STROKE - Resumen de Warlow en Lancet

For personal use. Only reproduce with permission from The Lancet publishing Group.
SEMINAR
Stroke is defined by WHO as the clinical syndrome of
rapid onset of focal (or global, as in subarachnoid
haemorrhage) cerebral deficit, lasting more than 24 h or
leading to death, with no apparent cause other than a
vascular one. There are three pathological types (figure 1):
ischaemic stroke (about 80% in white populations),
primary intracerebral haemorrhage (about 15%), and
subarachnoid haemorrhage (about 5%).
1
This article deals
with the first two types. Transient ischaemic attack (TIA)
differs from ischaemic stroke in its duration (less than
24 h, selected arbitrarily), differential diagnosis (eg, focal
seizures are more likely to mimic TIA than stroke), and
ease of diagnosis (the diagnosis of TIA is more difficult,
depending almost entirely on a reliable history rather than
signs or brain imaging). The 24 h cut-off is useful for
epidemiological purposes because it can be applied
consistently in different places and times. However, when
patients are seen within 24 h of symptom onset, best
clinical practice is to regard them all as having the medical
emergency of brain attack (in analogy to heart attack),
which may or may not recover in hours, days, or weeks.
We do not think the recent suggestion of differentiating
TIA from stroke on the basis of brain imaging
2
is helpful
in routine clinical practice (or in epidemiological
research), since this approach would require the
availability of the same techniques and equipment
worldwide. A TIA or stroke in one place might not be the
same as a TIA or stroke in another place, or at another
time, if the techniques differed or changed.
In white people, about 50% of all ischaemic strokes and
TIAs are probably due to atherothrombotic disease of the
extracranialor less commonly large intracranial
arteries; about 20% arise from emboli from the heart;
about 25% are so-called lacunar infarcts, probably due to
occlusion of one of the small, deep, perforating cerebral
arteries; and the remainder are due to a miscellany of
much rarer causes (eg, vasculitis, arterial dissection;
figure 1).
1
These proportions are approximations because,
Lancet 2003; 362: 121124
Division of Clinical Neurosciences, Western General Hospital,
Edinburgh EH4 2XU, UK (Prof C Warlow MD, C Sudlow DPhil,
Prof M Dennis MD, Prof J Wardlaw MD, Prof P Sandercock DM)
Correspondence to: Prof Charles Warlow
(e-mail: cpw@skull.dcn.ed.ac.uk)
particularly in older people, there can be more than one
potential cause (eg, atrial fibrillation and carotid stenosis),
or no definite cause may be found even after reasonable
investigations. Atheroma affecting the arteries to the brain
(eg, of the aortic arch or basilar artery) cannot always be
imaged easily, at least in routine clinical practice and
particularly in population-based (and so unbiased by
hospital admission) epidemiological studies.
Global burden of stroke
Stroke is the third commonest cause of death worldwide
after ischaemic heart disease and all types of cancer
combined. Two-thirds of stroke deaths occur in less
developed countries.
3
Stroke also caused 3% of the worlds
disability burden in 1990. By 2020, stroke mortality will
have almost doubled, mainly as a result of an increase in the
proportion of older people and the future effects of current
smoking patterns in less developed countries. However,
stroke attracts far less research funding than heart disease or
cancer.
4
Stroke
Charles Warlow, Cathie Sudlow, Martin Dennis, Joanna Wardlaw, Peter Sandercock
Seminar
THE LANCET Vol 362 October 11, 2003 www.thelancet.com 1211
Stroke is a major public-health burden worldwide. Prevention programmes are essential to reduce the incidence of
stroke and to prevent the all but inevitable stroke epidemic, which will hit less developed countries particularly hard
as their populations age and adopt lifestyles of the more developed countries. Efficient, effective, and rapid diagnosis
of stroke and transient ischaemic attack is crucial. The diagnosis of the exact type and cause of stroke, which
requires brain imaging as well as traditional clinical skills, is also important when it will influence management. The
treatment of acute stroke, the prevention and management of the many complications of stroke, and the prevention of
recurrent stroke and other serious vascular events are all improving rapidly. However, stroke management will only be
most effective when delivered in the context of an organised, expert, educated, and enthusiastic stroke service that
can react quickly to the needs of patients at all stages from onset to recovery.
Search strategy
Systematic searching for articles about epidemiology,
imaging, and other non-trial issues is difficult; we have done
our best, using systematic reviews where possible. For
treatment interventions we used the Cochrane Stroke Review
Groups register of trials, which now includes more than
6000 reports of trials relevant to the treatment,
rehabilitation, and secondary prevention of stroke,
5
and
Cochrane systematic reviews (abstracts available free of
charge at http://www.dcn.ed.ac.uk/csrg/cliblist.asp). Where
possible, we based recommendations on the strength of the
evidence from large randomised trials and systematic reviews
of trials. Additional useful sources of evidence-based and
other sensible guidance are Clinical Evidence;
6
the Scottish
Intercollegiate Guidelines Network;
7
the Royal College of
Physicians National Clinical Guideline for Stroke;
8
the
American Heart Association website, which provides free
copies of its stroke guidelines;
9
and the Internet Stroke
Center, an extremely useful resource for current and recently
completed trials.
10
Further useful stroke trial links and
resources can be found at www.dcn.ed.ac.uk/csrg. Where the
available evidence runs out, we have resorted to medicine
based on common sense, always realising that common
sense can turn out to be wrong when evidence does emerge.
Mortality
Stroke mortality varies widely among countries for which
routine death-certificate data are available. In the early
1990s it was lowest, and had been declining steeply, in
western Europe, the USA, Australia, and Japan, but was
two or three times higher in South America. Mortality was
up to ten times higher, and increasing, in eastern Europe
and the countries of the former Soviet Union.
11
Routine
mortality data are, however, limited by the inaccuracies of
death certificates and the lack of reliable information
about different pathological types of stroke. Furthermore,
mortality depends on both the incidence of stroke and
case-fatality and can give no information about strokes
that are disabling but not fatal.
Incidence
Few population-based studies on the incidence of stroke
have had rigorous enough methods to be comparable, and
they have been carried out almost exclusively in white
populations in Europe, Australasia, and the USA.
1218
These studies have shown little difference between
countries in the incidence of stroke standardised for age
and sex, although the incidence may be somewhat lower
in some parts of France and higher in Siberia.
12,19
A recent,
well-conducted study in the mainly black Caribbean
population of Martinique in the West Indies showed
similar stroke incidence to that found in white people,
21
but there are virtually no comparable data from less
developed countries (Africa, South America, Asia).
Although stroke does sometimes affect children and
young adults, it is mainly a disease of older people. There
is a steep rise in incidence with age, with three-quarters of
all first strokes occurring after the age of 65 years, at least
in white populations.
12,19
For reliable comparisons of the distribution of
pathological types of stroke between populations, studies
have to have high enough rates of brain imaging,
undertaken sufficiently early after stroke onset to be
certain that a substantial proportion of intracerebral
haemorrhages are not missed; existing studies have had
suboptimal rates and timing of imaging.
22
For what it is
worth, the studies with the highest rates of brain imaging
have shown very similar distributions of pathological
types.
1218,19
Although there may well be a higher
proportion of stroke due to primary intracerebral
haemorrhage in Asia and Africa, there have not been any
sufficiently well-conducted population-based studies to
confirm this difference.
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1212 THE LANCET Vol 362 October 11, 2003 www.thelancet.com
5% subarachnoid
haemorrhage
15% primary
intracerebral
haemorrhage
80% ischaemic
stroke
Rare causes
5%
Atherothromboembolism
50%
Cardiac source
of embolism
20%
Intracranial small-
vessel disease
25%
Figure 1: Approximate frequency of three main pathological
types of stroke (in white populations) and of main subtypes of
ischaemic stroke as shown by population-based studies
1
100
80
60
40
20
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(
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Type of stroke and ischaemic stroke subtype
P
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A
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Independent
Dependent
Dead
Figure 2: Proportion of patients who are dead, dependent, or
independent a year after first stroke by type of pathology and
by clinical subtype of ischaemic stroke
PICH=primary intracerebral haemorrhage; SAH=subarachnoid
haemorrhage; TACI=total anterior circulation infarct; PACI=partial anterior
circulation infarct; LACI=lacunar infarct; POCI=posterior circulation infarct.
Reproduced with permission from Warlow and colleagues.
20
Figure 3: Imaging in a patient who presented 10 days after a
minor left-hemisphere lacunar stroke
Brain CT (A) shows low density in the left basal ganglia (arrow) in keeping
with an infarct. However, T2-weighted MR (B) shows a dark haemosiderin
ring (arrow), which indicates that the lesion was a primary intracerebral
haemorrhage. CT would have to have been done within about 8 days of
the stroke to show distinct features of haemorrhage.
Methodologically rigorous studies examining trends in
the incidence of stroke over time are even more limited in
number.
19,2327
Their results vary, but overall they show
little change in standardised incidence rates over the past
two to three decades in the white populations studied;
thus, lower case-fatality, perhaps due to better medical
care or reduced stroke severity, may explain any decline in
mortality.
Outcome
Early death after stroke is generally due to the
complications of the brain lesion itself (eg, mass effect,
disruption of vital centres). Later, the complications of
dependency are a more likely cause (eg, pulmonary
embolism, infection). About 30% of patients die within a
year of a stroke. Recovery after stroke occurs through
several overlapping processes. In the first hours and days
these processes may include resolution of the ischaemic
penumbra, cerebral oedema, and comorbidities (eg,
infection) that exacerbate the functional effects of the
stroke itself. Later, neural plasticity by which neurons take
on new functions, the acquisition of new skills through
training (eg, physiotherapy and occupational therapy),
and modification of the patients environment lead to
further gains in function. Of stroke survivors, nearly half
are left dependent. However, the outcome depends on the
pathological type of stroke, and the subtype of ischaemic
stroke (figure 2). Simple models based on age, living
alone, independence before the stroke, arm power, the
ability to walk, and the verbal component of the Glasgow
coma scale can provide more reliable estimates of
prognosis for groups of patients.
28
Risk factors
Since stroke is pathologically heterogeneous, the risk-
factor patterns for all types and subtypes of stroke would
not be expected to be the same. However, the large
prospective studies of risk factors have rarely distinguished
between the main pathological types, let alone the various
subtypes of ischaemic stroke. Most conventional vascular
risk factorsage, cigarette smoking, diabetes, and
obesityare broadly similar for ischaemic stroke and for
vascular disease in other parts of the arterial tree.
However, the continuous relation between stroke and
blood pressure is steeper than that for ischaemic heart
disease.
29
Also, by contrast with ischaemic heart disease,
there is no overall association between plasma cholesterol
concentration and stroke.
30,31
Potential sources of
embolism from the heart (including atrial fibrillation,
cardiac valve disease, and patent foramen ovale) are
associated with an increased risk of stroke. Atrial
fibrillation is by far the most important because it is so
common, carries a high relative risk of
stroke, and is definitely causal in many
cases. There is much more uncertainty
about patent foramen ovale.
32
Recent years have seen an increasing
interest in novel risk factors for
vascular disease, including stroke.
Most are thought to operate by
accelerating atherosclerosis. They
include infections (eg, Helicobacter
pylori and Chlamydia pneumoniae),
inflammatory and rheological markers
(eg, C-reactive protein and plasma
fibrinogen), plasma homocysteine
concentration, and various genetic
polymorphisms.
3336
At present, any
associations with stroke remain
uncertain because most of the studies have been small and
many were methodologically flawed. For ischaemic heart
disease, larger, more reliable studies (and overviews of
these) are available; here, there are more convincing
associations with some inflammatory and rheological
markers.
37
However, clear associations with other novel
risk factors, including genetic factors, remain generally
unproven.
3840
The Barker hypothesis, that the origins of
adult vascular disease are to be found in fetal health, is
increasingly being challenged by systematic reviews of all
the available data as opposed to selective emphasis of the
results of particular studies.
41
Diagnosis of acute stroke: role of brain
imaging
Clinical diagnosis before imaging
The longer treatment is delayed, the less scope there is for
benefit from treatmenttime is brain. Acute stroke is a
medical emergency, and the clinician must work quickly
to answer several questions. Was the onset sudden? Can
the symptoms be attributed to a focal brain lesion? Is the
cause likely to be vascular? The diagnosis of stroke (versus
not stroke) is made reasonably accurately on clinical
grounds alone by specialists, but in general medical and
emergency-department settings up to 20% of patients
with suspected stroke turn out to have another diagnosis.
42
Furthermore, although clinical scoring systems can help,
43
infarction cannot be reliably distinguished from
haemorrhage without brain imaging. Whichever imaging
method is used, the radiologist needs to know the time
and date of stroke onset to interpret the images properly.
Diagnosis of haemorrhagic stroke
Computed tomography (CT) is the most reliable method
of demonstrating acute haemorrhage within the first week
after stroke onset. Generally, a non-enhanced scan is all
that is required. After that, small haemorrhages
progressively lose their characteristic white (hyperdense)
appearance and can easily be mistaken for infarcts
(figure 3). Therefore, if patients delay seeking medical
attention, perhaps because the stroke symptoms were
mild, or if their doctors delay scanning, imaging might not
be done until 2 weeks or longer after the stroke; an infarct
could then be misdiagnosed on CT, and inappropriate
management could follow.
22,44
Magnetic resonance (MR) imaging may not identify
acute haemorrhage correctly within the first few hours
because the haematoma can be mistaken for a tumour
before the characteristic MR signs of haemorrhage appear,
even when extremely blood-sensitive sequences are
used (figure 4). Thereafter, haemorrhage can be
diagnosed reliably on MR by its characteristic appearance,
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Figure 4: Imaging in a patient 25 h after a major left-hemisphere stroke
A: Diffusion-weighted MR image shows a large hyperintense left basal ganglia/hemispheric lesion. B:
Gradient echo image shows a mass lesion with few signs of haemorrhage-specific features on the
medial border (dark areas due to haemosiderin). C: CT immediately afterwards clearly shows an
intracerebral haemorrhage with extension into the left lateral ventricle.
which changes as the haemorrhage matures.
45
In
particular, haemosiderin, the breakdown product stored
indefinitely in macrophages in most patients, is visible as a
dark (hypodense) ring or smudge around the lesion.
Thus, when a patient presents longer than a week after
stroke and when it may be extremely important to know
whether the lesion was an infarct or haemorrhage
(influencing a decision to give anticoagulants, for
example), MR with gradient echo imaging (also known as
T2*) should be used.
46
Gradient echo imaging also detects apparently
asymptomatic microhaemorrhages. These are thought to
be associated with white-matter hyperintensities,
increasing age of the patient, amyloid angiopathy, and
future risk of haemorrhage, but their true clinical
significance is unknown.
Diagnosis of ischaemic stroke
CT may or may not show a definite infarct, but a normal
scan does not necessarily mean that the patient has not
had a stroke. CT is quick and can be done in almost all
patients, however ill. Its value in excluding haemorrhages
and tumours more than outweighs any deficiency in
positively identifying infarcts. After all, during the first few
hours, the idea is to prevent infarction, not display it.
About 50% of infarcts never become visible on CT; the
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Figure 5: Comparison of CT and DWI
A: Brain CT scan 4 h after a left-hemisphere stroke. Note the subtle low
density in the left external capsule and insular region (arrows). B: DWI MR
(same patient as in figure 3) 45 h after stroke, showing early increase in
signal (bright area) in the left insular/sylvian region. The bright lesion on
the dark background on MR is much more easily seen than the dark
lesion on the light background on CT.
Figure 6: A patient 2 days after a mild right-hemisphere lacunar
stroke
CT (A) suggests several possible infarcts in both hemispheres but DWI
MR (B) clearly shows the small lacunar infarct (arrow) in the posterior limb
of the right internal capsule that caused the recent symptoms.
proportion is higher in patients with milder strokes
(lacunar and small cortical or brainstem infarcts) and
lower in patients with severe strokes (medium to large
cortical or cerebellar infarcts). The proportion visible also
depends on the timing of scanning. Within the first few
hours, few infarcts can be seen,
47
but they become visible
over the first 17 days as dark hypodense wedge-shaped
areas (or round if lacunar), with mass effect. After that,
about 20% become invisible again for a few weeks
(fogging), thereafter reappearing as cerebromalacia, a
shrunken area of cerebrospinal-fluid (CSF) density,
indicating permanent damage.
48
MR imaging with conventional T2 weighting is in
general no better than CT; fogging also occurs
49
and,
although more holes are shown, most are probably
irrelevant. The advent of diffusion-weighted imaging
(DWI), however, has justified the wider use of MR in
acute stroke. DWI can identify ischaemia or infarction
within a few minutes as bright (increased signal) areas that
are very easy to identify (figure 5). But even with DWI,
some infarcts never become visible. Some severe infarcts
do not appear for several days, though the proportion of
infarcts not seen at all is much smaller than with CT. In
clinical practice, as well as in research, DWI is especially
useful in patients with minor stroke symptoms (the group
in whom CT or T2 MR is least likely to show the lesion;
figure 6).
50
It is also useful in patients with suspected
recurrent stroke (to discriminate from worsening
neurological deficit due to intercurrent illness) and to
identify multiple infarcts in different arterial territories,
which suggest cardioembolic stroke (figure 7). However,
MR cannot be used in patients with pacemakers, those
who are claustrophobic, or in the very ill safely, so it is not
as universally useful as CT.
Management of acute stroke
Table 1 shows the benefits of treatments for acute stroke
that are supported by evidence from randomised trials.
51
Specific drug treatments for acute ischaemic stroke
Aspirin should be given as soon as CT or MR has
excluded intracranial haemorrhage. Sometimes the scan
cannot be done until after treatment has started, but there
does not seem to be any influence on outcome. Ideally,
CT scanning should be done immediately, on
presentation. The aspirin dose is 160300 mg by mouth if
the patient can swallow safely, or per rectum as a
suppository or intravenously.
7,8,5254
The daily dose
thereafter is not crucial, but 75150 mg daily is sufficient.
Immediate aspirin treatment slightly lowers the risk of
early recurrent stroke and increases the chances of survival
free of disability; about one fewer patient dies or is left
dependent per 100 treated. However, because aspirin is
applicable to so many stroke patients, it has the potential
to have a substantial public-health effect (table 1).
53
Aspirin is also likely to reduce the risk of venous
thromboembolism.
52
In patients treated with
thrombolysis, aspirin should be delayed for 24 h.
Heparins or heparinoids lower the risk of arterial and
venous thromboembolism, but these benefits are offset by
a similar-sized risk of symptomatic intracranial
haemorrhage.
55
There is no reliable evidence to support
the routine unselective use of these drugs. Nor is there any
evidence that low-molecular-weight heparins or
heparinoids offer any net advantage over unfractionated
heparin in acute stroke.
56
For patients at high risk of deep-
venous thrombosis, low-dose subcutaneous heparin or
graded compression stockings may be worthwhile;
57
these
interventions have been approved for patients with acute
ischaemic stroke in North America and several European
countries, but use in routine clinical practice is still
limited.
Thrombolysis with intravenous recombinant tissue-
plasminogen activator (alteplase; 09 mg/kg over 1 h)
almost certainly increases survival free of disability for a
few, highly selected patients who can be assessed and
treated within 3 h of onset of symptoms, although
treatment is associated with a chance of fatal intracranial
haemorrhage of about one in 20.
58
The trial evidence is
limited, so guidelines vary. On the one hand, the Royal
SEMINAR
Figure 7: DWI MR 6 h after a stroke causing right-hemisphere
cortical symptoms and signs
In addition to the right parietal infarct (bright area) there is a further
recent infarct in the left parietal cortex. Multiple infarcts in disparate
arterial territories suggest a cardiac source of embolus. The patient was
in atrial fibrillation.
Treatment Effects measured in trials Effects on the population Indication to use
Relative-risk Numbers avoiding Number that can be Number of treated
reduction (%) death or dependency treated (% of all patients who avoid
per 1000 treated 2400 strokes) death or dependency
Admission to a stroke unit 9 56 1920 (80%) 107 Admit routinely
Aspirin 3 12 1900 (80%) 23 Use routinely in
ischaemic stroke
Intravenous thrombolytic drug 10 63 240 (10%) 15 Very selective use <3 h;
more trials needed
From reference 51.
Table 1: Benefits and effect on the population of treatments for acute stroke in a population of a million people, among whom 2400
first and recurrent strokes may occur in 1 year
College of Physicians of London recommends that alteplase
should be used only in the context of randomised trials, and
both the US and Canadian emergency guidelines for
physicians are similarly cautious. On the other hand, this
regimen has been approved in North America and several
European countries, albeit with very tight criteria, but rates
of use in routine clinical practice are still low.
Large-scale trials are needed to answer several questions
reliably. What is the precise duration of the therapeutic
time window in which the benefits outweigh the risksis it
longer than 3 h? What are the optimum selection criteria
eg, severe strokes only or all strokes, old as well as young
patients? What is the best agent, dose, and route of
administration?
5860
How cost-effective is the treatment?
60
Trials are under way to clarify these issues.
10
There are many other uncertainties. For example, is
visible infarction on CT a contraindication to thrombolysis?
Some trials have suggested that patients with visible
infarction involving more than a third of the territory of the
middle cerebral artery should not be given thrombolysis,
61
but others have not.
62,63
Furthermore, although scoring
systems help observers to recognise visible infarction, the
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Stroke, or atypical or
multiple cerebral TIAs
Brain imaging
CT scan as soon as
possible, if >7 days
after onset MRI to
exclude intracerebral
haemorrhage
Antiplatelet drugs
Aspirin 160300 mg stat,
then 75150 mg daily
Clopidogrel 75 mg daily
if aspirin intolerant*
Aspirin 75 mg + dipyridamole
modified release 200 mg
twice daily if cerebrovascular
event while on aspirin
Lower blood pressure
(target, perhaps 130/70 mm Hg
if no adverse effects)
Thiazide diuretic
ACE inhibitor (check renal
function)
Other agents
Usually wait 12 weeks after onset
of any stroke before starting
Lower cholesterol
If plasma
concentration
>35 mmol/L
Simvastatin
40 mg at night
Check liver
function
Warfarin if no
contraindications
Target INR 23
unless prosthetic
valve
Usually wait 12
weeks after onset
of any stroke
before starting
Consider
cardioversion
antiarrhythmic
(eg, amiodarone)
Single typical cerebral
TIA, or amaurosis fugax
Carotid territory, good
recovery and surgery
a possible option
If contraindications to
warfarineg, bleeding,
falls, binge drinking,
poor compliance
Refer if >70% stenosis
on symptomatic side,
for further vascular
imaging and expert
advice
Infarct or no evidence
of haemorrhage
Carotid endarterectomy
Carotid
duplex
Haemorrhagic
ECG
Atrial
fibrillation
Lifestyle modification
Smoking cessation
Lower salt intake
Lower fat intake
Lower excess alcohol
Increase exercise
Lose excess weight
Reduce risk of future
vascular events
Stroke, myocardial
infarction, or vascular
death
Arrange thyroid function
and echocardiogram if
not done previously
Sinus
rhythm
Figure 8: Guidelines for secondary prevention after stroke or transient ischaemic attack (see table 2)
ACE=angiotensin converting enzyme; INR=international normalised ratio. Currently there is evidence to support combinations: *Aspirin and clopidogrel only
in patients with unstable angina with electrocardiographic or enzyme changes. Warfarin and aspirin in patients with prosthetic heart valves. Take care in
lowering blood pressure if the patient has postural hypotension, abnormal renal function, or severe carotid stenosis. Consider pravastatin for use in
combination with warfarin or digoxin. No clear randomised evidence, but most believe this strategy to be helpful.
Intervention Relative-risk reduction of Absolute risk of stroke Absolute stroke-risk Numbers needed to treat over
stroke (%) without treatment over reduction over 2 years (%) 2 years to prevent one stroke
first 2 years (%)*
Aspirin in sinus rhythm 20 15 3 33
Systolic blood pressure 25 15 4 25
lower by 9 mm Hg
Cholesterol lower by 25 15 4 25
12 mmol/L
Carotid endarterectomy for 40 25 15 7
>70% stenosis
Warfarin in atrial fibrillation 67 24 16 6
All values are approximate. *Approximate averages; many individuals are at higher risk, and many at lower risk. From columns 1 and 2. From column 3. Apart from
surgery, these interventions will also reduce the risk of coronary events.
Table 2: Interventions to reduce risk of stroke after a transient ischaemic attack on ischaemic stroke
signs are subtle (figure 5) and patients may be wrongly
denied an effective treatment on the basis of a poorly
identified sign. Further details and an opportunity to
participate in improving CT reading are available at
www.thalia.dcn.ed.ac.uk. Another uncertainty is whether a
combination of DWI and perfusion MR can really identify
the ischaemic penumbra and so perhaps improve the
targeting of treatment for just those patients with still viable
brain.
64
Intra-arterial thrombolysis and mechanical clot removal
from large arteries are technically feasible options for the
few centres with appropriate skills and resources, but
further trials are needed to establish their place in wider
practice.
Inhibitors of glycoprotein IIb/IIIa may be useful in the
treatment of acute ischaemic strokes
65
and in strokes
complicating endovascular procedures on the coronary and
cerebral circulation.
66
Trials comparing these agents with
placebo and with thrombolytic agents are under way.
10
There is no indication to use these agents routinely.
Fibrinogen-depleting agents show promise, but more
reliable estimates of their effects will not be available until
the results of two recent large trials are included in the
Cochrane review.
67
Despite huge efforts, none of the large number of
compounds tested for neuroprotection seems to be effective
in practice and none has yet gained a product licence.
60
Intravenous magnesium appears safe and a promising
treatment for prehospital use; trials are under way.
68,69
Specific treatments for intracranial haemorrhage
Appropriately selected patients with acute, spontaneous
intracerebral haematomas may benefit from urgent removal
of the clot, particularly if it is in the cerebellum.
70
However,
selection criteria and choice of surgical procedure vary
widely between centres. Trials are investigating the place of
surgery and other invasive interventions.
10
Intracranial bleeding in patients on anticoagulants
Patients who develop headache or focal neurological
symptoms while receiving oral anticoagulants should
undergo immediate CT to exclude intracranial
haemorrhage. If haemorrhage is shown, urgent reversal of
the anticoagulation (generally by intravenous
administration of clotting-factor concentrates) seems
sensible, despite the lack of formal evidence. However, this
approach can be hazardous and the choice of reversal
method depends on several factors. It should be used only
under the guidance of the local haematologist.
7
Secondary prevention of stroke (and of other
serious vascular events)
Survivors of stroke and patients with TIA worry. Many ask
Will I have another? and What are you going to do
about it?. The risk is not just of stroke but also of
myocardial infarction and sudden presumed coronary
death. Recently, an encouraging amount of new
information has emerged to modify clinical practice in
secondary prevention of ischaemic stroke and TIA
(figure 8; table 2). There is now much more to offer than
just antithrombotic drugs and carotid endarterectomy. Less
is known about lowering long-term risk after primary
intracerebral haemorrhage, other than lowering the blood
pressure.
What are the risks after ischaemic stroke and TIA?
Commonly quoted risks are 5% per year for stroke
(maybe 10% in the first year), 3% per year for myocardial
infarction, and 7% per year for any one of stroke,
myocardial infarction, or vascular death.
71
But these
estimates come from older series in which, for many
reasons, patients were not seen until some time after the
cerebrovascular eventthe very early prognosis was
missed. We now know that the early risks are higher. 10%
of patients with TIA presenting to an emergency
department in the USA had a stroke within 90 days (even
with standard treatment).
72
And, in a reanalysis of the data
form the Oxfordshire Community Stroke Project, the risk
of stroke in the first 30 days may have been as high as
12%.
73
Clearly, patients must be investigated and
treatment started as quickly as possible for greatest effect.
Antiplatelet drugs after ischaemic stroke and TIA
Aspirin lowers the relative risk of serious vascular events:
stroke by about a fifth; myocardial infarction by a quarter;
and stroke, myocardial infarction, and vascular death by
about a fifth. 75150 mg per day is the best dose. For
lower doses there are not enough data, and for higher
doses there is no added effectiveness but more adverse
events.
74
Are any other antiplatelet regimens better? The
addition of modified-release dipyridamole to aspirin may
further lower stroke risk (but not risk of myocardial
infarction), and more trials are in progress.
74
Our practice
is to add dipyridamole to aspirin if the patient has another
ischaemic cerebrovascular event on aspirin (aspirin
failures, or a better term might be breakthrough events
on aspirin), but this is not strictly evidence based.
Clopidogrel may be slightly better than aspirin alone,
albeit at very high cost. It is a useful substitute for the few
patients who are genuinely aspirin intolerant.
75
The
combination of clopidogrel with aspirin is better than
aspirin alone in unstable angina
76
and is now being tested
after ischaemic stroke.
Oral anticoagulants
Long-term anticoagulation is not definitely better than
aspirin for patients with ischaemic stroke or TIA who are
in sinus rhythm.
77,78
However, it does decrease stroke risk
by about two-thirds compared with control in those with
atrial fibrillation, and it is certainly better than aspirin
alone.
79
Patients with TIA or very mild ischaemic strokes
can start oral anticoagulants within a day or so, but in
patients with larger infarcts anticoagulation should
probably be delayed a week or two. The target
international normalised ratio is 25 (range 2030).
80
For
patients in atrial fibrillation who cannot for whatever
reason cope with anticoagulation, aspirin still offers some
advantage.
74
Blood pressure
Lowering of blood pressure has been known for years to
reduce the risk of a first stroke.
81
The recent PROGRESS
trial showed that the same applies for secondary stroke
prevention, whether ischaemic or haemorrhagic,
notwithstanding theoretical concerns of causing stroke by
overtreatment.
82
Before PROGRESS, the trials were too
small or the results only preliminary.
83
The relative-risk
reduction of about a quarter associated with a decrease in
blood pressure of 9 mm Hg systolic and 4 mm Hg
diastolic is similar whatever the baseline blood pressure,
although the risks of stroke without treatment and hence
the absolute risk reductions are greater with higher
pressures, and thus the numbers needed to treat are
smaller. PROGRESS tested a combination of perindopril
and indapamide, as well as perindopril alone, and the
reduction in stroke risk was of the size predicted from
epidemiological observations. In other words, there was
probably no additional effect of the drugs tested over and
SEMINAR
above their blood-pressure-lowering effect. Similar drugs
would probably do as well for the same blood-pressure
reduction, although extrapolation to -blockers, calcium
antagonists, and other compounds is perhaps less certain.
Clearly, control of blood pressure must take into account
adverse effects in individual patients, with particular care
in those with severe arterial disease in the neck, but in
general the lower the pressure the better, down to perhaps
130/70 mm Hg, provided any adverse effects are
acceptable to the patient. Blood-pressure lowering should
probably wait until the acute phase of any stroke has
resolved, perhaps for a week or two, and be introduced
slowly; trials of very early blood-pressure lowering are in
progress.
Cholesterol
Although higher plasma cholesterol concentrations do not
seem to be associated with increased stroke risk, lowering
the concentration definitely decreases the risk.
84
The risk
of stroke, myocardial infarction, and the need for vascular
procedures is also reduced by about a quarter for
reduction of a fifth in cholesterol concentration. This
decrease can be achieved with statins, the natural statins
(simvastatin and pravastatin) being a well-tolerated class
of drugs provided they are not given to patients with
active liver or muscle disease. The dose should be
equivalent to 40 mg daily of simvastatin. The relative risk
reductions are much the same for any baseline cholesterol
concentration above 35 mmol/L.
Carotid endarterectomy
Stroke risk ipsilateral to a recently symptomatic carotid
stenosis is higher the more extreme the stenosis until the
artery distal to the stenosis begins to collapse, and highest
soon after the presenting event. Provided that the surgical
risk of stroke is less than about 7%, carotid
endarterectomy is a reasonable (although quite expensive)
option for patients with stenosis of more than 70% by the
NASCET method used in the North American trial
(>80% by the European trial method). However, patients
have to be prepared to take the small initial surgical risk to
gain the longer-term benefit in terms of almost abolishing
the high risk of ipsilateral ischaemic stroke.
85
Standard practice used to be to carry out an intra-
arterial carotid angiogram to assess stenosis severity, but
delays due to waiting for a hospital bed, risks of invasive
angiography in this predominantly older population with
symptomatic vascular disease, and the substantial
improvement in non-invasive vascular imaging have
together meant that many centres have adopted
alternative policies. Because the surgery trials were all
based on intra-arterial angiographic measurement of
carotid stenosis, whatever method is used nowadays in its
place must be accurate compared with angiography,
otherwise patients may be denied endarterectomy when
they need it or offered surgery when they dont.
Colour doppler ultrasonography, in experienced hands
with modern equipment, is a quick, practical, inexpensive,
and reliable tool for identifying carotid, vertebral, and
subclavian disease.
86
The available evidence, though not
extensive,
87
suggests that MR angiography tends to
overestimate the degree of stenosis, CT angiography tends
to underestimate it, and colour doppler ultrasonography is
in the middle
88
compared with the gold standard of
catheter angiography. Thus, a reasonable strategy is to
undertake ultrasonography first and, if severe stenosis is
suspected, arrange a further confirmatory non-invasive
imaging test (MR or CT angiography or repeat
ultrasonography) by an independent observer. If these two
disagree, addition of a third non-invasive test would result
in very few misclassified carotid stenoses. Furthermore,
any minor loss of accuracy with the use of non-invasive
tests probably more than offsets the complications of
intra-arterial angiography.
It is important to realise that the surgery decision is
finely balanced and depends not just on the degree of
stenosis but also on other factors that put an individual
patient at particular risk without surgery or as a result of
surgery.
90
Whether angioplasty and stenting will turn out
to be as effective and durable as endarterectomy remains
to be seen
91
and trials are in progress.
10
Hormonal treatments
There is now reasonably strong evidence from
randomised trials that in postmenopausal women, with or
without a history of vascular disease, hormone-
replacement therapy increases the risk of stroke and of
venous thromboembolism and may increase the risk of
myocardial infarction.
92
For women who have had a stroke
or TIA, the long-term absolute risks of HRT will generally
outweigh its benefits. Thus, most postmenopausal women
with a history of cerebrovascular disease should avoid
HRT, unless there are very pressing indications.
Lifestyle
The undoubted effectiveness of medical and surgical
interventions must not detract from lifestyle modification,
which should provide additional benefits, perhaps more
pleasantly and at lower cost, though with more effort by
the patient. There is no formal randomised evidence
SEMINAR
Patient with
stroke or TIA
General
practitioner
Ambulatory neuro-
vascular assessment
(in emergency department
or clinic) with one-stop
investigation and
initiation of secondary
prevention
*Early supported
discharge
with continuing
rehabilitation at home
Emergency
department
Brain attack team
Brain imaging
Hyperacute treatment
(eg, thrombolysis)*
Stroke unit*
Acute management
Early rehabilitation
Prolonged rehabilitation
The stroke unit may provide
all three (comprehensive
unit) or be split into acute
and rehabilitation units
Accelerated referral
to hospital
Institutional care
Tailored to meet needs
of patient and family
Long-term follow-up
*GP or hospital based
to monitor secondary
prevention and deal with
late-onset and persisting
problems
Home
with care needs
provided and
possibly a family
care worker*
Day hospital
or domiciliary
rehabilitation
Figure 9: Components of a comprehensive stroke service
*Supported by reviews in The Cochrane Library.
89
SEMINAR
Problem Estimate of frequency Importance Preventive measures Interventions for Potential adverse Evidence to
established problem effects of define balance of risk
intervention and benefit
Physiological abnormalities
High Common, especially Associated with poorer Routine antipyretics; Fanning; antipyretics; Prophylaxis may Some small RCTs
temperature in first few days outcomes but may be aggressive cooling treat underlying cause delay detection of have shown lower
a marker of other therapy underlying cause; temperatures with
complications aggressive cooling regular antipyretics;*
has many potential active cooling not
adverse effects adequately evaluated
in stroke
Low arterial Common in severe Likely to increase Positioning; avoidance Supplementary oxygen Oxygen free radicals A single quasi-
oxygen stroke and patients brain ischaemia of cardiorespiratory may be harmful randomised trial of
saturation with cardiorespiratory problems routine oxygen
disease therapy showed no
benefit
95
Low blood Uncommon but may May increase brain Avoid causes Treat causes May lead to fluid No studies
pressure reflect dehydration ischaemia overload
(common),
gastrointestinal (3%)
or other bleeding,
cardiac failure, or drugs
High blood Very common but May reflect pre-existing Blood-pressure Adverse effects of Current guidelines
pressure settles spontaneously hypertension or lowering drugs; could suggest avoidance of
during first week in reaction to acute stroke; increase brain blood-pressure
most patients may increase brain ischaemia lowering in acute
oedema or bleeding; phase but RCTs are
and may increase risk now in progress
of recurrence
High blood Plasma glucose Associated with worse Many units avoid Insulin sliding scale or Hypoglycaemia A large RCT testing a
glucose >67 mmol/L reported outcomes but may dextrose infusions in infusions of glucose, aggravating brain glucose, potassium,
in 2043% of patients reflect diabetic first few days potassium, insulin dysfunction insulin infusion in the
admitted to hospital comorbidity or first 24 h is in
increased stroke progress
96
severity
Neurological complications
Raised Reduced Most common cause Raising head of bed; Antioedema agents; Adverse effects of Overview of
intracranial consciousness level of death in first week avoid overhydration ventilation; drugs; increased inadequate number of
pressure is common after decompressive pressure gradients trials of glycerol,
severe stroke; reflects surgery between brain mannitol and other
raised intracranial compartments; antioedema agents;
pressure in most cases complications of RCTs of ventilation
ventilation and and decompressive
surgery surgery in progress*
Sleep Identified in up to Importance unclear Avoid sedatives; avoid Continuous positive Not well tolerated; Small RCTs in
disordered two-thirds of patients supine lying airways pressure resource intensive rehabilitation patients
breathing admitted to hospital
97
but no reliable
evidence of benefit
Dysphagia Up to half of patients Prevents oral hydration Routine screening for Nil by mouth; Dehydration and Optimum tube feeding
admitted to hospital and feeding; increases dysphagia with bedside parenteral fluids or poor oral hygiene; regimen being
risk of chest infection test; speech and enteral-tube feeding; infected intravenous tested
98
language therapy physical therapy or cannulae; aspiration Orthotics and therapy

assessment for those orthotic devices of stomach contents not assessed
who fail screen and tube adequately
complications
Epileptic Seizures occur in An important cause of Prophylactic Anticonvulsants, but Adverse effects of Not evaluated in
seizures about 5% of patients neurological worsening anticonvulsants not uncertainty about drugs context of stroke
within first couple of after stroke widely used and not which drug is best specifically*
weeks, most within evaluated and whether to start
24 h
99
after first seizure
Spasticity Frequency depends Limit function, may be Positioning, relief of Physiotherapy; Adverse effects of Orthotic devices being
and on preventive painful, and if severe factors that increase splinting; tone- drugs assessed* RCTs have
contractures measures and timing impede skin hygiene tone (eg, pain, anxiety, modifying drugs; shown benefit from
of assessments and lead to pressure overuse of unaffected botulinum toxin; botulinum toxin in
sores limbs) denervating selected patients*
procedures
Emotionalism Affects about 1 in 6 May interrupt therapy, Antidepressants; Adverse effects of RCTs of
(pathological patients; improves inhibit communication, cognitive behavioural drugs antidepressants
crying, with time in most
100
and lead to social therapy suggest that they are
emotional isolation effective*
incontinence)
General complications
Urinary Occurs in about 1 in 4 Commonly makes Maintain hydration and Antibiotics Adverse effects of Prophylactic
infection patients admitted to patient less well and avoid unnecessary antibiotics; infection antibiotics not
hospital within the functional level may fall catheterisation related to adequately evaluated
first month or two intravenous cannulae RCTs of antibiotics
probably not needed
(continues next page)
SEMINAR
Problem Estimate of frequency Importance Preventive measures Interventions for Potential adverse Evidence to
established problem effects of define balance of risk
intervention and benefit
Chest Occurs in about 1 in 5 Increases hypoxia and Early mobilisation; chest Appropriate Adverse effects of No RCTs available
infection patients admitted to decreases functional physiotherapy; avoidance antibiotics; antibiotics
hospital within the abilities; difficult to of aspiration chest physiotherapy;
first month distinguish from oxygen
pulmonary embolism;
common terminal
condition
Undernutrition Affects about 1 in 5 Independently Nutritional screening; Oral supplementation Excessive weight Routine oral
patients and may associated with poor routine oral supplements or enteral-tube feeding gain and poor supplements being
increase during outcomes glycaemic control; tested in FOOD
admission especially if reduction of food trial
98
feeding difficulties intake; complications
of tube feeding
Electrolyte Abnormalities of May cause neurological Ensure patient has Manage fluid status Aspiration with oral Small RCTs comparing
disturbance sodium and potassium sequelae (confusion, access to fluids and or nasogastric fluids; routes of hydration;
are common due to seizures) which monitor biochemistry infection at site of RCTs of
dehydration, aggravate stroke regularly intravenous or haemodilution may
inappropriate fluids, deficits subcutaneous have some relevance
diuretics, and cannulae
inappropriate
antidiuretic hormone
DVT and PE DVT detected with DVT may cause pain Early mobilisation; Anticoagulation for Even prophylactic Haemodilution
radiolabelled and fever but mainly adequate hydration; established venous interventions have associated with fewer
fibrinogen affects important as source of low-dose heparin; thromboembolism potential problems; DVTs; RCTs suggest
about half of patients PE; PE may cause antiplatelet drugs; but risk-benefit falls due to early that benefits of
with hemiplegia but hypoxia and graduated unclear in patients mobilisation; heparin offset by
clinically apparent DVT hypotension and thus compression with haemorrhagic bleeding into the bleeding risk; aspirin
in less than 5% cerebral ischaemia and stockings; stroke brain with associated with slight
PE diagnosed rarely is a quite frequent intermittent external antithrombotics; reduction in PE;
but is common at cause of death compression ischaemic skin graduated
autopsy damage from compression
compression stockings currently
stockings being evaluated in
CLOTS trial; very few
data on intermittent
external
compression
Urinary and Affects up to half of Demeaning and can Avoid exacerbating Treat underlying Small RCTs available
faecal patients admitted to cause skin breaks factorseg, diuretics, causes if possible; but no definitive
incontinence hospital; multifactorial excessive aperients bladder retraining; results
in most incontinence devices
(pads, catheters)
Pressure Frequency varies Painful, depressing Avoidable by positioning, Relieve pressure and Adverse effects of Small RCTs have
sores depending on and can be fatal regular turning, and pain, treat infection, antibiotics; shown effectiveness
definitions and pressure relieving and maintain nutrition avoidance of sitting of pressure relief;
amount of nursing mattresses and cushions and hydration; may lead to other interventions
care, generally less dressings; respiratory problems not adequately
than 3% debridement; physical tested
treatments (eg,
ultrasound);
supplements
(eg, vitamin C)
Falls and Falls reported in Loss of function due to Careful supervision; .. Limitation of RCTs have shown fall-
fractures about a third patients soft-tissue and bony avoidance of independent mobility prevention
admitted to hospital; injury, pain and precipitating factors; hip may slow recovery programmes and hip
less than 5% result reduced confidence protectors; drugs to protectors are
in fractures prevent osteoporosis effective in elderly
patients; drugs not
tested specifically in
stroke
Painful Common but probably Limits function and Avoid traction injury with Physiotherapy; Pain due to No reliable evidence
shoulder depends on affects mood careful handling and supports; analgesia; physiotherapy; poor from RCTs
preventive measures positioning local steroid injections posture due to
support device;
adverse effects of
drugs
Low mood, Very common and Associated with poor Maintain positive attitude Antidepressants; Drug adverse Small RCT of drugs
("post-stroke persistent; difficult to outcome among stroke-unit staff cognitive behavioural effects; opportunity show benefits in
depression") assess in patients therapy costs mood;* cognitive
and negative with communication behavioural therapy
attitudes difficulties not adequately
evaluated
RCT=randomised controlled trial; DVT=deep-venous thrombosis; PE=pulmonary embolism. *Cochrane review protocol available.
89
Cochrane review available.
89
Table 3: Physiological abnormalities and complications after acute stroke and their prevention and management
(which would be very difficult to obtain) that quitting
smoking, losing weight, taking regular exercise,
abandoning heavy alcohol consumption, and improving
diet (less salt and saturated fat) reduce vascular risk, but
these changes probably do all help.
Taking the medicine
A previously healthy person with a mild ischaemic stroke
or TIA is likely to be shocked when offered three drugs
(aspirin, simvastatin, and indapamide; or possibly even
five with perindopril and modified-release dipyridamole)
for life and asked to consider carotid surgery. All the
options must be presented sensitively by physicians who
know the risks (large and small) and benefits (large and
small) of the treatments, and quicklyon the day of
presentation or at the most within a week of onset because
of the high risk of stroke early on. Perhaps the drugs
should be introduced one at a time so that any early
adverse effects can be correctly attributed. This is
emphatically not cook-book or protocol-driven medicine;
the results of trials and meta-analyses (along with
common sense) have to be interpreted for, and applied to,
individual patients.
An integrated approach to meeting the patients needs
Stroke services include both acute care and rehabilitation.
They aim, through the application of pharmacological,
surgical, and physical interventions, to achieve the
greatest recovery and the lowest risk of complications and
further vascular events. There is much variation in
treatment policies between units, probably because so few
interventions have been adequately assessed in
randomised controlled trials. However, if a particular
treatment definitely affects outcome, any variation must
be unacceptable since it means that some patients are
receiving suboptimal treatment. The idea is to define the
best treatment and ensure that all appropriate patients
receive it.
Components of a specialised stroke service
A patient with an acute stroke, a TIA, or one of the many
disorders that can mimic either diagnosis needs
immediate access to a specialised stroke service, which
should provide an integrated approach to their evolving
needs (figure 9).
89
Depending on the patients condition,
this may include: rapid and accurate clinical and
radiological diagnosis; immediate medical (or surgical)
treatment; general care to limit the risk of complications
and to treat any comorbidity; a detailed assessment from
members of a multidisciplinary team (physician, nurse,
physiotherapist, occupational therapist, and speech and
language therapist); a period of rehabilitation during
which both short-term and long-term functional goals can
be agreed between the patient and team member; and
interventions to reduce the risk of further vascular events.
The notion of providing a comprehensive regional
stroke service is attractive, although its precise structure
will vary according to local geography, politics, prejudice,
history, funding arrangements, and the expectations of
patients and professionals. For example, the extent to
which a stroke service is provided as an outpatient service
or by admission to an acute or rehabilitation facility will
vary substantially between health-care systems (influenced
by payment systems) and will depend on the patients
functional level.
Patients with mild or transient symptoms who do not
necessarily need admission can be managed in emergency
departments that provide immediate access to a specialist,
brain and vascular imaging, and other investigations.
Alternatively, these facilities can be brought together in a
rapid-access outpatient clinic, although some delay
between the event, assessment, and treatment is
inevitable. There is a trade-off between practicality of
delivering the service equitably to all who may benefit and
the risk of patients developing avoidable problems before
assessment.
Inpatient care should be provided on stroke units with
early access to a specialised multidisciplinary team that
can coordinate all parts of care. There is reliable evidence
from systematic reviews of randomised trials that this
approach leads to lower mortality and better functional
outcomes.
93
Moreover, because stroke units are so widely
applicable they prevent more death and dependency than
thrombolysis (table 1). But if thrombolysis is an option, it
will necessitate: education of the public and family
doctors; paramedical training; very well-organised systems
to bring patients with suspected acute stroke to hospital
quickly; efficient well-trained brain attack teams to look
after them once they arrive; and sufficient spare capacity
in imaging and high-dependency care to deal with cases at
once, within minutes.
60
The features of stroke-unit care that lead to its
effectiveness are not clear.
94
The stroke units included in
the systematic review did not regularly use thrombolytic
agents or other acute specific treatments, and they did not
provide intensive monitoring of physiological variables.
Other features of care must be important, by reducing the
risks of complications and by identifying and treating
complications early. The number of potential post-stroke
physiological abnormalities, neurological, and general
complications that need to be expected, prevented,
detected, and effectively treated to optimise the outcome
for the patient is very extensive (table 3).
89,95100
Failure to
deal with these later sequelae of stroke is likely to negate
any benefits from acute pharmacological interventions.
Monitoring and treatment of physiological abnormalities
Many studies have shown associations between abnormal
physiological measurements (eg, temperature, blood
glucose) shortly after stroke and poor outcomes. If these
abnormalities are found consistently and are shown to be
independent predictors of outcome (ie, not explained by
an association with another prognostic factor such as age
or stroke severity), the possibility that they are causal is
raised. Such observations have led some to introduce
interventions that aim to return the physiological
measurement to normal (table 3). However, although
close monitoring of patients with acute stroke may be
reasonable, caution is needed in application of
interventions to prevent complications or normalise
physiological measurements. We are often less
imaginative in considering the biologically plausible harm
we might cause by intervening in these ways than in
finding a rationale for benefit. If our interventions could
have adverse effects or are very costly, they should
probably be evaluated in randomised trials to establish the
balance between benefit and risk. Few such trials have
been completed, although several are in progress.
Sometimes the abnormal measurement simply indicates
that the patient has developed a complication, such as
fever as a result of infection or venous thromboembolism.
Hence, an intervention that simply aims to normalise the
abnormality may not be very effective unless the
underlying cause is identified and treated.
The intensity with which patients are monitored for
physiological abnormalities and complications varies
substantially between stroke units. At one extreme, stroke
intensive-care units use one-to-one nursing, invasive
SEMINAR
monitoring of blood pressure and intracranial pressure,
and aggressive management of abnormal measurements.
At the other extreme, patients may have only pulse,
temperature, blood pressure, and Glasgow coma scale
recorded. Although monitoring may seem innocuous
enough, invasive monitoring has direct adverse effects (eg,
infection) and any monitoring could lead to potentially
harmful interventions (eg, overaggressive blood-pressure
reduction). Encouragingly, a small trial has shown that a
compromise with non-invasive monitoring, and protocols
for treating abnormal physiological measurements, can
reduce the frequency of early neurological deterioration.
101
Stroke units should provide an environment in which
attitudes, knowledge, and everyday practices ensure that
effective interventions, treatment, and prevention are
delivered to all eligible patients, and ideally where
unproven treatments can be properly assessed. Local
guidelines and protocols, integrated care pathways, staff
training, and audit and quality assurance systems are
needed to optimise performance and thus outcomes for
patients.
Conflict of interest statement
We have been and are principal investigators on steering committees and
data-monitoring committees of trials and collaborative groups concerned
with the treatment and prevention of stroke. However, we do not have
and have not had in the past 5 years any departmental funding from
commercial organisations to do this work. Our department received a
grant from Boehringer-Ingelheim, Novartis, and Schering to establish a
research MR scanner as part of a joint industry/government scheme, in
total less than 5% of the total set-up cost. Sanofi provided a grant of
20 000 to develop a module for a system to audit quality of outpatient
stroke services in Scotland and for us to pilot it in Edinburgh. Some of us
have had honoraria to speak at meetings funded by industry, but no more
than 1000, and to advise companies for fees, which in aggregate come to
no more than 3000 per person per year. None of us holds any shares in
relevant companies. For more detail please see
www.dcn.ed.ac.uk/members/conflict.htm.
Role of the funding source
We are paid by the University of Edinburgh, the Wellcome Trust, and the
Lothian University Hospitals Trust, and we currently receive research
grants from the Wellcome Trust, the PPP Foundation, the Chief Scientist
Office of the Scottish Executive, the Stroke Association, Chest, Heart and
Stroke Scotland, the Department of Health, Novartis, and Boehringer-
Ingelheim. These funders did not see this article before publication.
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SEMINAR
Bone-marrow fibrin-ring granuloma
Patrick Blanco, Jean-Franois Viallard, Marie Parrens,
Patrick Merci, Jean-Luc Pellegrin
Clinical picture
Clinique de Mdecine Interne et Maladies Infectieuses (P Blanco MD, J F Viallard MD, J L Pellegrin MD, P Merci MD), Laboratoire
d'Anatomopathologie (M Parrens MD), Hpital Haut-Lvque, 33604 Pessac Cedex, France
A 74-year-old woman presented with fever, asthenia,
anorexia, and weight loss of 4 kg. She had no medical
history. On physical examination she had polyadenopathy
without splenomegaly. Results of laboratory investigations
were as follows: white blood cell (WBC) count
17710
9
/L (total lymphocyte count 6710
9
/L, with
09310
9
/L hyperbasophilic atypical lymphocytes);
haemoglobin 121 g/L; platelets 267000/L; raised aspar-
tate and alanine aminotransferase 50 IU/L (normal
1035 IU/L) and 79 IU/L (normal 540 IU/L),
respectively. Analysis of lymphocyte subpopulations
revealed a low CD4/CD8 ratio (11/186). Bone-
marrow biopsy specimen contained multiple fibrin-ring
granulomas (figure). Specific serological tests for Epstein-
Barr virus detected IgM and IgG anti-early antigen (EA)
but no antibodies to Epstein-Barr nuclear antigen
(EBNA), indicating a primary infection. Heterophil
antibodies were present. Paracetamol resolved clinical
symptoms within 2 weeks. 6 months later the patient was
asymtomatic. Routine haematological test results were
normal, including the CD4/CD8 ratio. IgG anti-
EBNA antibodies had appeared and IgM anti-EA had
disappeared.

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