J Neurol (2015) 262:239242

DOI 10.1007/s00415-014-7607-1

JOURNAL CLUB

Acute stroke management

E. C. Tallantyre N. P. Robertson

Published online: 12 December 2014

Springer-Verlag Berlin Heidelberg 2014

Stroke disease is the second leading cause of death in the

world. Even if stroke incidence remains stable, the number
of new acute strokes in Europe is projected to increase
markedly by 2025. In 2007, the SITS-MOST trial provided
the first conclusive evidence that intravenous thrombolysis
with recombinant tissue plasminogen activator (rTPA) was
beneficial in the acute period for patients with cerebral
infarct. Evidence from the same year showed that decompressive hemicraniectomy can double the rate of survival
with a favourable outcome for young patients with malignant middle-cerebral artery infarct. These studies and
others from that period altered the landscape of stroke
management dramatically. Reperfusion has become a
central component of acute stroke strategy and neurosurgical intervention for acute stroke has become commonplace in many European centres.
In this months journal club, we review three papers
which aim to refine or expand our current use of acute
interventions for cerebral infarction. The first paper
examines the appropriateness of intravenous thrombolysis
therapy for patients with mild cognitive impairment, the
second investigates the additional value of mechanical
reperfusion and the third investigates the benefit of neurosurgery for older patients with extensive arterial
infarction.

E. C. Tallantyre
Department of Clinical Neurology, University Hospital of
Wales, Heath Park, Cardiff, UK
N. P. Robertson (&)
Department of Neurology, Institute of Psychological Medicine
and Clinical Neuroscience, Cardiff University, Cardiff, UK
e-mail: robertsonnp@cardiff.ac.uk

Thrombolytic therapy for stroke in patients

with pre-existing cognitive impairment
Since intravenous thrombolysis with rTPA was first shown
to be effective for acute cerebral infarction, evidence has
emerged showing that the degree of benefit differs in different patient groups. At least 10 % of patients with stroke
have pre-existing dementia, and uncertainty exists regarding the benefit of intravenous thrombolysis for individuals
who have pre-existing cognitive impairment. Cognitive
impairment may reflect cerebral pathology such as amyloid
angiopathy, hypertensive vasculopathy or diffuse white
matter ischaemic change, which may predispose to intracerebral haemorrhage. There is also a theoretical risk that
rTPA may be neurotoxic to some patients with dementia.
Pre-existing cognitive impairment may also result in a
patient being dependent on assistance for activities of daily
living, an exclusion criterion from the most recent rTPA
treatment trial which extended use into the population aged
over 80 years. Previous studies have given rise to conflicting results about the benefit of iv thrombolysis for
acute stroke in patients with dementia.
This article reports results of the OPHELIE-COG study,
a prospective observational study which aimed to evaluate
the influence of pre-existing cognitive impairment on outcomes following intravenous rTPA for acute stroke. In
total, 205 consecutive patients who received rTPA for
ischaemic stroke, treated within several French and Japanese centres during 20122013, were followed up for
3 months. All patients had evidence of MCA territory
infarction and were functioning independently prior to the
stroke [modified Rankin score (mRS) 01]. Pre-stroke
cognitive impairment (PSCI) was defined as a score greater
than 3 using the Informant Questionnaire on Cognitive
Decline in the Elderly (IQCoDE). The IQCoDE relies on

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collateral history of cognitive decline, obtained from an

informant who has had at least weekly contact with the
patient for the last 10 years. An IQCoDE greater than 3 out
of 80 was expected to identify patients with very mild
degrees of cognitive impairment. Patients were excluded if
informant data could not be acquired within 48 h unless
cognitive impairment had previously been diagnosed by a
specialist. The primary study outcome was favourable
outcome (mRS 01) at 3 months. Secondary outcomes
were mortality, mRS 02 at 3 months and symptomatic
intracerebral haemorrhage. Patients recruited in Japan
received a lower dose of rTPA than those in France and
until September 2012 were only thrombolysed up to 3 h
post-symptom onset.
Although the OPHELIE-COG study group aimed to
recruit at least 500 patients, the trial was stopped prematurely when a related study suggested that OPHELIE-COG
trial design was inadequate to reliably detect a significant
difference.
Of the 205 recruited patients who consecutively
received IV thrombolysis, 62 patients (30 %) were found
to have pre-existing cognitive impairment. Those defined
as having PSCI had a median IQCoDE of 3.25 compared
with a median IQCoDE of 3 in those defined as having no
PSCI. Those with PSCI were older and more likely to
have a pre-morbid mRS of 1 than patients without PSCI.
Although patients with PSCI were more likely to experience symptomatic intracerebral haemorrhage (OR 3.5;
95 % CI 1.011.5) and less likely to be independent at
3 months (0.52; 95 % CI 0.280.97), these differences
became non-significant in a model adjusting for baseline
NIHSS, age and onset-to-needle time. Pooled analysis
using data from similar studies (Biostroke and Strokedem)
did not show any significant differences in the outcome of
patients with PSCI compared with their cognitively normal counterparts.
Comments and conclusion
This study is said to provide class IV evidence that patients
with pre-existing cognitive impairment, but who were
functionally independent, are likely to have an equally
favourable outcome from IV thrombolysis for acute stroke
as patients who were cognitively intact. However, serious
limitations of this study include its non-randomised design,
the limited clinical spectrum (MCA strokes only), the
heterogeneity in treatment protocol and the strong likelihood that it was underpowered. In particular, it is likely
that a considerably larger sample size would be required to
detect a meaningful difference in outcome between two
groups whose estimated pre-morbid cognition differed by
only 0.25 points out of a possible 80. Even with pooled
data from three studies, the confidence intervals for

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outcome data remained wide. These results raise as many

questions they answer, but they do focus the need for
further trials to refine our patient selection for stroke
thrombolysis. This subject also raises an ethical question
about whether it is possible to run a randomised controlled
trial, withholding an evidence-based therapy from a subset
of patients based on theoretical risks.
Murao et al. (2014) Neurology 82: 20482054.

Time to angiographic reperfusion and clinical outcome

after acute ischaemic stroke: an analysis of data
from the Interventional Management of Stroke (IMS
III) phase 3 trial
Early studies of rTPA demonstrated a benefit of intravenous thrombolysis administered within 3 h of acute stroke.
However, until publication of the IST-3 trial, intravenous
rTPA was not thought to be beneficial beyond 3 h of stroke
onset. At that time, intra-arterial thrombolysis was investigated as an alternative means of achieving reperfusion
and was found to be beneficial within 6 h of stroke onset.
In recognition of the fact that around 50 % of patients who
receive rTPA for acute stroke are still disabled at 3 months,
the Interventional Management of Stroke (IMS III) study
sought to investigate whether endovascular treatment after
intravenous rTPA provided additional benefit over rTPA
alone. The IMS III trial recruited 656 patients, all of whom
had received intravenous rTPA within 3 h of ischaemic
stroke and randomised them to receive an additional endovascular intervention or standard supportive care. The
trial was stopped prematurely for futility when it was found
that the primary outcome of mRS 02 at 90 days did not
differ significantly between the two treatment arms.
However, in light of previous data to supporting the crucial
effect of onset-to-reperfusion time, a post hoc analysis had
been incorporated into the trial design to determine whether a neutral result may have arisen due to angiographic
intervention occurring too late.
This paper reports the outcome of the pre-planned subgroup analysis of patients in IMS III who underwent
angiographic intervention. Patients were included if they
had angiographic evidence of complete occlusion of the
M1 or M2 branches of MCA or the ICA terminus and had
completed endovascular treatment within 7 h of stroke
onset. Time to reperfusion (defined as time between stroke
onset and completion of the endovascular treatment) in this
subgroup of 240 patients was used to calculate the relative
risk of a favourable primary outcome (mRS 02 at
90 days) for each 30 min of time delay. Results were
adjusted for any variables which were found to independently affect the primary outcome (baseline NIHSS, premorbid ability, ASPECTS score).

J Neurol (2015) 262:239242

Of the 240 patients investigated, 182 achieved angiographic evidence of reperfusion while 58 patients did not.
The mean time from stroke onset to completion of endovascular treatment was 5 h 25 mins. For each 30 min delay
in treatment, patients had an adjusted 12 % reduction in
achieving a favourable outcome. Increased time to endovascular treatment also predisposed to a greater risk of
serious adverse events, but not symptomatic intracerebral
haemorrhage or death.
Comments and conclusion
This post hoc analysis of a selected subgroup supports
existing data that time to reperfusion crucially impacts on
stroke outcome. An interesting advantage of this study was
the prospective recording of the breakdown of time delays
to completion of treatment, enabling the authors to predict
where valuable time might be gained in the future. In fact,
their results suggested that hypothetically, time to reperfusion would need to be reduced by 100 min in patients
receiving intravenous rTPA plus endovascular intervention
to demonstrate 10 % superiority over intravenous thrombolysis alone. Even if endovascular techniques or devices
improved to give better reperfusion rates, the authors predicted that time to treatment completion would still need to
be reduced by around 70 min to show superiority. Time
gained would need to be within the short window between
intravenous rTPA and endovascular completion if it was to
favour the interventional arm. Perhaps these techniques
will become limited to situations where imaging can
identify penumbral tissue which could be salvaged by endovascular intervention.
Khatri et al. (2014) Lancet Neurology 13: 567574.

Hemicraniectomy in older patients with extensive

middle-cerebral-artery stroke
Large territory infarction is known to be associated with
very poor outcomes, particularly in young patients where
the space-occupying effect has catastrophic consequences.
Pooled results from three studies have shown that decompressive hemicraniectomy in a population of patients under
the age of 60 years with malignant MCA infarction reduces
1 year mortality from 78 to 29 % and improves survival
with minimal disability from 21 to 43 %. The multicentre
DESTINY II study aimed to investigate the benefit of decompressive hemicraniectomy for patients over the age of
60 years who had suffered a malignant MCA infarct within
the last 48 h.
Patients were recruited across 13 German sites during
20092013. Patients were all over the age of 60 years and
had clinical symptoms compatible with an acute unilateral

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MCA infarct within the last 48 h. Patients found to have

high stroke severity (NIHSS [ 14 for non-dominant
hemisphere consciousness strokes and [ 19 for dominant
hemisphere strokes), reduced level of consciousness and
imaging demonstrating an infarct involving more than twothirds of MCA territory were included. Patients were
excluded if they had been previous dependent on any care,
or if they had signs of irreversible brainstem herniation
(GCS \ 6 or absent pupillary light reflexes). Patients were
randomised to undergo a more than 12 cm decompressive
hemicraniectomy or to receive full active treatment on an
intensive care unit. Primary outcome was defined as mRS
of 04 at 6 months, which was felt to reflect a favourable
outcome. Secondary outcomes included survival, functional ability (mRS and Barthel), depression, cognition and
quality of life at 12 months. Statistical analysis was performed using iterative calculations of primary outcome at
the time that each individual reached their 6 month milestone to determine whether a significant harm, benefit or
futility had been demonstrated.
Recruitment was terminated after randomisation of 112
patients because of demonstration of significant benefit.
Decompressive hemicraniectomy was shown to improve
the likelihood of a favourable primary outcome compared
with active supportive management (38 vs. 18 %; OR 2.91;
95 % CI 1.067.49). Hemicraniectomy also offered a significant survival benefit at 12 months compared with supportive management 57 % (95 % CI: 4272) versus 24 %
(95 % CI: 1437). However, all other secondary outcome
measures at 12 months were driven solely by survival;
none of the secondary outcomes were significantly
improved in survivors. Although the primary outcome
measure was a modified Rankin score of between 0 and 4,
no patient in either group achieved a score of 0, 1 or 2
(asymptomatic, symptomatic but independent or slight
disability requiring some assistance). Only 7 % of surgical
patients and 3 % of controls achieved mRS of 3 (moderate
disability but able to walk without assistance) at 6 months.
The vast majority of patient achieved mRS 4 (unable to
attend to own bodily needs without assistance; hemicraniectomy 32 %; control 15 %), or 5 (bedridden, incontinent
and requiring constant nursing care and attention; hemicraniectomy 28 %; control 13 %) at 6 months.
Comments and conclusion
The interpretation of the results of this study hinges around
our definition of what constitutes a favourable outcome.
Had the primary outcome been defined as mRS 03, the
trial would have been negative. The judgement about
whether to employ decompressive hemicraniectomy in
patients over 60 years with malignant MCA infarction,
therefore, depends on whether it is deemed that survival in

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a dependent state is preferable to death. Comparison of this

data with the DESTINY I trial does suggest that the benefit
to be gained by hemicraniectomy is far greater in younger
patients, of whom almost half achieved mRS between 0
and 3 at 12 months following hemicraniectomy. This issue
of hemicraniectomy in older patients is not clear-cut and
seems to raise further ethical questions, but these data are
useful in the counselling of relatives and liaison with surgical colleagues, which will arise in these challenging
cases.
Juettler et al. DESTINY II Investigators (2014) N Engl J
Med 370: 10911100.

Summary
Despite huge advances in the management of acute cerebral infarction in recent years, these studies highlight some

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of the complexities faced by doctors providing emergency

stroke care. Reperfusion improves outcome considerably if
used promptly. However, a completed infarction or the
presence of other brain pathology may predispose to
intracerebral haemorrhage. An ethical challenge is also
posed by interpretation of functional outcome measures;
the definition of a favourable outcome will vary considerably between individuals. Furthermore, our interpretation
of clinical trials on the whole must adapt to the use of new
analytical techniques which result in studies frequently
terminating prematurely when data monitoring committees
find evidence of benefit, harm or futility.

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