the diagnosis of posterior circulation stroke and [159], but this is not yet a proven strategy for improving
lacunar or small cortical infarctions. MRI can also detect the response to thrombolysis up to 9 h [160]. There is dis-
small and old haemorrhages for a prolonged period with agreement on how to best identify irreversible ischaemic
T2* (gradient echo) sequences [144]. However, DWI can brain injury and to define critically impaired blood flow
be negative in patients with definite stroke [145]. [150, 153, 161]. Quantification of MR perfusion is prob-
Restricted diffusion on DWI, measured by the appar- lematic [162], and there are widely differing associations
ent diffusion coefficient (ADC), is not 100% specific for between perfusion parameters and clinical and radiolog-
ischaemic brain damage. Although abnormal tissue on ical outcomes [150]. Decreases in cerebral blood flow on
DWI often proceeds to infarction it can recover, which CT are associated with subsequent tissue damage [151,
indicates that DWI does not show only permanently 152], but the therapeutic value of CT perfusion imaging
damaged tissue [146, 147]. Tissue with only modestly re- is not yet established. Although infarct expansion may
duced ADC values may be permanently damaged; there occur in a high proportion of patients with mismatch, up
is as yet no reliable ADC threshold to differentiate dead to 50% of patients without mismatch may also have in-
from still viable tissue [148, 149]. Other MRI sequences farct growth and so might benefit from tissue salvage
(T2, FLAIR, T1) are less sensitive in the early detection of [153, 163]. The imaging/clinical mismatch, i.e. the mis-
ischaemic brain damage. match between the extent of the lesion seen on DWI or
MRI is particularly important in acute stroke patients CT and the extent of the lesion as expected from the se-
with unusual presentations, stroke varieties, and uncom- verity of the neurological deficit, has produced mixed re-

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sults [164, 165]. Hence, neither perfusion imaging with and those from certain ethnic groups do not have an ad-
CT or MRI nor the mismatch concept can be recom- equate acoustic window [174, 175]. This problem can be
mended for routine treatment decisions. considerably reduced by using ultrasound contrast agents,
Microhaemorrhages are present on T2* MRI in up to which also allow perfusion studies in the acute phase
60% of patients with haemorrhagic stroke, and are associ- [176178] and continuous monitoring of cerebral haemo-
ated with older age, hypertension, diabetes, leukoaraio- dynamic responses [179]. The combination of ultrasound
sis, lacunar stroke, and amyloid angiopathy [166]. The imaging techniques and MRA reveals excellent results
incidence of symptomatic intracranial haemorrhage fol- equal to digital subtraction angiography [180]. Cerebral
lowing thrombolysis in ischaemic stroke patients was not reactivity and cerebral autoregulation are impaired in pa-
increased in those having cerebral microbleeds on pre- tients with occlusive extracerebral arterial disease (par-
treatment T2*-weighted MRI [167]. ticularly carotid stenosis and occlusion) and inadequate
Vascular imaging should be performed rapidly to collateral supply, who are at increased risk of recurrent
identify patients with tight symptomatic arterial stenosis stroke [181, 182]. TCD is the only technique that detects
who could benefit from endarterectomy or angioplasty. circulating intracranial emboli [183], which are particu-
Non-invasive imaging with colour-coded duplex imag- larly common in patients with large artery disease. In pa-
ing of the extracranial and intracranial arteries, CT an- tients with symptomatic carotid artery stenoses, they are
giography (CTA), or contrast-enhanced MR angiography a strong independent predictor of early recurrent stroke
(CE-MRA) is widely available. These approaches are rel- and TIA [184], and have been used as a surrogate marker
atively risk-free, whereas intra-arterial angiography has a to evaluate antiplatelet agents [185]. TCD microbubble
13% risk of causing stroke in patients with symptomatic detection can be used to identify a right-to-left shunt
carotid lesions [168, 169]. Digital subtraction angiogra- which mainly results from a patent foramen ovale (PFO)
phy may be needed in some circumstances, for example [186].
when other tests have been inconclusive.
Carotid ultrasound, MRA and CTA visualise carotid Imaging in Patients with TIA, Minor Non-Disabling
stenosis. Systematic reviews and individual patient data Stroke, and Stroke with Spontaneous Recovery
meta-analysis indicate that CE-MRA is the most sensitive Patients presenting with TIA are at high risk of early
and specific non-invasive imaging modality for carotid recurrent stroke (up to 10% in the first 48 h) [187]. They
artery stenosis, closely followed by Doppler ultrasound therefore need urgent clinical diagnosis to treat associ-
and CTA, with non-contrast MRA being the least reliable ated general abnormalities, modify active risk factors and
[170, 171]. identify specific treatable causes, particularly arterial ste-
Some data suggest that vertebrobasilar TIA and minor nosis and other embolic sources. Vascular imaging is a
stroke are associated with a high risk of recurrent stroke priority in those patients with TIA or minor stroke, more
[172]. Extracranial vertebral ultrasound diagnosis is use- than in those with major stroke in whom surgery is not
ful, but intracranial ultrasound of the vertebrobasilar going to be of benefit in the short term. Immediate pre-
system can be misleading due to low specificity. Limited ventive treatment will reduce stroke, disability and death
data suggest that contrast-enhanced MRA and CTA offer [86, 188]. Simple clinical scoring systems can be used to
better non-invasive imaging of the intracranial vertebral identify patients at particularly high risk [187]. Patients
and basilar arteries [173]. with minor non-disabling stroke and rapid spontaneous
Unlike other imaging modalities ultrasound is fast, clinical recovery are also at high risk of recurrent stroke
non-invasive and can be administered using portable [58].
machines. It is therefore applicable to patients unable to Patients with widely varying brain pathology may
co-operate with MRA or CTA [158]. However, Doppler present with transient neurological deficits indistin-
studies alone often provide only limited information, are guishable from TIA. CT reliably detects some of these
investigator dependent and require skilled operators, al- pathologies (e.g. intracerebral haemorrhage, subdural
though they allow repeated measurements at the bed- haematoma, tumours) [130], but others (e.g. multiple
side. sclerosis, encephalitis, hypoxic brain damage, etc.) are
Transcranial Doppler ultrasound (TCD) is useful for better identified on MRI, while others (e.g. acute meta-
the diagnosis of abnormalities in the large cerebral arter- bolic disturbances) are not visible at all. Intracranial
ies at the base of the skull. However, between 7 and 20% haemorrhage is a rare cause of TIA.
of acute stroke patients, particularly elderly individuals

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Between 2050% of patients with TIAs may have Table 5. Subsequent laboratory tests, according to the type of
acute ischaemic lesions on DWI [145, 189, 190]. These stroke and suspected aetiology
patients are at increased risk of early recurrent disabling
All patients Full blood count, electrolytes, glu-
stroke [190]. However, there is currently no evidence that cose, lipids, creatinine, CRP or
DWI provides better stroke prediction than clinical risk erythrocyte sedimentation rate
scores [191]. The risk of recurrent disabling stroke is also
Cerebral venous Thrombophilia screen, AT3, factor
increased in patients with TIA and an infarct on CT thrombosis, 2, 5, mutations, factor 8, protein C,
[192]. hypercoagulopathy protein S, antiphospholipid anti-
The ability of DWI to identify very small ischaemic le- bodies, d-dimer, homocysteine
sions may be particularly helpful in patients presenting Bleeding disorder INR, activated partial thrombo-
late or in patients with mild non-disabling stroke, in plastin time, fibrinogen, etc.
whom the diagnosis may be difficult to establish on clin- Vasculitis or Cerebral spinal fluid, autoantibody
ical grounds [131]. T2* MRI is the only reliable method to systemic disorder screen, specific antibodies or PCR
identify haemorrhages after the acute phase, when blood for HIV, syphilis, borreliosis, tuber-
is no longer visible on CT [144]. culosis, fungi, illicit drug screening,
blood culture
Suspected genetic disor- Genetic testing
Other Diagnostic Tests ders, e.g. mitochondrial
disorders (MELAS),
Recommendations CADASIL, sickle cell
In patients with acute stroke and TIA, early clinical evalua- disease, Fabry disease,
tion, including physiological parameters and routine blood multiple cavernoma, etc.
tests, is recommended (Class I, Level A)
For all stroke and TIA patients, a sequence of blood tests is
recommended (tables 3 and 5)
It is recommended that all acute stroke and TIA patients
should have a 12-lead electrocardiography (ECG). In addi-
tion, continuous ECG recording is recommended for isch-
aemic stroke and TIA patients (Class I, Level A) to detect new AF in a stroke unit setting [197]. A recent
It is recommended that for stroke and TIA patients seen after systematic review found that new AF was detected by
the acute phase, 24-hour Holter ECG monitoring should be Holter ECG in 4.6% of patients with recent ischaemic
performed when arrhythmias are suspected and no other stroke or TIA, irrespective of baseline ECG and clinical
causes of stroke are found (Class I, Level A) examination [198]. Extended duration of monitoring,
Echocardiography is recommended in selected patients (Class
III, Level B) prolonged event loop recording, and confining Holter
monitoring to patients with non-lacunar stroke may im-
prove detection rates [199].
Cardiac Evaluation Echocardiography can detect many potential causes of
Cardiac and ECG abnormalities are common in acute stroke [200], but there is controversy about the indica-
stroke patients [193]. In particular, prolonged heart rate tions for, and type of, echocardiography in stroke and
corrected QT interval, ST depression, and T wave inver- TIA patients. Transoesophageal echocardiography (TOE)
sion are prevalent in acute ischaemic stroke, especially if has been claimed to be superior to transthoracic echocar-
the insular cortex is involved [194, 195]. Hence, all acute diography for the detection of potential cardiac sources
stroke and TIA patients should have a 12-channel ECG. of embolism [201], independent of age [202].
Cardiac monitoring should be conducted routinely af- Echocardiography is particularly required in patients
ter an acute cerebrovascular event to screen for serious with:
cardiac arrhythmias. It is unclear whether continuous evidence of cardiac disease on history, examination, or
ECG recording at the bedside is equivalent to Holter ECG
monitoring for the detection of atrial fibrillation (AF) in suspected cardiac source of embolism (e.g. infarctions
acute stroke patients. Holter monitoring is superior to in multiple cerebral or systemic arterial territories)
routine ECG for the detection of AF in patients antici- suspected aortic disease
pated to have thromboembolic stroke with sinus rhythm suspected paradoxical embolism
[196]; however, serial 12-channel ECG might be sufficient no other identifiable causes of stroke.

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Table 6. NNT to prevent one stroke per year in patients who un- Management of Vascular Risk Factors
dergo surgery for ICA stenosis (modified from Hankey and War-
low [583] and Rothwell et al. [339]) Recommendations
BP should be checked regularly. It is recommended that high
Disease NNT to avoid BP should be managed with lifestyle modification and indi-
one stroke/year vidualized pharmacological therapy (Class I, Level A) aiming
at normal levels of 120/80 mm Hg (Class IV, GCP). For pre-
Asymptomatic (6099%) 85 hypertensive (120139/8090 mm Hg) with congestive heart
Symptomatic (7099%) 27 failure, MI, diabetes, or chronic renal failure antihyperten-
Symptomatic (5069%) 75 sive medication is indicated (Class 1, Level A)
Symptomatic (>50%) in men 45 Blood glucose should be checked regularly. It is recommend-
Symptomatic (>50%) in women 180 ed that diabetes should be managed with lifestyle modifica-
Symptomatic (>50%) >75 years 25 tion and individualized pharmacological therapy (Class IV,
Symptomatic (>50%) <65 years 90 Level C). In diabetic patients, high BP should be managed in-
Symptomatic (>50%) <2 weeks after the event 25 tensively (Class I, Level A) aiming for levels below 130/80 mm
Symptomatic (>50%) >12 weeks after the event 625 Hg (Class IV, Level C). Where possible, treatment should in-
Symptomatic (50%) No benefit clude an angiotensin-converting enzyme inhibitor or angio-
tensin receptor antagonist (Class I, Level A)
All percentages reflect the NASCET method. Blood cholesterol should be checked regularly. It is recom-
mended that high blood cholesterol (e.g. LDL 1150 mg/dl;
3.9 mM) should be managed with lifestyle modification (Class
IV, Level C) and a statin (Class I, Level A)
It is recommended that cigarette smoking be discouraged
(Class III, Level B)
Transthoracic echocardiography is sufficient for eval- It is recommended that heavy use of alcohol be discouraged
uation of mural thrombi, particularly in the apex of the (Class III, Level B)
left ventricle; this technique has 190% sensitivity and Regular physical activity is recommended (Class III, Level B)
specificity for ventricular thrombi after MI [203]. TOE is A diet low in salt and saturated fat, high in fruit and vegeta-
bles and rich in fibre is recommended (Class III, Level B)
superior for evaluation of the aortic arch, left atrium, and Subjects with an elevated body mass index are recommended
atrial septum [200]. It also allows risk stratification for to take a weight-reducing diet (Class III, Level B)
further thromboembolic events in patients with AF Antioxidant vitamin supplements are not recommended
[204]. (Class I, Level A)
The role of cardiac CT and cardiac MRI in the detec- Hormone replacement therapy is not recommended for the
primary prevention of stroke (Class I, Level A)
tion of embolic sources in stroke patients has not been
evaluated systematically.
A healthy lifestyle, consisting of abstinence from
Blood Tests smoking, low-normal body mass index, moderate alcohol
Blood tests required on emergency admission are list- consumption, regular exercise and healthy diet, is associ-
ed in table 3. Subsequent tests depend on the type of ated with a reduction in ischaemic stroke (RR 0.29; 95%
stroke and suspected aetiology (table 5). CI 0.140.63) [205].

High Blood Pressure


Primary Prevention A high (1120/80 mm Hg) BP is strongly and directly
related to vascular and overall mortality without evidence
The aim of primary prevention is to reduce the risk of of any threshold [206]. Lowering BP substantially reduces
stroke in asymptomatic people. Relative risk (RR), abso- stroke and coronary risks, depending on the magnitude
lute risk (AR), odds ratio (OR), numbers needed to treat of the reduction [207209]. BP should be lowered to 140/85
(NNT) to avoid one major vascular event per year, and mm Hg or below [210]; antihypertensive treatment should
numbers needed to harm to cause one major complica- be more aggressive in diabetic patients (see below) [211].
tion per year, are provided for each intervention in tables A combination of two or more antihypertensive agents is
68. often necessary to achieve these targets.
Most studies comparing different drugs do not suggest
that any class is superior [207, 208, 212]. However, the
LIFE (Losartan Intervention for Endpoint reduction in

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Table 7. RR reduction (RRR), AR reduction (ARR) and NNT to avoid one major vascular event per year in pa-
tients with antithrombotic therapy (modified from CAPRIE Steering Committee [319], Halkes et al. [322],
Hankey and Warlow [583])

Disease Treatment RRR ARR NNT to avoid


% %/year 1 event/year

Non-cardioembolic Aspirin/PCB 13 1.0 100


ischaemic stroke or TIA Aspirin + DIP/PCB 28 1.9 53
Aspirin + DIP/aspirin 18 1.0 104
Clop/PCB 23 1.6 62
Clop/aspirin 10 0.6 166
Atrial fibrillation Warfarin/PCB 62 2.7 37
(primary prevention) Aspirin/PCB 22 1.5 67
Atrial fibrillation Warfarin/PCB 67 8 13
(secondary prevention) Aspirin/PCB 21 2.5 40

PCB = Placebo; Clop = clopidogrel; DIP = dipyridamole.

Table 8. RRR, ARR and NNT to avoid one major vascular event per year in patients with risk factor modifications (modified from
Yusuf et al. [288], PROGRESS Collaborative Group [290], Amarenco et al. [294], Hankey and Warlow [583])

Clinical condition Treatment RRR ARR NNT to avoid


% %/year 1 event/year

General population with increased BP Antihypertensive 42 0.4 250


General population with increased vascular risk ACE inhibitor 22 0.65 154
Post-stroke/TIA with increased BP Antihypertensive 31 2.2 45
Post-stroke/TIA with normal BP ACE inhibitor 8 diuretic 24 0.85 118
Post-stroke/TIA Statins 16 0.44 230
Smoking cessation 33 2.3 43

hypertension) trial found that losartan was superior to Hyperlipidaemia


atenolol in hypertensive patients with left ventricular hy- In a review of 26 statin trials (95,000 patients), the in-
pertrophy (NNT to prevent stroke 270) [213, 214]. Simi- cidence of stroke was reduced from 3.4 to 2.7% [221]. This
larly, the ALLHAT (Antihypertensive and Lipid-Lower- was due mainly to a reduction in non-fatal stroke, from
ing treatment to prevent Heart Attack) trial found that 2.7 to 2.1%. The review included the Heart Protection
chlorthalidone was more effective than amlodipine and Study which was, in part, a secondary prevention trial
lisinopril [215]. Beta-blockers may still be considered an [222]; this trial found an excess of myopathy of one per
option for initial and subsequent antihypertensive treat- 10,000 patients treated per annum [222]. There are no
ment [210]. In elderly subjects, controlling isolated sys- data to suggest that statins prevent stroke in patients with
tolic hypertension (systolic BP 1140 mm Hg and diastol- low-density lipoprotein cholesterol below 150 mg/dl (3.9
ic BP !90 mm Hg) is beneficial [208, 216]. mM).

Diabetes Mellitus Cigarette Smoking


There is no evidence that improving glucose control Observational studies have shown cigarette smoking
reduces stroke [217]. In diabetic patients, BP should be to be an independent risk factor for ischaemic stroke
lowered to below 130/80 mm Hg [211]. Treatment with a [223] in both men and women [224228]. Spousal ciga-
statin reduces the risk of major cardiovascular (CV) rette smoking may be associated with an increased stroke
events, including stroke [218220]. risk [229]. A meta-analysis of 22 studies indicates that

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smoking doubles the risk of ischaemic stroke [230]. Sub- events and stroke despite there being an 8.2% reduction
jects who stop smoking reduce this risk by 50% [225]. of total fat intake and an increased consumption of veg-
Making workplaces smoke-free would result in consider- etables, fruits and grains [242].
able health and economic benefits [231].
Body Weight
Alcohol Consumption A high body mass index (625) is associated with an
Heavy alcohol drinking (160 g/day) increases the risk increased risk of stroke in men [243] and women [244],
of ischaemic stroke (RR 1.69; 95% CI 1.342.15) and mainly mediated by concomitant arterial hypertension
haemorrhagic stroke (RR 2.18; 95% CI 1.483.20). In con- and diabetes. Abdominal adiposity is a risk factor for
trast, light consumption (!12 g/day) is associated with a stroke in men but not women [245]. Although weight loss
reduction in all stroke (RR 0.83; 95% CI 0.750.91) and reduces BP [246], it does not lower stroke risk [247].
ischaemic stroke (RR 0.80; 95% CI 0.670.96), and mod-
erate consumption (1224 g/day) with a reduction in Vitamins
ischaemic stroke (RR 0.72; 95% CI 0.570.91) [232]. Red A low intake of vitamin D is associated with an in-
wine consumption is associated with the lowest risk in creased risk of stroke [248], but supplements of calcium
comparison with other beverages [233]. BP elevation ap- plus vitamin D do not reduce the risk of stroke [249].
pears to be an important intermediary in the relation be- Supplements of tocopherol and beta carotene do not re-
tween alcohol consumption and stroke [234]. duce stroke [250]. A meta-analysis of trials with vitamin
E supplementation found that it might increase mortality
Physical Activity when used at high doses (6400 IU/day) [251].
In a meta-analysis of cohort and case-control studies, High homocysteine levels are associated with in-
physically active individuals had a lower risk of stroke or creased stroke risk (OR 1.19; 95% CI 1.051.31) [252].
death than those with low activity (RR 0.73; 95% CI 0.67 Since folic acid fortification of enriched grain products
0.79). Similarly, moderately active individuals had a low- was mandated by the US Food and Drug Administration,
er risk of stroke, compared with those who were inactive there has been a reduction in stroke mortality rates, in
(RR 0.80; 95% CI 0.740.86) [235]. This association is me- contrast to countries without fortification [253]. A meta-
diated, in part, through beneficial effects on body weight, analysis concluded that folic acid supplementation can
BP, serum cholesterol, and glucose tolerance. Leisure- reduce the risk of stroke (RR 0.82; 95% CI 0.681.00)
based physical activity (25 h per week) has been inde- [254]; the benefit was greatest in trials with long treat-
pendently associated with a reduced severity of ischaemic ment durations or larger homocysteine-lowering effects,
stroke at admission and better short-term outcome and in countries where grain was not fortified.
[236].
Postmenopausal Oestrogen Replacement Therapy
Diet Stroke rates rise rapidly in women after the meno-
Fruit, Vegetable, and Fish Intake pause. However, in an analysis based on a 16-year follow-
In observational studies, high fruit and vegetable in- up of 59,337 postmenopausal women participating in the
take was associated with a decreased risk of stroke, com- Nurses Health Study, there was only a weak association
pared with lower intake (RR 0.96 for each increment of 2 between stroke and oestrogen replacement [255]. Accord-
servings/day; 95% CI 0.931.00) [237]. The risk of isch- ing to the HERS II trial, hormone replacement in healthy
aemic stroke was lower in people who consumed fish at women is associated with an increased risk of ischaemic
least once per month (RR 0.69; 95% CI 0.480.99) [238]. stroke [256]. A Cochrane systematic review [257] found
Whole grain intake was associated with a reduction in hormone replacement therapy to be associated with an
CV disease (OR 0.79; 95% CI 0.730.85) but not stroke increased risk of stroke (RR 1.44; 95% CI 1.101.89). A
[239]. Dietary calcium intake from dairy products was secondary analysis of the Womens Health Initiative ran-
associated with lower mortality from stroke in a Japanese domized controlled trial suggests that the risk of stroke
population [240]. However, in a further study there was is increased with hormone replacement therapy only in
no interaction between the intake of total fat or choles- women with prolonged hormone use (15 years; RR 1.32;
terol, and stroke risk in men [241]. 95% CI 1.121.56) [258, 259].
In a randomized controlled trial in women, dietary
interventions did not reduce the incidence of coronary

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Antithrombotic Therapy Subjects with Vascular Risk Factors
A systematic review of randomized studies comparing
Recommendations antithrombotic agents with placebo in patients with ele-
Low-dose aspirin is recommended in women aged 45 years or vated BP and no prior CV disease showed that aspirin
more who are not at increased risk for intracerebral haemor-
did not reduce stroke or total CV events [267]. In the
rhage and who have good gastrointestinal tolerance; however,
its effect is very small (Class I, Level A) CHARISMA (Clopidogrel for High Atherothrombotic
It is recommended that low-dose aspirin may be considered Risk and Ischemic Stabilization, Management, and
in men for the primary prevention of MI; however, it does not Avoidance) trial, the combination of aspirin and clopido-
reduce the risk of ischaemic stroke (Class I, Level A) grel was less effective than aspirin alone in the subgroup
Antiplatelet agents other than aspirin are not recommended
of patients with multiple vascular risk factors but no isch-
for primary stroke prevention (Class IV, GCP)
Aspirin may be recommended for patients with non-valvular aemic event [269].
AF who are younger than 65 years and free of vascular risk
factors (Class I, Level A) Large Artery Atheroma
Unless contraindicated, either aspirin or an oral anticoagu- Patients with atherosclerotic arterial disease have an
lant (international normalized ratio, INR, 2.03.0) is recom-
increased risk of MI, stroke, and CV death. Aspirin re-
mended for patients with non-valvular AF who are aged 65
75 years and free of vascular risk factors (Class I, Level A) duces MI in patients with asymptomatic carotid artery
Unless contraindicated, an oral anticoagulant (INR 2.03.0) disease [270], and reduces stroke after carotid artery sur-
is recommended for patients with non-valvular AF who are gery [271].
aged 175, or who are younger but have risk factors such as
high BP, left ventricular dysfunction, or diabetes mellitus
(Class I, Level A)
Atrial Fibrillation
It is recommended that patients with AF who are unable to AF is a strong independent risk factor for stroke. A
receive oral anticoagulants should be offered aspirin (Class I, meta-analysis of randomized trials with at least 3 months
Level A) follow-up showed that antiplatelet agents reduced stroke
It is recommended that patients with AF who have mechani- (RR 0.78; 95% CI 0.650.94) in patients with non-valvu-
cal prosthetic heart valves should receive long-term antico-
agulation with a target INR based on the prosthesis type, but
lar AF [272]. Warfarin (target INR 2.03.0) is more effec-
not less than INR 23 (Class II, Level B) tive than aspirin at reducing stroke (RR 0.36; 95% CI
Low-dose aspirin is recommended for patients with asymp- 0.260.51) [272]. As the risk of stroke in people with AF
tomatic ICA stenosis 150% to reduce their risk of vascular varies considerably, risk stratification should be used to
events (Class II, Level B) determine whether patients should be given oral anti-
coagulation, aspirin or nothing [14]. Oral anticoagula-
Low-Risk Subjects tion is more effective in patients with AF who have one
Six large randomized trials have evaluated the benefits or more risk factors, such as previous systemic embo-
of aspirin for the primary prevention of CV events in men lism, age over 75 years, high BP or poor left ventricular
and women (47,293 on aspirin, 45,580 controls) with a function [14]. In the meta-analysis described above, ab-
mean age of 64.4 years [260265]. Aspirin reduced coro- solute increases in major extracranial haemorrhage were
nary events and CV events, but not stroke, CV mortality, less than the absolute reductions in stroke [272]. The
or all-cause mortality [266]. In women, aspirin reduced WASPO (Warfarin vs. Aspirin for Stroke Prevention in
stroke (OR 0.83; 95% CI 0.700.97) and ischaemic stroke Octogenarians) [273] and BAFTA (Birmingham Atrial
(OR 0.76; 95% CI 0.630.93) [267]. In a separate study in Fibrillation Treatment of the Aged) [274] trials showed
39,876 healthy women aged 45 years or more, aspirin re- that warfarin was safe and effective in older individuals.
duced stroke (RR 0.83; 95% CI 0.690.99) and ischaemic The ACTIVE W (Atrial fibrillation Clopidogrel Trial
stroke (RR 0.76; 95% CI 0.630.93), and caused a non-sig- with Irbesartan for prevention of Vascular Events) study
nificant increase in haemorrhagic stroke, over 10 years; it found that the combination of aspirin and clopidogrel
did not reduce the risk of fatal or nonfatal MI, or CV was less effective than warfarin and had a similar bleed-
death [268]. ing rate [275].
No data are currently available on the use of other an- Patients with a prosthetic heart valve, with or without
tiplatelet agents in primary prevention in low-risk sub- AF, should receive long-term anticoagulation with a tar-
jects. get INR based on the prosthesis type (bio-prosthetic
valves: INR 2.03.0; mechanical valves: INR 3.04.0
[276]).

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Carotid Surgery and Angioplasty It is recommended that blood glucose should be checked reg-
ularly. It is recommended that diabetes should be managed
Recommendations with lifestyle modification and individualized pharmacolog-
Carotid surgery is not recommended for asymptomatic indi- ical therapy (Class IV, GCP)
viduals with significant carotid stenosis (North American In patients with type 2 diabetes who do not need insulin,
Symptomatic Carotid Endarterectomy Trial NASCET 60 treatment with pioglitazone is recommended after stroke
99%), except in those at high risk of stroke (Class I, Level C) (Class III, Level B)
Carotid angioplasty, with or without stenting, is not recom- Statin therapy is recommended in subjects with non-cardio-
mended for patients with asymptomatic carotid stenosis embolic stroke (Class I, Level A)
(Class IV, GCP) It is recommended that cigarette smoking be discouraged
It is recommended that patients should take aspirin before (Class III, Level C)
and after surgery (Class I, Level A) It is recommended that heavy use of alcohol be discouraged
(Class IV, GCP)
Trials of carotid surgery for asymptomatic carotid ste- Regular physical activity is recommended (Class IV, GCP)
A diet low in salt and saturated fat, high in fruit and vegeta-
nosis have concluded that although surgery reduces the bles, and rich in fibre is recommended (Class IV, GCP)
incidence of ipsilateral stroke (RR 0.470.54) and any Subjects with an elevated body mass index are recommended
stroke, the absolute benefit is small (approximately 1% to adopt a weight-reducing diet (Class IV, Level C)
per annum) [277279], whereas the perioperative stroke Antioxidant vitamin supplements are not recommended
or death rate is 3%. Medical management is the most ap- (Class I, Level A)
Hormone replacement therapy is not recommended for the
propriate option for most asymptomatic subjects; only secondary prevention of stroke (Class I, Level A)
centres with a perioperative complication rate of 3% or Sleep-disordered breathing such as obstructive sleep apnoea
less should contemplate surgery. Patients with a high risk (OSA) is recommended to be treated with continuous positive
of stroke (men with stenosis of more than 80% and a life airway pressure breathing (Class III, Level GCP)
expectancy of more than 5 years) may derive some ben- It is recommended that endovascular closure of PFO be con-
sidered in patients with cryptogenic stroke and high-risk PFO
efit from surgery in appropriate centres [277, 279]. All (Class IV, GCP)
stenoses are graded following the NASCET method (dis-
tal stenosis) [280].
Carotid endarterectomy (CEA) is effective in younger High Blood Pressure
patients, and possibly also in older individuals, but does A meta-analysis of seven randomized controlled trials
not appear to benefit women [277]. Patients with occlu- showed that antihypertensive drugs reduced stroke re-
sion of the ICA contralateral to the operated carotid ar- currence after stroke or TIA (RR 0.76; 95% CI 0.630.92)
tery do not benefit from CEA [281, 282]. The risk of ipsi- [286]. This analysis included the PATS (indapamide, a
lateral stroke increases with the degree of stenosis [281, diuretic), HOPE (ramipril) and PROGRESS (perindopril,
283]; CEA appears to be effective irrespective of the de- with or without indapamide) studies [287290]. The re-
gree of ipsilateral stenosis over the range of 6099% [277]. duction in stroke occurs regardless of BP and type of
CEA is not beneficial for asymptomatic patients who stroke [290]. Hence, BP should be lowered and monitored
have a life expectancy of less than 5 years. Aspirin should indefinitely after stroke or TIA. The absolute target BP
not be stopped in patients undergoing carotid surgery level and reduction are uncertain and should be individ-
[284]. Patients should be followed-up by the referring ualized, but benefit has been associated with an average
physician after surgery. There are no data from random- reduction of about 10/5 mm Hg, and normal BP levels
ized trials about the benefits and risks of carotid angio- have been defined as !120/80 mm Hg [291]. However, BP
plasty, compared with CEA, in asymptomatic patients should not be lowered intensively in patients with sus-
[285]. pected haemodynamic stroke or in those with bilateral
carotid stenosis. The angiotensin receptor antagonist
eprosartan may be more effective than the calcium chan-
Secondary Prevention
nel blocker nitrendipine [292].
Optimal Management of Vascular Risk Factors
Diabetes Mellitus
Recommendations The prospective, double-blind PROactive trial ran-
It is recommended that BP be checked regularly. BP lowering domized 5,238 patients with type 2 diabetes and a his-
is recommended after the acute phase, including in patients tory of macrovascular disease to pioglitazone or placebo.
with normal BP (Class I, Level A) In patients with previous stroke (n = 486 in the piogli-

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tazone group, n = 498 in the placebo group), there was a mortality [304]. More than 50% of stroke patients have
trend towards benefit with pioglitazone for the combined sleep-disordered breathing, mostly in the form of OSA.
end point of death and major vascular events (HR 0.78; This can improve spontaneously after stroke, but may
95% CI 0.601.02; p = 0.067). In a secondary analysis, need treatment. Continuous positive airway pressure is
pioglitazone reduced fatal or nonfatal stroke (HR 0.53; the treatment of choice for OSA. Oxygen and other forms
95% CI 0.340.85; p = 0.0085) and CV death, nonfatal of ventilation may be helpful in other (e.g. central) forms
MI, or nonfatal stroke (HR 0.72; 95% CI 0.521.00; p = of SDB.
0.0467) [293].
Patent Foramen Ovale
Hyperlipidaemia Case reports and case control studies indicate an as-
In the SPARCL (Stroke Prevention by Aggressive Re- sociation between the presence of PFO and cryptogenic
duction in Cholesterol Levels) trial, statin therapy with stroke in both younger and older stroke patients [305,
atorvastatin reduced stroke recurrence (HR 0.84; 95% CI 306]. Two population-based studies pointed in the same
0.710.99) [294], while in the Heart Protection Study sim- direction but did not confirm a significant association
vastatin reduced vascular events in patients with prior [307, 308]. In patients with PFO alone the overall risk of
stroke, and reduced stroke in patients with other vascular recurrence is low. However, when the PFO is combined
disease (RR 0.76) [222]. Neither trial assessed efficacy by with an atrial septal aneurysm, an Eustachian valve, a
stroke subtype, and SPARCL did not include patients Chiari network, or in patients who have suffered more
with presumed cardioembolic stroke [222, 294]. The risk than one stroke the risk of recurrence can be substantial
of haemorrhagic stroke was slightly increased in both tri- [309]. Endovascular closure of PFOs with or without sep-
als [222, 294]. The AR reduction achieved with statin tal aneurysms is feasible in such patients [310] and may
therapy is low (NNT 112143 for 1 year). Statin with- lower the risk of recurrent stroke compared to medical
drawal at the acute stage of stroke may be associated with treatment [311]; however, RCTs are still lacking.
an increased risk of death or dependency [295].
Postmenopausal Oestrogen Replacement Therapy
Cigarette Smoking Hormone replacement therapy does not protect against
There are no specific data in secondary prevention. vascular events and may increase stroke severity [312].
See Primary Prevention.

Diet Antithrombotic Therapy


Overweight
Recommendations
There are no specific data in secondary prevention. It is recommended that patients receive antithrombotic ther-
See Primary Prevention. Weight loss may be beneficial apy (Class I, Level A)
after stroke as it lowers BP [246]. It is recommended that patients not requiring anticoagula-
tion should receive antiplatelet therapy (Class I, Level A).
Vitamins Where possible, combined aspirin and dipyridamole, or clop-
idogrel alone, should be given. Alternatively, aspirin alone, or
Beta carotene increased the risk of CV death in a meta- triflusal alone, may be used (Class I, Level A)
analysis of primary and secondary prevention trials (RR The combination of aspirin and clopidogrel is not recom-
1.10; 95% CI 1.031.17) [296]. Vitamin E supplementation mended in patients with recent ischaemic stroke, except in
does not prevent vascular events [297]. Fat-soluble anti- patients with specific indications (e.g. unstable angina or
oxidant supplements may increase mortality [298]. non-Q-wave MI, or recent stenting); treatment should be giv-
en for up to 9 months after the event (Class I, Level A)
Vitamins which lower homocysteine (folate, B12, B6) It is recommended that patients who have a stroke on anti-
do not appear to reduce stroke recurrence and may in- platelet therapy should be re-evaluated for pathophysiology
crease vascular events [299302], but further trials are and risk factors (Class IV, GCP)
ongoing [303]. Oral anticoagulation (INR 2.03.0) is recommended after
ischaemic stroke associated with AF (Class I, Level A). Oral
anticoagulation is not recommended in patients with co-
Sleep-Disordered Breathing morbid conditions such as falls, poor compliance, uncon-
Sleep-disordered breathing represents both a risk fac- trolled epilepsy, or gastrointestinal bleeding (Class III, Level
tor and a consequence of stroke and is linked with poor- C). Increasing age alone is not a contraindication to oral an-
er long-term outcome and increased long-term stroke ticoagulation (Class I, Level A)

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It is recommended that patients with cardioembolic stroke Clopidogrel plus Aspirin
unrelated to AF should receive anticoagulants (INR 2.03.0) Compared with clopidogrel alone, the combination of
if the risk of recurrence is high (Class III, Level C) aspirin and clopidogrel did not reduce the risk of isch-
It is recommended that anticoagulation should not be used aemic stroke, MI, vascular death, or re-hospitalization
after non-cardio-embolic ischaemic stroke, except in some
specific situations, such as aortic atheromas, fusiform aneu- [325]; however, life-threatening or major bleeding was in-
rysms of the basilar artery, cervical artery dissection, or PFO creased with the combination. Similarly, in the CHARIS-
in the presence of proven deep vein thrombosis (DVT) or atri- MA study, the combination of aspirin and clopidogrel did
al septal aneurysm (Class IV, GCP) not reduce the risk of MI, stroke, or death from CV causes,
It is recommended that combined low-dose aspirin and di- compared with aspirin alone [269]. In patients who have
pyridamole should be given if oral anticoagulation is contra-
indicated (Class IV, GCP) had an acute coronary event within 12 months, or coro-
nary stenting, the combination of clopidogrel and aspirin
reduces the risk of new vascular events [326].
Antiplatelet Therapy
Antiplatelet therapy reduces vascular events, includ- Oral Anticoagulation
ing non-fatal MI, nonfatal stroke and vascular death in Oral anticoagulation after non-cardiac ischaemic
patients with previous stroke or TIA (RR 0.78; 95% CI stroke is not superior to aspirin, but causes more bleeding
0.760.80) [313]. [327329]. Oral anticoagulation (INR 2.03.0) reduces
the risk of recurrent stroke in patients with non-valvular
Aspirin AF (whether of permanent, chronic or paroxysmal type)
Aspirin reduces recurrence irrespective of dose (50 [330] and most other cardiac sources of emboli. Antico-
1,300 mg/day) [314317], although high doses (1150 mg/ agulation should be taken long term, or for at least 3
day) increase adverse events. In patients with symptom- months after cardioembolic stroke due to MI [331]. There
atic intracranial atherosclerosis, aspirin is as effective as is a controversial discussion about the optimal time point
oral anticoagulation and has fewer complications [318]. when to start oral anticoagulation. After TIA or minor
stroke, one could start immediately, but after major stroke
Clopidogrel with significant infarction upon neuroimaging (e.g.
Clopidogrel is slightly more effective than aspirin in above a third of the MCA territory) one should wait for
preventing vascular events (RR 0.91; 95% CI 0.840.97) some (e.g. 4) weeks. However, this decision has to be in-
[319]. It may be more effective in high-risk patients (i.e. dividualized.
those with previous stroke, peripheral artery disease, In patients with AF and stable coronary disease, aspi-
symptomatic coronary disease, or diabetes) [269]. rin should not be added to oral anticoagulation [332]. An-
ticoagulation may be beneficial in patients with aortic
Dipyridamole atheroma [333], fusiform aneurysms of the basilar artery
Dipyridamole reduces stroke recurrence with similar [334] or cervical dissection [335]. The ongoing ARCH tri-
efficacy to aspirin [320]. al is comparing the combination of clopidogrel plus aspi-
rin with oral anticoagulation in secondary prevention of
Triflusal patients with atherosclerotic plaques in the aortic arch.
Triflusal reduces stroke recurrence with similar effi-
cacy to aspirin but with fewer adverse events [321]. Recurrent Vascular Event on Antiplatelet Therapy
The treatment of patients who have a recurrent vascu-
Dipyridamole plus Aspirin lar event on antiplatelet therapy remains unclear. Alter-
The combination of aspirin (38300 mg/day) and di- native causes of stroke should be sought and consistent
pyridamole (200 mg extended release twice daily) reduc- risk-factor management is mandatory especially in those
es the risk of vascular death, stroke or MI, compared with patients. Alternative treatment strategies may be consid-
aspirin alone (RR 0.82; 95% CI 0.740.91) [320, 322]. Di- ered: leave unchanged, change to another antiplatelet
pyridamole may cause headache; the incidence of this agent, add another antiplatelet agent, or use oral antico-
may be reduced by increasing the dose gradually [323, agulation.
324].

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Surgery and Angioplasty sis fugax, severe stenosis and a high risk profile should be
considered for CEA; those with amaurosis fugax and few
Recommendations risk factors do better with medical treatment. Patients
CEA is recommended for patients with 7099% stenosis with mild-to-moderate intracranial stenosis and severe
(Class I, Level A). CEA should only be performed in centres extracranial stenosis should be considered for CEA.
with a perioperative complication rate (all strokes and death)
of less than 6% (Class I, Level A) The benefit from CEA is less in patients with lacunar
It is recommended that CEA be performed as soon as possible stroke [342]. Patients with leukoaraiosis carry an increased
after the last ischaemic event, ideally within 2 weeks (Class II, perioperative risk [343]. Occlusion of the contralateral
Level B) ICA is not a contraindication to CEA but carries a higher
It is recommended that CEA may be indicated for certain pa- perioperative risk. The benefit from endarterectomy is
tients with stenosis of 5069%; males with very recent hemi-
spheric symptoms are most likely to benefit (Class III, Level marginal in patients with carotid near-occlusion.
C). CEA for stenosis of 5069% should only be performed in
centres with a perioperative complication rate (all stroke and Carotid Angioplasty and Stenting
death) of less than 3% (Class I, Level A) Several trials have compared CAS and CEA in second-
CEA is not recommended for patients with stenosis of less ary stroke prevention (table 9) [344347]. However, the
than 50% (Class I, Level A)
It is recommended that patients remain on antiplatelet ther- SAPPHIRE (Stenting and Angioplasty with Protection in
apy both before and after surgery (Class I, Level A) Patients at High Risk for Endarterectomy) trial included
Carotid percutaneous transluminal angioplasty and/or stent- more than 70% asymptomatic patients, and therefore
ing (CAS) is only recommended in selected patients (Class I, should not be used for decisions about secondary preven-
Level A). It should be restricted to the following subgroups of tion [346]. In CAVATAS (Carotid and Vertebral Artery
patients with severe symptomatic carotid artery stenosis:
those with contra-indications to CEA, stenosis at a surgically Transluminal Angioplasty Study), the majority of the pa-
inaccessible site, re-stenosis after earlier CEA, and post-ra- tients in the endovascular group underwent angioplasty,
diation stenosis (Class IV, GCP). Patients should receive a and only 26% were treated with a stent [347]. The two
combination of clopidogrel and aspirin immediately before most recent studies revealed different results. SPACE
and for at least 1 month after stenting (Class IV, GCP)
(Stent-protected Angioplasty versus Carotid Endarterec-
It is recommended that endovascular treatment may be con-
sidered in patients with symptomatic intracranial stenosis tomy in symptomatic patients) marginally failed to prove
(Class IV, GPC) the non-inferiority of CAS compared to CEA; for the end-
point ipsilateral stroke or death up to day 30, the event
Carotid Endarterectomy rates after 1,200 patients were 6.8% for CAS and 6.3% for
The grading of stenosis should be performed accord- CEA patients (absolute difference 0.5%; 95% CI 1.9% to
ing to the NASCET criteria. Although ECST (European 2.9%; p = 0.09) [345]. The French EVA3S (Endarterecto-
Carotid Surgery Trialists) and NASCET use different my versus Stenting in Patients with Symptomatic Severe
methods of measurement, it is possible to convert the per- Carotid Stenosis) trial was stopped prematurely after the
centage stenosis derived by one method to the other [336]. inclusion of 527 patients because of safety concerns and
CEA reduces the risk of recurrent disabling stroke or lack of efficacy. The RR of any stroke or death after CAS,
death (RR 0.52) in patients with severe (7099%) ipsilat- compared with CEA, was 2.5 (95% CI 1.25.1) [344]. An
eral ICA stenosis [280, 337, 338]. Patients with less severe updated meta-analysis of these studies revealed a signifi-
ipsilateral carotid stenosis (5069%) may also benefit cantly higher risk of any stroke and death within 30 days
[338]. Surgery is potentially harmful in patients with mild after CAS, compared with CEA (OR 1.41; 95% CI 1.07
or moderate degrees of stenosis (!50%) [338]. 1.87; p = 0.016). However, significant heterogeneity was
CEA should be performed as soon as possible (ideally found in this analysis (p = 0.035) [348]. After the peripro-
within 2 weeks) after the last cerebrovascular event [339]. cedural period, few ipsilateral strokes occurred with ei-
Surgical procedure is important in preventing stroke; ca- ther procedure (table 9).
rotid patch angioplasty may reduce the risk of periopera-
tive arterial occlusion and restenosis [340]. Intracranial and Vertebral Artery Occlusive Disease
Older patients (175 years) without organ failure or se- Extracranial-Intracranial Anastomosis
rious cardiac dysfunction benefit from CEA [339]. Wom- Anastomosis between the superficial temporal and
en with severe (170%) symptomatic stenosis should un- middle cerebral arteries is not beneficial in preventing
dergo CEA, whereas women with more moderate stenosis stroke in patients with MCA or ICA stenosis or occlusion
should be treated medically [341]. Patients with amauro- [349].

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Table 9. Risk of stroke or death from large-scale randomized trials comparing endovascular and surgical treatment in patients with
severe carotid artery stenosis (intention to treat data)

Outcome Any stroke or death at 30 days Disabling stroke or death at 30 days Ipsilateral stroke after 30 days
CAS CEA CAS CEA CAS CEA

CAVATAS [347] 25 (10.0) 25 (9.9) 16 (6.4) 15 (5.9) 61 101


SAPPHIRE [346] 8 (4.8) 9 (5.4) unknown unknown unknown unknown
SPACE [345, 584] 46 (7.7) 38 (6.5) 29 (4.8) 23 (3.9) 4 (0.7)2 1 (0.2)2
EVA3S [344] 25 (9.6) 10 (3.9) 9 (3.4) 4 (1.5) 2 (0.6)2 1 (0.3)2

Figures in parentheses indicate percentages.


1
Follow-up duration 1.95 years in mean. 2 Up to 6 months.

Stenting of Intracranial or Vertebral Artery Stenoses Routine BP lowering is not recommended following acute
Patients with symptomatic intracranial stenoses of stroke (Class IV, GCP)
650% are at high risk of recurrent strokes, both in the Cautious BP lowering is recommended in patients with ex-
tremely high BPs (1220/120 mm Hg) on repeated measure-
anterior and posterior circulation (12% after 1 year and ments, or with severe cardiac failure, aortic dissection, or hy-
15% after 2 years in the territory of the stenosed artery) pertensive encephalopathy (Class IV, GCP)
[318, 350]. Severe stenoses (670%) carry a higher risk It is recommended that abrupt BP lowering be avoided (Class
than moderate stenoses (50 to !70%) [350]. After stent- II, Level C)
ing, recurrent strokes are reported in about 57% of pa- It is recommended that low BP secondary to hypovolaemia or
associated with neurological deterioration in acute stroke
tients with moderate or severe stenoses after 1 year, and should be treated with volume expanders (Class IV, GCP)
in around 8% after 2 years [351, 352]. However, the inci- Monitoring serum glucose levels is recommended (Class IV,
dence of complications after either angioplasty or stent- GCP)
ing may be up to 6% [353355]. No randomized controlled Treatment of serum glucose levels 1180 mg/dl (110 mM) with
trials have evaluated angioplasty, stenting or both for in- insulin titration is recommended (Class IV, GCP)
It is recommended that severe hypoglycaemia [!50 mg/dl
tracranial stenosis. Several non-randomized trials have (! 2.8 mM)] should be treated with intravenous dextrose or
shown feasibility and acceptable safety of intracranial infusion of 1020% glucose (Class IV, GCP points)
stenting, but the risk of restenosis remains high [355, It is recommended that the presence of pyrexia (temperature
356]. Also stenting of the extracranial segments of the 137.5 C) should prompt a search for concurrent infection
vertebral artery is technically feasible with a moderate (Class IV, GCP)
Treatment of pyrexia (temperature 137.5 C) with paracetamol
periprocedural risk as, for example, demonstrated in the and fanning is recommended (Class III, Level C)
SSYLVIA trial; but especially at the origin, there is a par- Antibiotic prophylaxis is not recommended in immunocom-
ticularly high rate of restenoses [356]. petent patients (Class II, Level B)

The term general treatment refers to treatment strat-


General Stroke Treatment egies aimed at stabilizing the critically ill patient in order
to control systemic problems that may impair stroke re-
Recommendations
Intermittent monitoring of neurological status, pulse, BP, covery; the management of such problems is a central
temperature and oxygen saturation is recommended for 72 h part of stroke treatment [2, 106]. General treatment in-
in patients with significant persisting neurological deficits cludes respiratory and cardiac care, fluid and metabolic
(Class IV, GCP) management, BP control, the prevention and treatment
It is recommended that oxygen should be administered if the of conditions such as seizures, venous thromboembo-
oxygen saturation falls below 95% (Class IV, GCP)
Regular monitoring of fluid balance and electrolytes is rec- lism, dysphagia, aspiration pneumonia, other infections,
ommended in patients with severe stroke or swallowing prob- or pressure ulceration, and occasionally management of
lems (Class IV, GCP) elevated intracranial pressure (ICP). However, many as-
Normal saline (0.9%) is recommended for fluid replacement pects of general stroke treatment have not been adequate-
during the first 24 h after stroke (Class IV, GCP) ly assessed in randomized clinical trials (RCTs).

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It is common practice to actively manage neurological troponin levels indicative of cardiac damage [363]. Every
status and vital physiological functions such as BP, pulse, stroke patient should have an initial ECG. Cardiac mon-
oxygen saturation, blood glucose and temperature. Neu- itoring should be conducted to screen for AF. Optimizing
rological status can be monitored using validated neuro- cardiac output with maintenance of high normal BP and
logical scales such as the NIH Stroke Scale [104] or the a normal heart rate is a standard component of stroke
Scandinavian Stroke Scale [357]. There is little direct ev- management. The use of inotropic agents is not routine
idence from RCTs to indicate how intensively monitoring practice, but fluid replacement therapy is commonly used
should be carried out, but in stroke unit trials [119] it was to correct hypovolaemia. Increases in cardiac output may
common practice to have a minimum of 4-hourly obser- increase cerebral perfusion. Restoration of normal car-
vations for the first 72 h after stroke. Clinical trials using diac rhythm using drugs, cardioversion or pacemaker
continuous telemetry [358, 359] suggest there may be support may occasionally be required.
some benefit from more intensive continuous monitoring
in terms of improved detection of complications and re-
duced length of stay, but clinical outcomes are inconclu- Fluid Replacement Therapy
sive. In practice, more intensive monitoring is often pro-
vided for subgroups of patients, such as those with re- Many stroke patients are dehydrated on admission to
duced consciousness, progressing neurological deficits, hospital, and this is associated with a poor outcome [364].
or a history of cardiorespiratory disease. Close monitor- Although clinical trial evidence is limited, delivery of in-
ing is also required for the first 24 h after thrombolysis. travenous fluids is commonly considered part of general
More invasive monitoring procedures, such as central ve- management of acute stroke, particularly in patients at
nous catheters or ICP monitoring, are used only in high- risk of dehydration due to reduced consciousness or im-
ly selected patient groups. paired swallowing. Experience in the management of hy-
perglycaemia supports the avoidance of dextrose in the
early post-stroke phase [365]. More specialist fluid re-
Pulmonary Function and Airway Protection placement therapy with haemodilution has not been
shown to improve stroke outcomes [366].
Normal respiratory function with adequate blood ox-
ygenation is believed to be important in the acute stroke
period to preserve ischaemic brain tissue. However, there Blood Pressure Management
is no convincing evidence that routine provision of oxy-
gen at low flow rates to all acute stroke patients is effective BP monitoring and treatment is a controversial area in
[360]. Identification and treatment of hypoxia is believed stroke management. Patients with the highest and lowest
to be important in individuals with extensive brain stem levels of BP in the first 24 h after stroke are more likely to
or hemispheric stroke, seizure activity, or complications have early neurological decline and poorer outcomes
such as pneumonia, cardiac failure, pulmonary embo- [367]. A low or low-normal BP at stroke onset is unusual
lism (PE), or exacerbation of COPD. Blood oxygenation [368], and may be the result of a large cerebral infarct,
is usually improved by the administration of 24 l of ox- cardiac failure, ischaemia, hypovolaemia or sepsis. BP
ygen via a nasal tube. Ventilation may be necessary in can usually be raised by adequate rehydration with crys-
patients with severely compromised respiratory func- talloid (saline) solutions; patients with low cardiac output
tion. However, before ventilation is performed the gen- may occasionally need inotropic support. However clini-
eral prognosis, coexisting medical conditions, and the cal trials of actively elevating a low BP in acute stroke
presumed wishes of the patient need to be considered. have yielded inconclusive results.
A systematic review covering a variety of BP-altering
agents has not provided any convincing evidence that ac-
Cardiac Care tive management of BP after acute stroke influences pa-
tient outcomes [369]. Small studies looking at surrogate
Cardiac arrhythmias, particularly AF, are relatively markers of cerebral blood flow such as SPECT have indi-
common after stroke, and heart failure, MI and sudden cated that neither perindopril nor losartan lower cerebral
death are also recognized complications [361, 362]. A sig- blood flow when given within 27 days of stroke onset
nificant minority of stroke patients show raised blood [370]. Several ongoing trials are examining whether BP

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should be lowered after acute stroke, and whether anti- Body Temperature Management
hypertensive therapy should be continued or stopped in
the first few days after stroke [371, 372]. In the absence of In experimental stroke, hyperthermia is associated with
reliable evidence from clinical trials, many clinicians increased infarct size and poor outcome [380]. Raised tem-
have developed protocols for the management of ex- perature can be centrally driven or a result of concurrent
tremely high BP. In some centres it is common practice infection, and is associated with poorer clinical outcomes
to begin cautious BP reduction when levels exceed 220 [381383]. A raised body temperature should prompt a
mm Hg systolic and 120 mm Hg diastolic. However, in search for infection and treatment where appropriate.
many centres BP reduction is only considered in the pres- Studies with antipyretic medication have been inconclu-
ence of severe cardiac insufficiency, acute renal failure, sive, but treatment of raised body temperature (137.5 C)
aortic arch dissection, or malignant hypertension. In pa- with paracetamol is common practice in stroke patients.
tients undergoing thrombolysis, it is common practice to
avoid systolic BPs above 185 mm Hg.
Specific Treatment
The use of sublingual nifedipine should be avoided be-
cause of the risk of an abrupt decrease in BP [373]. Intra- Recommendations
venous labetalol or urapadil are frequently used in North Intravenous rtPA (0.9 mg/kg body weight, maximum 90 mg),
America. Sodium nitroprusside is sometimes recom- with 10% of the dose given as a bolus followed by a 60-min
mended. infusion, is recommended within 3 h of onset of ischaemic
stroke (Class I, Level A)
Intravenous rtPA may be of benefit also for acute ischaemic
stroke beyond 3 h after onset (Class I, Level B) but is not rec-
Blood Glucose Management ommended for routine clinical practice
The use of multimodal imaging criteria may be useful for pa-
Hyperglycaemia occurs in up to 60% of stroke patients tient selection for thrombolysis but is not recommended for
routine clinical practice (Class III, Level C)
without known diabetes [374, 375]. Hyperglycaemia after It is recommended that BP of 185/110 mm Hg or higher is
acute stroke is associated with larger infarct volumes and lowered before thrombolysis (Class IV, GCP)
cortical involvement, and with poor functional outcome It is recommended that intravenous rtPA may be used in pa-
[376378]. There is limited evidence as to whether active tients with seizures at stroke onset, if the neurological deficit
reduction of glucose in acute ischaemic stroke improves is related to acute cerebral ischaemia (Class IV, GCP)
It is recommended that intravenous rtPA may also be admin-
patient outcomes. The largest randomized trial of blood istered in selected patients under 18 years and over 80 years
glucose lowering by glucose potassium insulin infusion of age, although this is outside the current European labelling
[365], compared with standard intravenous saline infu- (Class III, Level C)
sion, found no difference in mortality or functional out- Intra-arterial treatment of acute MCA occlusion within a
6-hour time window is recommended as an option (Class II,
comes in patients with mild-to-moderate blood glucose Level B)
elevations [median 137 mg/dl (7.6 mM)]. This regime was Intra-arterial thrombolysis is recommended for acute basilar
labour intensive and associated with episodes of hypogly- occlusion in selected patients (Class III, Level B). Intravenous
caemia. At present, the routine use of insulin infusion thrombolysis for basilar occlusion is an acceptable alternative
regimes in patients with moderate hyperglycaemia can- even after 3 h (Class III, Level B)
It is recommended that aspirin (160325 mg loading dose) be
not be recommended. However, it is common practice in given within 48 h after ischaemic stroke (Class I, Level A)
stroke units to reduce blood glucose levels exceeding 180 It is recommended that if thrombolytic therapy is planned or
mg/dl (10 mM) [119]. The use of intravenous saline and given, aspirin or other antithrombotic therapy should not be
avoidance of glucose solutions in the first 24 h after stroke initiated within 24 h (Class IV, GCP)
is common practice, and appears to reduce blood glucose The use of other antiplatelet agents (single or combined) is not
recommended in the setting of acute ischaemic stroke (Class
levels [365]. III, Level C)
Hypoglycaemia [!50 mg/dl (2.8 mM)] may mimic an The administration of glycoprotein-IIb-IIIa inhibitors is not
acute ischaemic infarction, and should be treated by in- recommended (Class I, Level A)
travenous dextrose bolus or infusion of 1020% glucose Early administration of unfractionated heparin (UFH), low
molecular weight heparin or heparinoids is not recommend-
[379]. ed for the treatment of patients with acute ischaemic stroke
(Class I, Level A)
Currently, there is no recommendation to treat ischaemic stroke
patients with neuroprotective substances (Class I, Level A)

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Thrombolytic Therapy However, a RCT has recently been stopped for undis-
closed reasons.
Intravenous Tissue Plasminogen Activator Intravenous rtPA may be of benefit also for acute isch-
Thrombolytic therapy with rtPA (0.9 mg/kg body aemic stroke beyond 3 h after onset, but is not recom-
weight, maximum dose 90 mg) given within 3 h after mended in clinical routine. The use of multimodal imag-
stroke onset significantly improves outcome in patients ing criteria may be useful for patient selection. Several
with acute ischaemic stroke [126]: the NNT to achieve a large observational studies suggest improved safety and
favourable clinical outcome after 3 months is 7. By con- possibly improved efficacy in patients treated with intra-
trast, the ECASS (European Cooperative Acute Stroke venous rtPA beyond 3 h based on advanced imaging find-
Study) and ECASS II studies did not show statistically ings [131, 160, 400, 401]. However, available data on mis-
significant superiority of rtPA for the primary endpoints match, as defined by multimodal MRI or CT, are too lim-
when treatment was given within 6 h [384, 385]. Trials ited to guide thrombolysis in routine practice (see also
with rtPA, involving a total of 2,889 patients, have shown the section on imaging) [153].
a significant reduction in the number of patients with Patients with seizures at stroke onset have been exclud-
death or dependency (OR 0.83; 95% CI 0.730.94) [386]. ed from thrombolytic trials because of potential confu-
A pooled analysis of individual data of rtPA trials showed sion with post-ictal Todds phenomena. Case series have
that, even within a 3-hour window, earlier treatment re- suggested that thrombolysis may be used in such patients
sults in a better outcome (090 min: OR 2.11; 95% CI when there is evidence for new ischaemic stroke [389].
1.333.55; 90180 min: OR 1.69; 95% CI 1.092.62) [387]. Post-hoc analyses have identified the following poten-
This analysis suggested a benefit up to 4.5 h. Ongoing tri- tial factors associated with increased risk of intracerebral
als (ECASS III, IST-3) are further investigating the ben- bleeding complications after rtPA use [402]:
efits of rtPA beyond 3 h. elevated serum glucose
The NINDS (National Institute of Neurological Dis- history of diabetes
orders and Stroke) Study showed that the extent of early baseline symptom severity
ischaemic changes (using the ASPECT score) had no ef- advanced age
fect on treatment response within the 3-hour time win- increased time to treatment
dow [388]. However, European regulatory agencies do previous aspirin use
not advocate rtPA treatment in patients with severe stroke history of congestive heart failure
(NIHSSS 625), extended early ischaemic changes on CT low plasminogen activator inhibitor activity
scan, or age above 80 years (unlike the US labelling). Nev- NINDS protocol violations.
ertheless, observational studies suggest that rtPA given However, none of these factors reversed the overall
within 3 h of stroke onset is safe and effective in patients benefit of rtPA.
over 80 years of age [389391], but more randomized data
are pending. The effect of gender on the response to rtPA Other Intravenous Thrombolytics
is uncertain [392]. Intravenous streptokinase was associated with an un-
Thrombolytic therapy appears to be safe and effective acceptable risk of haemorrhage and death [403, 404]. In-
across various types of hospitals, if the diagnosis is estab- travenous desmoteplase administered 39 h after acute
lished by a physician with stroke expertise and brain CT ischaemic stroke in patients selected on the basis of per-
is assessed by an experienced physician [393395]. When- fusion/diffusion mismatch was associated with a higher
ever possible, the risks and benefits of rtPA should be rate of reperfusion and better clinical outcome, compared
discussed with the patient and family before treatment is with placebo, in two small RCTs [405, 406]. These find-
initiated. ings were not confirmed in the phase III DIAS (Des-
BP must be below 185/110 mm Hg before, and for the moteplase in Acute Ischemic Stroke)-II study, but this
first 24 h after, thrombolysis. Management of high BP is agent will be evaluated further.
required [126]. Protocol violations are associated with
higher mortality rates [396, 397]. Intra-Arterial and Combined (IV+ IA) Thrombolysis
Continuous transcranial ultrasound was associated Intra-arterial thrombolytic treatment of proximal
with an increased rate of early recanalization after rtPA MCA occlusion using pro-urokinase (PUK) within 6 h
in a small randomized trial [398]; this effect may be fa- was significantly associated with better outcome in the
cilitated by the administration of microbubbles [399]. PROACT II (Pro-urokinase for Acute Ischemic Stroke)

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trial [154]. Additional smaller RCTs with PUK (PROACT with placebo (RR 0.95; 95% CI 0.621.45) in patients with
I) or urokinase (MELT) and a meta-analysis of PROACT incomplete paresis [417].
I, PROACT II and MELT indicate a benefit of intra-arte- The use of clopidogrel, dipyridamole, or combinations
rial thrombolytic therapy in patients with proximal MCA of oral antiplatelet agents in acute ischaemic stroke has
occlusions [407]. PUK is not available and intra-arterial not been evaluated.
thrombolysis with tPA is not substantiated by RCTs, but In a double-blind phase II, the glycoprotein-IIb-IIIa
observational data and non-randomised comparisons are inhibitor abciximab produced a non-significant shift in
available [155, 408]. favourable outcomes, as measured by modified Rankin
A randomized trial comparing standard intravenous scores (mRS) at 3 months, compared with placebo (OR
rtPA with a combined intravenous and intra-arterial ap- 1.20; 95% CI 0.841.70) [418]. A phase III study evaluat-
proach (IMS3) has started [409]. ing the safety and efficacy of abciximab was terminated
Intra-arterial treatment of acute basilar occlusion with prematurely after 808 patients had been enrolled because
urokinase or rtPA has been available for more than 20 of an increased rate of symptomatic or fatal intracranial
years, but has not been tested in an adequately powered bleeding with abciximab compared to placebo (5.5 vs.
RCT [410], although encouraging results have been ob- 0.5%; p = 0.002). This trial also did not demonstrate an
tained in observational studies [411, 412]. A systematic improvement in outcomes with abciximab [419].
analysis found no significant differences between intra-
venous or intra-arterial thrombolysis for basilar occlu-
sion [413]. Early Anticoagulation

Intra-Arterial Recanalization Devices Subcutaneous UFH at low or moderate doses [415], na-
The MERCI (Mechanical Embolus Removal in Cere- droparin [420, 421], certoparin [422], tinzaparin [423],
bral Embolism) trial evaluated a device that removed the dalteparin [424] and intravenous danaparoid [425] have
thrombus from an intracranial artery. Recanalization failed to show an overall benefit of anticoagulation when
was achieved in 48% (68/141) of patients in whom the de- initiated within 2448 h from stroke onset. Improve-
vice was deployed within 8 h of the onset of stroke symp- ments in outcome or reductions in stroke recurrence
toms [414]. No RCTs with outcome data are available for rates were mostly counterbalanced by an increased num-
any recanalization devices. ber of haemorrhagic complications. In a meta-analysis of
22 trials, anticoagulant therapy was associated with about
nine fewer recurrent ischaemic strokes per 1,000 patients
Antiplatelet Therapy treated (OR 0.76; 95% CI 0.650.88), and with about nine
more symptomatic intracranial haemorrhages per 1,000
The results of two large randomized, non-blinded, in- (OR 2.52; 95% CI 1.923.30) [426]. However, the quality
tervention studies indicate that aspirin is safe and effec- of the trials varied considerably. The anticoagulants test-
tive when started within 48 h after stroke [415, 416]. In ed were standard UFH, low molecular weight heparins,
absolute terms, 13 more patients were alive and indepen- heparinoids, oral anticoagulants, and thrombin inhibi-
dent at the end of follow-up for every 1,000 patients treat- tors.
ed. Furthermore, treatment increased the odds of mak- Few clinical trials have assessed the risk-benefit ratio
ing a complete recovery from the stroke (OR 1.06; 95% CI of very early administration of UFH in acute ischaemic
1.011.11): 10 more patients made a complete recovery for stroke. In one study, patients with nonlacunar stroke an-
every 1,000 patients treated. Antiplatelet therapy was as- ticoagulated within 3 h had more self-independence (38.9
sociated with a small but definite excess of two symptom- vs. 28.6%; p = 0.025), fewer deaths (16.8 vs. 21.9%; p =
atic intracranial haemorrhages for every 1,000 patients 0.189), and more symptomatic brain haemorrhages (6.2
treated, but this was more than offset by a reduction of vs. 1.4%; p = 0.008) [427]. In the RAPID (Rapid Antico-
seven recurrent ischaemic strokes and about one PE for agulation Prevents Ischemic Damage) trial, patients al-
every 1,000 patients treated. located UFH had fewer early recurrent strokes and a sim-
A randomized, double-blind, placebo-controlled trial ilar incidence of serious haemorrhagic events, compared
showed that aspirin (325 mg), given once daily for 5 con- with those receiving aspirin [428]. In the UFH group,
secutive days and starting within 48 h of stroke onset, did ischaemic or haemorrhagic worsening was associated
not significantly reduce stroke progression, compared with inadequate plasma levels of UFH. In view of these

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findings, the value of UFH administered shortly after up to a third of patients can have neurological deteriora-
symptom onset is still debated [429, 430]. tion within 24 h after symptom onset [436, 437].
RCTs have not identified a net benefit of heparin for
any stroke subtype. A meta-analysis restricted to pa- Medical Therapy
tients with acute cardioembolic stroke showed that anti- Medical therapy in patients with large space-occupy-
coagulants given within 48 h of clinical onset were as- ing infarctions and brain oedema is based mostly on ob-
sociated with a non-significant reduction in recurrence servational data. Basic management includes head posi-
of ischaemic stroke, but no substantial reduction in death tioning at an elevation of up to 30, avoidance of noxious
or disability [431]. Despite this lack of evidence, some stimuli, pain relief, appropriate oxygenation and normal-
experts recommend full-dose heparin in selected pa- izing body temperature. If ICP monitoring is available,
tients, such as those with cardiac sources of embolism cerebral perfusion pressure should be kept above 70 mm
with high risk of re-embolism, arterial dissection or Hg [438]. Intravenous glycerol (4 ! 250 ml of 10% glyc-
high-grade arterial stenosis prior to surgery. Contrain- erol over 3060 min) or mannitol (2550 g every 36 h)
dications for heparin treatment include large infarcts is first line medical treatment if clinical or radiological
(e.g. more than 50% of MCA territory), uncontrollable signs of space-occupying oedema occur [439, 440]. Intra-
arterial hypertension and advanced microvascular venous hypertonic saline solutions are probably similarly
changes in the brain. effective [441]. Hypotonic and glucose-containing solu-
tions should be avoided as replacement fluids. Dexa-
methasone and corticosteroids are not useful [442]. Thio-
Neuroprotection pental given as a bolus can quickly and significantly
reduce ICP, and can be used to treat acute crises. Barbi-
No neuroprotection programme has shown improved turate treatment requires ICP and electroencephalogra-
outcome on its predefined primary endpoint. Recent phy (EEG) monitoring and careful haemodynamic mon-
RCTs with the free radical trapping agent NXY-059 [432], itoring, as a significant BP drop may occur.
and magnesium sulphate [433] were negative. A random-
ized, placebo-controlled, phase III trial of intravenous Hypothermia
rtPA followed by antioxidant therapy with uric acid is Mild hypothermia (i.e. brain temperature between
ongoing, following a safe phase II study [434]. A meta- 3233 C) reduces mortality in patients with severe MCA
analysis has suggested a mild benefit with citocoline infarcts, but may cause severe side effects including re-
[435]; a clinical trial with this agent is in progress. current ICP crisis during re-warming [443, 444]. In a
small RCT, mild hypothermia (35 C) in addition to de-
compressive surgery produced a trend towards a better
Brain Oedema and Elevated Intracranial Pressure clinical outcome than decompressive surgery alone (p =
0.08) [445].
Recommendations
Surgical decompressive therapy within 48 h after symptom Decompressive Surgery
onset is recommended in patients up to 60 years of age with
evolving malignant MCA infarcts (Class I, Level A)
Malignant MCA Infarction
It is recommended that osmotherapy can be used to treat el- A pooled analysis of 93 patients included in the DEC-
evated ICP prior to surgery if this is considered (Class III, IMAL (decompressive craniectomy in malignant MCA
Level C) infarcts), DESTINY (decompressive surgery for the treat-
No recommendation can be given regarding hypothermic ment of malignant infarction of the MCA), and HAM-
therapy in patients with space-occupying infarctions (Class
IV, GCP)
LET (hemicraniectomy after MCA infarction with life-
It is recommended that ventriculostomy or surgical decom- threatening edema trial) trials showed that, compared
pression be considered for treatment of large cerebellar in- with the control group, at 1 year more patients in the de-
farctions that compress the brainstem (Class III, Level C) compressive surgery group had an mRS ^4 or mRS ^3,
and more survived (NNTs 2, 4 and 2, respectively) [446,
Space-occupying brain oedema is a main cause of ear- 447]. There was no increase in the proportion of patients
ly deterioration and death in patients with large supraten- who survived surgery in a vegetative stage (mRS 5). Inclu-
torial infarcts. Life-threatening brain oedema usually de- sion criteria for this combined analysis were age 1860
velops between the 2nd and 5th day after stroke onset, but years, NIHSSS 115, decrease in level of consciousness to

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a score of 1 or greater on item 1a of the NIHSS, infarct Swallowing assessment is recommended but there are insuf-
signs on CT of 50% or more of the MCA territory or 1145 ficient data to recommend a specific approach for treatment
(Class III, GCP)
cm3 on DWI, and inclusion !45 h after onset (surgery Oral dietary supplements are only recommended for non-
!48 h). Follow-up of survival and functional status be- dysphagic stroke patients who are malnourished (Class II,
yond 1 year is currently ongoing in the DECIMAL and Level B)
DESTINY studies [447]. Early commencement of nasogastric (NG) feeding (within
A systematic review of 12 observational retrospective 48 h) is recommended in stroke patients with impaired swal-
lowing (Class II, Level B)
studies found age above 50 years to be a predictor of poor It is recommended that percutaneous enteral gastrostomy
outcome. The timing of surgery, side of infarction, clini- (PEG) feeding should not be considered in stroke patients in
cal signs of herniation before surgery, and involvement of the first 2 weeks (Class II, Level B)
other vascular territories did not significantly affect out-
come [448].
Aspiration and Pneumonia
Cerebellar Infarction
Ventriculostomy and decompressive surgery are con- Bacterial pneumonia is one of the most important
sidered treatments of choice for space-occupying cere- complications in stroke patients [449], and is mainly
bellar infarctions, although RCTs are lacking. As in caused by aspiration [450]. Aspiration is frequently found
space-occupying supratentorial infarction, the operation in patients with reduced consciousness and in those with
should be performed before signs of herniation are pres- swallowing disturbances. Oral feeding should be with-
ent. The prognosis among survivors can be very good, held until the patient has demonstrated intact swallowing
even in patients who are comatose before surgery. with small amounts of water and intact coughing on
command. NG or PEG feeding may prevent aspiration
pneumonia, although reflux of liquid feed, hypostasis,
Prevention and Management of Complications diminished cough and immobilization increase the risk.
Frequent changes of the patients position in bed and pul-
Recommendations monary physical therapy may prevent aspiration pneu-
It is recommended that infections after stroke should be treat- monia. A brain-mediated immunodepressive state con-
ed with appropriate antibiotics (Class IV, GCP)
Prophylactic administration of antibiotics is not recommend- tributes to post-stroke infection [451, 452]. Prophylactic
ed, and levofloxacin can be detrimental in acute stroke pa- administration of levofloxacin (500 mg/100 ml/day for 3
tients (Class II, Level B) days) is not better than optimal care for the prevention of
Early rehydration and graded compression stockings are rec- infection in patients with nonseptic acute stroke and was
ommended to reduce the incidence of venous thromboembo- inversely associated with outcome at day 90 (OR 0.19;
lism (Class IV, GCP)
Early mobilization is recommended to prevent complications 95% CI 0.04 to 0.87; p = 0.03) [453].
such as aspiration pneumonia, DVT and pressure ulcers
(Class IV, GCP)
It is recommended that low-dose subcutaneous heparin or Deep Vein Thrombosis and Pulmonary Embolism
low molecular weight heparins should be considered for pa-
tients at high risk of DVT or PE (Class I, Level A)
Administration of anticonvulsants is recommended to pre- It is generally accepted that the risk of DVT and PE can
vent recurrent post-stroke seizures (Class I, Level A). Prophy- be reduced by early hydration and early mobilization. Al-
lactic administration of anticonvulsants to patients with re- though graded compression stockings are effective in
cent stroke who have not had seizures is not recommended preventing venous thromboembolism in surgical pa-
(Class IV, GCP) tients, their efficacy after stroke is unproven [454]. In
An assessment of falls risk is recommended for every stroke
patient (Class IV, GCP) stroke patients, low-dose LMWH reduced the incidence
Calcium/vitamin D supplements are recommended in stroke of both DVT (OR 0.34; 95% CI 0.190.59) and PE (OR
patients at risk of falls (Class II, Level B) 0.36; 95% CI 0.150.87), without an increased risk of in-
Bisphosphonates (alendronate, etidronate and risedronate) tracerebral (OR 1.39; 95% CI 0.533.67) or extracerebral
are recommended in women with previous fractures (Class haemorrhage (OR 1.44; 95% CI 0.1316), NNT: 7 and 38
II, Level B)
In stroke patients with urinary incontinence, specialist as- for DVT and PE, respectively, while low-dose UFH de-
sessment and management is recommended (Class III, Lev- creased the thrombosis risk (OR 0.17; 95% CI 0.110.26),
el C) but had no influence on PE (OR 0.83, 95% CI 0.531.31);

482 Cerebrovasc Dis 2008;25:457507 ESO Executive Committee and


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the risk of ICH was not statistically significantly in- hip fractures (which are fourfold more common than in
creased (OR 1.67; 95% CI 0.972.87) [455]. Nevertheless, age-matched controls [467]), which is associated with
prophylaxis with subcutaneous low-dose heparin (5,000 poor outcome [468]. Exercise [469], calcium supplements
IU twice daily) or low molecular weight heparins is indi- [470] and bisphosphonates [471] improve bone strength
cated in patients at high risk of DVT or PE (e.g. due to and decrease fracture rates in stroke patients. Hip protec-
immobilization, obesity, diabetes, previous stroke) [456, tors can reduce the incidence of fracture for high-risk
457]. groups in institutional care, but evidence is less convinc-
ing for their use in a community setting [472].

Pressure Ulcer
Urinary Tract Infections and Incontinence
In patients at high risk of developing pressure ulcers,
use of support surfaces, frequent repositioning, optimiz- The majority of hospital-acquired urinary tract infec-
ing nutritional status, and moisturizing sacral skin are tions are associated with the use of indwelling catheters
appropriate preventive strategies [458]. The skin of the [473, 474]. Intermittent catheterization has not been
incontinent patient must be kept dry. For patients at par- shown to reduce the risk of infection. Once urinary infec-
ticularly high risk, an air-filled or fluid-filled mattress tion is diagnosed, appropriate antibiotics should be cho-
system should be used. sen: to avoid bacterial resistance developing, prophylactic
antibiotics are best avoided.
Urinary incontinence is common after stroke, partic-
Seizures ularly in older, more disabled and cognitively impaired
patients [475]. Recent estimates suggest a prevalence of
Partial or secondary generalized seizures may occur 4060% in an acute stroke population, of whom 25% are
in the acute phase of ischaemic stroke. Standard anti-ep- still incontinent at discharge and 15% remain incontinent
ileptic drugs should be used based on general principles at 1 year [476]. Urinary incontinence is a strong predictor
of seizure management. There is no evidence that pri- of poor functional outcome, even after correcting for age
mary prophylactic anticonvulsive treatment is benefi- and functional status [477]. However, data from the avail-
cial. able trials are insufficient to guide continence care of
adults after stroke [474, 478]. However, there is suggestive
evidence that professional input through structured as-
Agitation sessment and management of care and specialist conti-
nence nursing may reduce urinary incontinence and re-
Agitation and confusion may be a consequence of lated symptoms after stroke. Structured assessment and
acute stroke, but may also be due to complications such physical management have been shown to improve con-
as fever, volume depletion or infection. Adequate treat- tinence rates in both inpatients and outpatients [474, 476].
ment of the underlying cause must precede any type of However, trials of interventions are insufficient in num-
sedation or antipsychotic treatment. ber and quality to make any recommendations [478].

Falls Dysphagia and Feeding

Falls are common (up to 25%) after stroke in the acute Oropharyngeal dysphagia occurs in up to 50% of pa-
setting [459], during in-patient rehabilitation [460], and tients with unilateral hemiplegic stroke [479]. The preva-
in the long term [461]. Likely risk factors for falls in stroke lence of dysphagia is highest in the acute stages of stroke,
survivors [462] include cognitive impairment, depres- and declines to around 15% at 3 months [480]. Dysphagia
sion, polypharmacy and sensory impairment [463, 464]. is associated with a higher incidence of medical compli-
A multidisciplinary prevention package that focuses on cations and increased overall mortality [479].
personal and environmental factors has been found to be Withholding or limiting oral intake can worsen the
successful in general rehabilitation settings [465, 466]. catabolic state that may be associated with an acute ill-
There is a 5% incidence of serious injury [459], including ness such as stroke. Estimates of the incidence of malnu-

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trition vary from 715% at admission [481, 482] and 22 It is recommended to continue rehabilitation after discharge
35% at 2 weeks [483]. Among patients requiring pro- during the first year after stroke (Class II, Level A)
longed rehabilitation, the prevalence of malnutrition may It is recommended to increase the duration and intensity of
rehabilitation (Class II, Level B)
reach 50% [484]. Malnutrition predicts a poor functional
outcome [485] and increased mortality [486, 487]. How-
ever, routine supplementation for all acute stroke patients A key characteristic of stroke units is rehabilitation de-
did not improve outcomes or reduce complications [488]. livered by a specialized multidisciplinary team [494]. The
There are no adequately powered trials of targeting sup- Stroke Unit Trialists Collaboration [61] has shown im-
plementation to stroke patients at high risk of malnutri- proved survival and functional outcomes for patients
tion. treated in a dedicated stroke ward, and there are also long-
For patients with continuing dysphagia, options for term functional benefits of dedicated stroke unit care; fol-
enteral nutrition include NG or PEG feeding. A trial of low-up at 5 and 10 years has revealed persisting efficacy
early (median 48 h after stroke) versus delayed (1 week) compared with controls [495, 496]. The financial and
NG feeding found no significant benefit of early feeding, social implications of prolonged hospitalization have
although there was a trend to fewer deaths in the early prompted increasing interest in services to facilitate early
NG group [488]. In a related trial examining PEG and NG return to the community. A multidisciplinary early sup-
feeding within 30 days, PEG feeding was no better than ported discharge team with stroke expertise, comprising
NG and in fact was potentially harmful [488]. PEG feed- (at least) nursing, physiotherapy and OT, can significantly
ing has also been studied in longer-term dysphagia. Two reduce bed days for selected stroke patients [497] who have
trials comparing PEG and NG feeding found a trend to- mild or moderate impairment at baseline [498]. However,
wards improved nutrition with PEG feeding that did not specialist discharge services are required: mortality was
reach statistical significance [489, 490]. Studies that have substantially increased when patients were discharged
addressed quality of life found it was not improved by early with only generic community support [499].
PEG feeding [491, 492]. A meta-analysis showed that continued rehabilitation
after discharge during the 1st year after stroke reduces
the risk of deterioration in function and improves activi-
Rehabilitation ties of daily living (ADL) [500]. The interventions includ-
ed OT, physiotherapy, and multidisciplinary teams, and
Even with optimal stroke unit care including throm- therefore no definitive statement can be made concern-
bolysis, fewer than one third of patients recover fully ing the optimal mode of service delivery.
from stroke [387]. Rehabilitation aims to enable people
with disabilities to reach and maintain optimal physical,
intellectual, psychological and/or social function [493]. Timing, Duration and Intensity of Rehabilitation
Goals of rehabilitation can shift from initial input to
minimize impairment to more complex interventions de- The optimal timing of rehabilitation is unclear. Pro-
signed to encourage active participation. ponents of early therapy cite evidence from functional
neuroimaging [501] and animal studies [502, 503] that
define the peri-infarct period as the crucial time to begin
Setting for Rehabilitation rehabilitation. Early initiation of rehabilitation is a key
component of stroke unit care [61] but there is a lack of
Recommendations consensus on the definition of early therapy. Trials com-
Admission to a stroke unit is recommended for acute stroke paring early and late initiation of rehabilitation have
patients to receive coordinated multidisciplinary rehabilita- reported improved prognosis if therapy is started within
tion (Class I, Level A)
Early initiation of rehabilitation is recommended (Class III,
2030 days [504, 505]. Many of the immediate complica-
Level C) tions of stroke (DVT, skin breakdown, contracture for-
It is recommended that early discharge from stroke unit care mation, constipation, and hypostatic pneumonia) are re-
is possible in medically stable patients with mild or moderate lated to immobility [506], and hence mobilization is a
impairment providing that rehabilitation is delivered in the fundamental component of early rehabilitation. The op-
community by a multidisciplinary team with stroke expertise
(Class I, Level A)
timal timing of first mobilization is unclear, but mobili-
zation within the first few days appears to be well toler-

484 Cerebrovasc Dis 2008;25:457507 ESO Executive Committee and


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ated [507]. Preliminary results from the ongoing AVERT It is recommended that botulinum toxin be considered to
study of rehabilitation within 24 h suggest that immedi- treat post-stroke spasticity, but functional benefits are uncer-
ate physical therapy is well tolerated with no increase in tain (Class III, Level B)
adverse events [508].
There are few studies of rehabilitation beyond a year
after the acute event, and data are inconclusive to make a The results from stroke unit trials favour coordinated
recommendation on rehabilitation in this phase [509]. multidisciplinary teams of staff with expertise in stroke
Greater intensity of rehabilitation, especially time care [515]. The composition of these teams is not formal-
spent working on ADL, is associated with improved func- ly prescribed, but usually includes stroke physicians,
tional outcomes [510, 511]. A systematic review of re- nursing staff, physiotherapists, occupational therapists,
habilitation therapies for improving arm function also and speech and language therapists.
suggests a dose-response relationship, although hetero-
geneity of included studies precluded a formal measure Physiotherapy
of effect size [512]. Greatest benefits were observed in There is no clearly superior model of physiotherapy for
studies of lower limb exercises and general ADL train- stroke rehabilitation [516, 517], but some evidence exists
ing. to support specific interventions. Several groups have
Organisation and quality of care may be more impor- shown that strength can be improved in a dose-depen-
tant than absolute hours of therapy [513]. In a comparison dent manner, without increasing spasticity [512]. Func-
between a dedicated stroke multidisciplinary team and tional electrical stimulation may increase strength, but
usual ward-based rehabilitation, the dedicated team the effect on clinically relevant outcomes is uncertain
achieved better outcomes with significantly fewer hours [518].
of therapy [514]. A systematic review did not demonstrate efficacy of
treadmill training to improve walking [519]. Electrome-
chanical gait training in combination with physical ther-
Elements of Rehabilitation apy may be more effective than physiotherapy alone [520].
There are limited data to support the widespread use of
Recommendations orthoses and assistive devices [521].
Physiotherapy is recommended, but the optimal mode of de- CV fitness can deteriorate during the recovery phase
livery is unclear (Class I, Level A) of a stroke. This physical deconditioning impairs active
Occupational therapy is recommended, but the optimal mode
of delivery is unclear (Class I, Level A) rehabilitation and is a risk marker for further events [522].
While assessment for communication deficits is recommend- Meta-analysis has shown that aerobic training can im-
ed, there are insufficient data to recommend specific treat- prove exercise capacity in individuals with mild to mod-
ments (Class III, GCP) erate motor deficit after stroke [469].
It is recommended that information is provided to patient and Constraint-induced movement therapy involves in-
carers but evidence does not support use of a dedicated stroke
liaison service for all patients (Class II, Level B) tensive task-orientated exercise of the paretic limb, with
It is recommended that rehabilitation be considered for all restraint of the non-paretic limb. The EXCITE study re-
stroke patients, but there is limited evidence to guide appro- ported positive results for this method 39 months after
priate treatment for the most severely disabled (Class II, Lev- stroke in a group of medically stable stroke survivors,
el B) with some arm movement benefit persisting at 1 year
While assessment for cognitive deficits appears desirable,
there are insufficient data to recommend specific treatments [523].
(Class I, Level A)
It is recommended that patients be monitored for depression Occupational Therapy
during hospital stay and throughout follow-up (Class IV, Lev- A systematic review of nine trials comparing OT-
el B) based ADL therapy with usual care reported improved
Drug therapy and non-drug interventions are recommended
to improve mood (Class I, Level A) functional outcomes in the active intervention group
Drug therapy should be considered to treat post-stroke emo- [524]. The data do not justify conclusions on the optimal
tionalism (Class II, Level B) mode of OT delivery.
Tricyclic or anticonvulsant therapy is recommended to treat A meta-analysis of community-based OT trials found
post-stroke neuropathic pain in selected patients (Class III,
improved performance on ADL measures. The greatest
Level B)
effects were seen in older patients and with the use of

Guidelines for Management of Ischaemic Cerebrovasc Dis 2008;25:457507 485


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targeted interventions [525]. Specific leisure-based OT Other Groups
therapies did not translate into improved ADL. A trial of Depending on patient-specific goals, input from vari-
providing OT intervention to care home residents after ous other therapists may be appropriate. Such groups in-
stroke found less functional deterioration in the active clude dieticians, orthoptists and social workers. Although
intervention group [526]. No controlled trial data de- there has been limited formal research in this area, some
scribe the effectiveness of OT beyond 1 year after authors have argued that dedicated staffing creates an en-
stroke. riched environment that encourages practice in rehabili-
tation activities outside periods of formal therapy [540].
Speech and Language Therapy
SLT may optimize safe swallowing, and may assist
communication. Two trials of formal SLT input for dys- Cognitive Deficits
phagia found no significant difference to usual care [527].
A study comparing simple written instruction to graded Cognitive deficits are common following stroke and
levels of speech and language intervention for dysphagia impact on quality of life. At present, there is no evidence
found no difference in outcomes between the groups for the efficacy of specific memory rehabilitation [541].
[528]. Cognitive training for attention deficit has not resulted in
Aphasia and dysarthria are common symptoms after meaningful clinical improvement in ADL measures [542].
stroke, and impact on quality of life [529]. A systematic Training for spatial neglect has improved impairment
review of SLT for dysarthria in non-progressive brain measures, but an effect on ADL performance has not been
damage (stroke and head injury) found no good-quality demonstrated [543]. A few studies have assessed rehabili-
evidence for benefit [530]. Similarly, a systematic review tation training strategies in visual inattention and aprax-
of SLT for aphasia [531] reported insufficient good-qual- ia: no specific conclusions can be drawn [544].
ity evidence to recommend formal or informal interven-
tions. The studies included in this review were commu-
nity based and had an average time to therapy of 3 months: Sexuality
they offer little to inform acute ward-based rehabilita-
tion. Two related meta-analyses of studies with weaker Sexuality can suffer after a stroke. Underlying physi-
design concluded that improvement in speech is greater cal limitations and comorbid vascular disease may be
if SLT is initiated early [532, 533]. Limited evidence sup- compounded by side effects of medications [545]. It may
ports the possible use of modified constraint-induced be desirable to discuss issues of sexuality and intimacy
therapy for patients with aphasia [534, 535]. with patients [546]. Provision of support and information
is important: many patients wrongly fear that resuming
Stroke Liaison and Information Provision an active sex life may result in further stroke [547].
A recent systematic review comparing dedicated
stroke liaison to usual care found no evidence of improve-
ment in ADL, subjective health status or carers health Complications Affecting Rehabilitation
[536]. On subgroup analysis, success of a stroke liaison
service was predicted by younger age, less severe deficit, Rehabilitation can be compromised by complications,
and an emphasis on education within the service. which may be strong predictors of poor functional out-
Inadequate provision of information is predictive of come and mortality. Common complications during in-
poor quality of life in stroke patients and their families patient rehabilitation include depression, shoulder pain,
[537]. There is some evidence that combining informa- falls, urinary disturbances and aspiration pneumonia
tion with educational sessions improves knowledge and [548]. Some of these are discussed under Prevention and
is more effective than providing information alone [538]. Management of Complications.
As the patient progresses from hospital-based rehabilita-
tion to the community, involvement of carers in rehabil-
itation becomes increasingly important. Formal training Post-Stroke Depression
of caregivers in delivery of care reduces personal costs
and improves quality of life [539]. Post-stroke depression is associated with poor reha-
bilitation results and ultimately poor outcome [549, 550].

486 Cerebrovasc Dis 2008;25:457507 ESO Executive Committee and


ESO Writing Committee

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In clinical practice, only a minority of depressed patients functional benefits are less well studied [567569]. Oral
are diagnosed and even fewer are treated [551]. Depres- agents are limited in their use because of side effects
sion has been reported in up to 33% of stroke survivors, [570].
compared with 13% of age- and sex-matched controls
[552], but reliable estimates of the incidence and preva-
lence of depression in a stroke cohort are limited [550]. Eligibility for Rehabilitation
Predictors of post-stroke depression in the rehabilitation
setting include increasing physical disability, cognitive An important predictor of rehabilitation outcome is
impairment and stroke severity [550]. There is no consen- initial stroke severity [549]. Pre-stroke disability is
sus on the optimal method for screening or diagnosis of clearly also a strong determinant of outcome [571]. Oth-
post-stroke depression. Standard depression screening er factors, such as sex [572], stroke aetiology [573], age
tools may be inappropriate for patients with aphasia or [574] and topography of lesion [575], have all been stud-
cognitive impairment [553, 554]. ied as potential predictors of rehabilitation outcome;
Antidepressant drugs such as selective serotonin re- however, there is no evidence that these non-modifiable
uptake inhibitors (SSRIs) and heterocyclics can improve factors should influence decisions on rehabilitation
mood after stroke [555, 556], but there is less evidence [576]. Admission to a dedicated stroke unit improves
that these agents can effect full remission of a major de- outcomes for all strokes irrespective of age, sex and se-
pressive episode or prevent depression. SSRIs are better verity [61].
tolerated than heterocyclics [557]. There is no good evi- Exclusion from rehabilitation on the basis of pre-
dence to recommend psychotherapy for treatment or pre- stroke dependence remains a contentious issue [577,
vention of post-stroke depression [558], although such 578]. Patients with the most severe cognitive or physi-
therapy can elevate mood. There is a lack of robust evi- cal impairments have been excluded from most reha-
dence regarding the effect of treating post-stroke depres- bilitation trials, and therefore caution is required in
sion on rehabilitation or functional outcomes. extrapolating results to this group [579]. Limited data
Emotionalism is a distressing symptom for patients suggest that active rehabilitation allows severely dis-
and carers. SSRIs may reduce emotional outbursts but ef- abled patients to return home [580, 581]. For those un-
fects on quality of life are not clear [559]. able to participate actively, passive movements to pre-
vent contractures or pressure sores have been recom-
mended [2].
Pain and Spasticity

Post-stroke shoulder pain is common [560], especially Acknowledgement


in patients with impaired arm function and poor func-
We want to thank Dr. Michael Shaw for his assistance during
tional status, and is associated with poorer outcome. Pas-
the preparation of the manuscript.
sive movement of a paretic limb may be preventive [561].
Electrical stimulation is commonly used for treatment,
but its efficacy is unproven [562]. A Cochrane systematic
review found insufficient data to recommend the use of
orthotic devices for shoulder subluxation, despite a trend
towards efficacy for arm strapping of the affected limb
[563].
Lamotrigine and gabapentin may be considered for
neuropathic pain [564]. They appear to be well tolerated,
but cognitive side effects should be considered.
Spasticity in the chronic phase may adversely affect
ADL and quality of life [565]. Posture and movement
therapy, relaxing therapy, splints and supports are all
commonly employed, but a sound evidence base is lack-
ing [566]. Pharmacotherapy with botulinum toxin has
proven effects on muscle tone in arms and legs, but

Guidelines for Management of Ischaemic Cerebrovasc Dis 2008;25:457507 487


Stroke and TIA 2008

www.belimantil.info
Disclosure Statements

488
Author Employment Research Grant Other research support Speakers bureau/honoraria Ownership Consultant/Advisory Board
interest

Bath, P. University of Nottingham none Boehringer-Ingelheim AZ, Boehringer-Ingelheim none AZ, BI, Lundbeck, ReNeurone, Servier
Bousser, M.G. Paris 7 University SANOFI, Servier SANOFI, Servier, Novo- none none Servier, Sanofi
Nordisk, Paion
Brainin, M. Danube University Ebewe, Novo Nordisk Boehringer-Ingelheim, Novartis, Boehringer-Ingelheim, none Boehringer-Ingelheim, Ebewe
Krems Sanofi-Aventis, Solvaypharma Sanofi-Aventis, Ebewe,
Solvaypharma
Caso, V. no conflict no conflict no conflict no conflict none none
Cervera, A. Hospital Clinic, IDIBAPS, none none none none none
Spain
Chamorro, A. University of Barcelona none none BMS, Sanofi, Boehringer none Servier, Sanofi
Cordonnier, C. Lille University Hospital, none none none none none
France
Csiba, L. Debrecen University, UCB EGIS Zrt, Gedeon Richter, Boehringer-Ingelheim, PAION, none Pfizer Hungary, Johnson & Johnson, Paion,
Hungary Aventis Lundbeck A/S, Pfizer, EGIS Zrt, Gedeon Richter, Boehringer-Ingelheim
Sanofi-Aventis, Novo-Nordisk A/S,

Cerebrovasc Dis 2008;25:457507


Astra-Zeneca, Johnson&Johnson,
Gedeon Richter, MSD, UCB,
Convex
Davalos, A. Institut de Recerca none none Ferrer, PAION, Lundbeck, Pfizer, none Ferrer, PAION, Lundbeck, Pfizer, Astra-
Biomdica Germans Trias i Astra-Zeneca, BMS, Zeneca, BMS, Thrombogenics,
Pujol, Badalona, Spain Thrombogenics, Boehringer- Boehringer-Ingelheim
Ingelheim
Diener, H.C. University of Duisburg- AstraZeneca, GSK, German Research Council Abbott, AstraZeneca, Bayer Vital, none Abbott, AstraZeneca, Bayer Vital,
Essen Boehringer-Ingelheim, (DFG), German Ministry of Boehringer-Ingelheim, D-Pharm, Boehringer-Ingelheim, D-Pharm,
Novartis, Janssen-Cilag, Education and Research Fresenius, GlaxoSmithKline, Fresenius, GlaxoSmithKline, Janssen Cilag,
Sanofi-Aventis (BMBF), European Union, Janssen Cilag, MSD, Novartis, MSD, Novartis, Novo-Nordisk, Paion,

www.belimantil.info
Bertelsmann Foundation, Novo-Nordisk, Paion, Parke-Davis, Parke-Davis, Pfizer, Sanofi-Aventis,
Heinz-Nixdorf Foundation Pfizer, Sanofi-Aventis, Sankyo, Sankyo, Servier, Solvay, Wyeth, Yamaguchi
Servier, Solvay, Wyeth, Yamaguchi
Ferro, J.M. University of Lisbon Tecnifar, Boehringer- Bayer, Sanofi-Aventis Tecnifar, Ferrer none Sanofi-Aventis, Uriach, Servier, Ferrer
Ingelheim
Ford, G. University of Newcastle Boehringer-Ingelheim, none Boehringer-Ingelheim, AstraZeneca none Boehringer-Ingelheim
Servier, NTI, Lundbeck,
Paion
Hacke, W. University of Heidelberg DFG, BMBF none Sanofi Aventis, Novo-Nordisk, none Sanofi Aventis, BMS, Novo-Nordisk,
Ferrer, Boehringer-Ingelheim Boehringer-Ingelheim, Nuvelo, Novothera,
Bayer, J&J, Brainsgate, Paion, Ferrer, Lilly,
Centocor, ImarX
Hennerici, M.G. University of Heidelberg DFG, BMBF, EU RCTs grants several studies from Pfizer, none SPARCL, ESTAT, ECASSII, etc.
specific foundations Boehringer, Sanofi, Bayer, Knoll,
Janssen, etc.

ESO Writing Committee


Kaste, M. Helsinki University Central none none Boehringer-Ingelheim, none Bayer, BMS, Boehringer-Ingelheim,
Hospital Sanofi-Aventis, Pfizer, Ferro Mitsubishi, PAION, Brainsgate, Ferrer,
Neurobiological Technologies, Lundbeck

ESO Executive Committee and


A/S, Orion Oy, Pfizer, Astellas, Glaxo-
Wellcome, Servier, Encorium, Forest
Laboratories, Concentric Medical, Sanofi-
Aventis, Novo-Nordisk A/S, Astra-Zeneca,
Centocor, Johnson&Johnson
Langhorne, P. no conflict no conflict no conflict Previous Boehringer, Pfizer, Sanofi. none none
None current
Lees, K. no conflict MRC, Stroke no conflict AstraZeneca, BMS, NTI, Sanofi, NTI see honoraria
Association, Lundbeck, Paion, Forest, Lundbeck,
AstraZeneca, Boehringer-Ingelheim,
Boehringer-Ingelheim, GlaxoSmithKline, Mitsubishi,
Servier, NTI, Brainsgate, Bayer, Ferrer, Novonordisk, D-
etc. Pharm, Brainsgate, Thrombogenics,

Stroke and TIA 2008


Servier
Leys, D. University of Lille Sanofi, BMS, Astra none none none Paion
Zeneca, Boehringer-
Ingelheim,
NovoNordisk, Servier
Lodder, J. University Maastricht none Boehringer-Ingelheim Boehringer-Ingelheim none Boehringer-Ingelheim
Markus, H. no conflict no conflict no conflict Sanofi none Sanofi, GE, Boehringer
Mas, J.L. University of Paris 5 Sanofi, BMS none Sanofi, BMS, Servier, Boehringer, none Sanofi, BMS, Servier

Guidelines for Management of Ischaemic


Hpital Sainte Anne Johnson & Johnson
Mattle, H. Inselspital, University of AGA Medical, Bayer- Biogen-Idec, Merck-Serono, Servier, Pfizer, Sanofi-Aventis, Novartis, Pfizer, Merck Sharp & Dohme
Bern Schering Sanofi-Aventis Bristol Myers Squib, Boehringer- Roche
Ingelheim
Muir, K.W. University of Glasgow Shire Pharmaceuticals, none Novo Nordisk, Sanofi none GSK, Paion, Lilly, Novo Nordisk,
BMS, Sanofi ThromboGenics
Norrving, B. University of Lund, none none MSD, SHIRE none Boehringer, Pfizer, Servier
Sweden
Obach, V. University of Barcelona none none none none none
Paolucci, S. S. Lucia Foundation, Rome no conflict no conflict Boehringer-Ingelheim, Eli Lilly none none
Ringelstein, B. University of Mnster Novartis, NTI (Ancrod) none Boehringer-Ingelheim, Sanofi- none INC Research, AstraZeneca, Bayer-
and INC Research Aventis, Altana, UCB, BMS Schering Health Care
Ringleb, P.A. University of Heidelberg none none Paion, Sanofi, Boehringer none Paion
Schellinger, P.D. Erlangen University none none Boehringer-Ingelheim, Paion, none Boehringer-Ingelheim, Ferrer, ImarX
Hospital, Germany Sanofi-Aventis, Ferrer, ImarX,

www.belimantil.info
Solvay, Altana
Sivenius, J. University of Kuopio none none Boehringer-Ingelhein, Pfizer none Boehringer-Ingelheim, Pfizer
Skvortsova, V. Russian State Medical none none Boehringer-Ingelheim, Ebewe, none Boehringer-Ingelheim
University Sanofi Aventis
Stibrant University of Gothenburg none none none none none
Sunnerhagen, K.
Thomassen, L. Haukeland University none restricted research funding Pfizer, Boehringer-Ingelheim, none Sanofi, Boehringer, Gore reduce trial
Hospital from Boehringer-Ingelheim Sanofi, Astra Zeneca, MSD, etc.

Cerebrovasc Dis 2008;25:457507


Toni, D. University of Rome Boehringer-Ingelheim, none Boehringer-Ingelheim, none Boehringer-Ingelheim
SHIRE NovoNordisk, Sanofi-Aventis,
Astra-Zeneca
von Kummer, R. TU Dresden none none Boehringer-Ingelheim, Bayer Boehringer-Ingelheim, Paion, Bayer
Schering Schering, NovoNordisk, Nuvelo, Astellas
Wahlgren, N. Karolinska Institute Boehringer-Ingelheim Boehringer-Ingelheim, Bayer, Boehringer-Ingelheim, Bayer, none Boehringer-Ingelheim, Bayer, AstraZeneca,
AstraZeneca, Sanofi-Aventis, Astra-Zeneca, Sanofi-Aventis, Sanofi-Aventis, Novo-Nordisk
Novo-Nordisk, Novo-Nordisk
Thrombogenics, Servier
Walker, M. University of Nottingham none none none none none
Wardlaw, J. University of Edinburgh none none none none none

489
Appendix Prevention
Co-Chairs: Philip Bath, Nottingham, UK; Didier Leys, Lille,
ESO (EUSI) Recommendation Writing Committee France.
Chair: Werner Hacke, Heidelberg, Germany. Members: lvaro Cervera, Barcelona, Spain; Lszl Csiba,
Co-Chairs: Marie-Germaine Bousser, Paris, France; Gary Debrecen, Hungary; Jan Lodder, Maastricht, The Netherlands;
Ford, Newcastle, UK. Nils Gunnar Wahlgren, Stockholm, Sweden.

Education, Referral and Emergency Room General Treatment


Co-Chairs: Michael Brainin, Krems, Austria; Jos Ferro, Lis- Co-Chairs: Christoph Diener, Essen, Germany; Peter Lang-
bon, Portugal. horne, Glasgow, UK.
Members: Charlotte Cordonnier, Lille, France; Heinrich P. Members: Antony Davalos, Barcelona, Spain; Gary Ford,
Mattle, Bern, Switzerland; Keith Muir, Glasgow, UK; Peter D. Newcastle, UK; Veronika Skvortsova, Moscow, Russia.
Schellinger, Erlangen, Germany.
Substantial assistance received from: Isabel Henriques, Lis- Acute Treatment and Treatment of Complications
bon, Portugal. Co-Chairs: Angel Chamorro, Barcelona, Spain; Bo Norrving,
Lund, Sweden.
Stroke Units Members: Valerica Caso, Perugia, Italy; Jean-Louis Mas, Paris,
Co-Chairs: Hans-Christoph Diener, Essen, Germany; Peter France; Victor Obach, Barcelona, Spain; Peter A. Ringleb, Heidel-
Langhorne, Glasgow, UK. berg, Germany; Lars Thomassen, Bergen, Norway.
Members: Antony Davalos, Barcelona, Spain; Gary Ford,
Newcastle, UK; Veronika Skvortsova, Moscow, Russia. Rehabilitation
Co-Chairs: Kennedy Lees, Glasgow, UK; Danilo Toni, Rome,
Imaging and Diagnostics Italy.
Co-Chairs: Michael Hennerici, Mannheim, Germany; Mark- Members: Stefano Paolucci, Rome, Italy; Juhani Sivenius,
ku Kaste, Helsinki, Finland. Kuopio, Finland; Katharina Stibrant Sunnerhagen, Gteborg,
Members: Hugh S. Markus, London, UK; E. Bernd Ringel- Sweden; Marion F. Walker, Nottingham, UK.
stein, Mnster, Germany; Rdiger von Kummer, Dresden, Ger- Substantial assistance received from: Dr. Yvonne Teuschl, Dr.
many; Joanna Wardlaw, Edinburgh, UK. Isabel Henriques, Dr. Terence Quinn.
Substantial assistance received from: Dr. Oliver Mller, Hei-
delberg, Germany.

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