Review

Malignant middle cerebral artery infarction: clinical

characteristics, treatment strategies, and future perspectives
Hagen B Huttner, Stefan Schwab

Space-occupying, malignant middle cerebral artery (MCA) infarctions are still one of the most devastating forms of Lancet Neurol 2009; 8: 949–58
ischaemic stroke, with a mortality of up to 80% in untreated patients. An early diagnosis is essential and depends on Department of Neurology,
CT and MRI to aid the prediction of a malignant course. Several pharmacological strategies have been proposed but University of Erlangen,
Germany (H B Huttner MD,
the efficacy of these approaches has not been supported by adequate evidence from clinical trials and, until recently,
S Schwab MD)
treatment of malignant MCA infarctions has been a major unmet need. Over the past 3 years, results from randomised
Correspondence to:
controlled trials and their pooled analyses have provided evidence that an early hemicraniectomy leads to a substantial Stefan Schwab, Department of
decrease in mortality at 6 and 12 months and is likely to improve functional outcome. Hemicraniectomy is now in Neurology, University of
routine use for the clinical management of malignant MCA infarction in patients younger than 60 years of age. Erlangen-Nuremberg,
Schwabachanlage 6,
However, there are still important questions about the individual indication for decompressive surgery, particularly
90154 Erlangen, Germany
with regard to the ideal timing of hemicraniectomy, a potential cut-off age for the procedure, the hemisphere affected, stefan.schwab@uk-erlangen.
and ethical considerations about functional outcome in surviving patients. de

Introduction malignant MCA infarctions. We then assess the evidence

Although space-occupying, malignant middle cerebral
artery (MCA) infarction has not been defined as a distinct
disorder, its definition is usually based on clinical
presentation, typical clinical course, and neuroradiological
findings.1 Patients with subtotal or complete MCA
infarctions typically present with hemiparalysis, severe
sensory deficits, head and eye deviation, hemi-inattention,
and, if the dominant hemisphere is involved, global
aphasia.2,3 Patients with malignant MCA infarctions show
a progressive deterioration of consciousness over the first
24–48 h and commonly have a reduced ventilatory drive,
requiring mechanical ventilation.4,5 Malignant MCA
infarctions constitute between 1% and 10% of all
supratentorial ischaemic strokes,4 and treatment of this
disorder has been a major unsolved problem in
neurocritical care.6,7 Several pharmacological treatment
approaches, such as osmotic therapy, steroids,
hyperventilation, barbiturates, and trishydroxymethyl-
aminomethane (THAM) buffers, have been proposed to
reduce cerebral oedema formation, but so far none of
these therapeutic strategies has been supported by
adequate evidence of efficacy from clinical trials.8–10
Between 2007 and 2009, data from randomised trials
were published that provided evidence of a substantial
decrease in mortality of patients who underwent
decompressive surgery (hemicraniectomy) for treatment
of space-occupying MCA infarction.5,11,12 Meta-analyses
supported this finding;5,13 however, as some primary
outcome measures were neutral, there are fundamental
questions about trial design and interpretation and about
the benefits of this surgery on functional outcome in
surviving patients. Moreover, although the survival
benefit from hemicraniectomy is undisputed, the
functional outcome of surviving patients treated with
this procedure is variable and often poor, raising
important ethical considerations.
In this Review, we briefly outline the epidemiology,
clinical characteristics, and imaging findings in
for current treatment strategies, with a particular focus
on hemicraniectomy and the implications of the recent
trials. Questions about the individual indication for
hemicraniectomy in specific patients with malignant
MCA infarction are discussed and we give our perspective
on future clinical studies.
Epidemiology and clinical features
Generally, subtotal or complete MCA infarctions are
found in up to 10% of patients with supratentorial
ischaemia.4,15 The yearly incidence of a malignant acute
ischaemic stroke is between about 10 and 20 per
100 000 people.4,16,17 Compared with other patients with
ischaemic stroke, substantially fewer of those who have
malignant MCA infarction have a history of ischaemic
stroke and women are more likely to be affected.16,18
Moreover, patients with malignant MCA infarction seem
to be younger and more commonly have involvement of
the anterior choroidal artery than patients who do not
develop space-occupying infarctions.19
The aetiology of malignant MCA infarctions is mostly
due to thrombosis or embolic occlusion of either the
internal carotid artery or the proximal MCA. Depending
on anatomical variances, the anterior and/or posterior
cerebral artery territories might be involved
concomitantly.19 Anatomical variances and pathological
findings that predispose an individual to a malignant
MCA infarction include abnormalities of parts of the
ipsilateral circle of Willis (mainly a hypoplasia or an
atresia) and an insufficient number and calibre of
leptomeningeal collateral vessels that are available for
collateralisation.19,20
Clinical assessment of patients with a malignant MCA
infarction is based on the National Institutes of Health
stroke scale (NIHSS); the latter has been shown to
underestimate the severity of infarctions of the
non-dominant hemisphere.21 The NIHSS score typically
exceeds 16–20 if the dominant hemisphere is involved,

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 Review
and is more than 15–18 in malignant MCA infarctions
of the non-dominant hemisphere.5,11,12 Within
24–48 h of stroke, there is usually a progressive
deterioration in the patient’s level of consciousness
owing to the commonly associated serious brain swelling
that develops within 1–5 days after stroke.7,21 The resulting
increased intracranial pressure and tissue shifts lead to
further destruction of formerly healthy brain tissue,
giving rise to the term malignant MCA infarction.4 These
large cerebral infarctions often result in severe shifting of
midline structures with subsequent uncal or even
transtentorial herniation,22 and thus have been associated
with a poor prognosis in more than 80% of cases.23–26
The pathophysiological processes that lead to a
malignant MCA infarction are not yet completely
known.27–30 As in stroke in general, the ischaemic cascade
mainly consists of an excitatory phase, followed by
peri-ischaemic depolarisations that lead to inflammation,
apoptosis, and, finally, oedema formation (figure 1).31,32
Imaging and prediction of a malignant course
Cranial CT is widely used for the diagnosis and monitoring
of patients with malignant MCA infarction (figure 2).1,3,33,34
However, as repeated CT imaging up to the first 3 days
after stroke onset might be necessary to determine the
definite area of infarction and the extent of any associated
brain swelling and midline shift, several studies have
focused on identifying variables that allow an early
prediction of a malignant course by use of multi-slice CT,
CT angiography, CT perfusion, and MRI.34–37 Generally, a
neuroradiological definition of a malignant MCA
infarction assumes that at least two-thirds of the MCA
territory is affected. Other authors predict a malignant
course with development of severe oedema if more than
50% of the rostral MCA territory and the basal ganglia
show ischaemic alterations.12,37 Additionally, infarctions of
Intracranial blood
CSF
Change in
intracranial
Intracranial pressure
pressure
Brain tissue
Change in volume
Intracranial volume
Figure 1: Brain oedema formation
Schematic diagram of cerebral compliance. An increase in oedematous brain tissue requires a compensatory
decrease in the other two physiological compartments contained in the skull: intravascular blood and CSF. If these
limited compensatory mechanisms are not sufficient, even a small increase in the intracranial volume might result
in a substantial rise in intracranial pressure. Similarly, even a small decrease in brain oedema can substantially
lower the intracranial pressure.
950
the ipsilateral anterior or posterior cerebral arteries can
occur concomitantly with MCA infarctions. The definite
infarction volume visualised on MRI is evident as
hyperintense lesions on FLAIR (fluid-attenuated inversion
recovery) sequences; however, in the hyperacute stages,
even diffusion-weighted sequences can be used to reliably
predict a malignant MCA infarction if the lesion volume
is more than 145 cm³.11,36,37 Analysis of the permeability of
the blood–brain barrier by use of data from MRI, PET,
and SPECT (single photon emission computed
tomography) can be used to predict a space-occupying
course of MCA infarction;38–40 these new approaches,
however, need further prospective evaluations.1
Conservative management
Pharmacological approaches
Patients with large, space-occupying MCA infarctions
require immediate intensive care on a specialised
neurocritical care unit. Sedation, intubation, and
mechanical ventilation are often indicated early, and even
electively once the malignant course of the disease has
been verified, to prevent aspiration and to allow invasive
treatment to be started.9,41 There are many pharmacological
approaches to the prevention and management of the
developing brain oedema.9 Treatment with osmotic
compounds, such as mannitol, glycerol, and hypertonic
saline, reduce increased intracranial pressure and seem
to affect outcome, but their efficacy has not yet been
proven in randomised clinical trials.9,10 Unfortunately, all
other approaches, such as barbiturates, hyperventilation,
head elevation, THAM buffers, indometacin, steroids,
and furosemide, are not supported by adequate evidence
of efficacy and these treatment strategies might even be
detrimental.9,42–44 Case series on outcome of patients with
malignant MCA infarctions who received maximum
conservative treatment did not report significant clinical
effects of these procedures.4,23
Hypothermia
There is a strong association between fever and a poor
outcome after stroke.45 Consequently, moderate hypo-
thermia with target temperatures between 33°C and 35°C,
achieved with endovascular catheters, is a promising
approach for neuroprotection in patients with large MCA
infarctions.46,47 Hypothermia reduces the cerebral
metabolic rate and stabilises the blood–brain barrier.
Decreasing the formation of free radicals and the release
of excitatory neurotransmitters results in less brain
oedema and attenuates the postischaemic inflammatory
response and apoptosis.48 Results from various animal
studies have been confirmed by data from clinical
observational studies (although only a few patients
treated with moderate hypothermia were analysed),
which indicate both a reduced mortality and a good
functional outcome in the surviving patients.48–54 In light
of the strong association between fever and poor outcome
after stroke,45 these results with hypothermia are
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 Review

promising; however, the findings should be considered

A B
as preliminary because there is no evidence from
randomised trials on the efficacy of cooling as a treatment
for malignant MCA infarction.

Decompressive surgery
Surgical techniques
Decompressive surgery is based on a hemicraniectomy
in combination with a duraplasty.55 After incision of the
skin in the shape of a question mark, a bone flap that has
a diameter of at least 12 cm is removed, including parts
of the frontal, parietal, temporal, and occipital squama.56,57
The removed bone flap must be of a sufficient size to
prevent additional ischaemic lesions.58 After opening of
the dura, a dural patch is inserted, which usually consists
of homologous periosteum or a temporal fascia. C D
Ischaemic brain tissue is not resected. An intracranial
pressure probe can be inserted for further monitoring.
After 6 weeks and up to 6 months after removal, the
stored bone flap, or an artificial replacement, is used for
reconstituting cranioplasty.59
The main aim of decompressive surgery is to remove
part of the cranium to enable outward swelling of
ischaemic brain tissue without compromising healthy
brain areas by midline shift and ventricular
compression.55,60 The normalising of increased intra-
cranial pressure levels results in raised cerebral blood
flow and improved cerebral perfusion pressure, which
leads to better oxygenation of brain tissue that is still
Figure 2: Brain imaging findings before and after hemicraniectomy in malignant MCA infarction
healthy (figure 3).10,61–63
(A) Axial cranial CT 7 h after stroke onset. Arrows indicate the margins of the infarction. (B) Axial
diffusion-weighted MRI in the acute phase of malignant MCA infarction. (C) and (D) Axial CT on day 2 after
Experimental and clinical observational studies symptom onset after hemicraniectomy. Note that despite decompressive surgery, a compression of the ventricular
Various animal studies have been undertaken to system with slight midline shifting (C; axial CT at the level of the basal ganglia) and a beginning outward swelling
(D; axial CT at the supraventricular level) of the ischaemic brain tissue is evident. Images courtesy of the
experimentally investigate the potential benefits of
Department of Neuroradiology, University of Erlangen, Germany. MCA=middle cerebral artery.
surgical decompression. Craniotomy was proven to
correlate with early reperfusion and decreased final
infarction volume.64 However, this effect might be immediate hypothermia might further improve outcome:
limited to an intervention done early after vessel although reporting on only a few patients (n=25), a study
occlusion.65 In rat studies, a decrease in mortality and by Els and colleagues83 indicated a statistical trend
improved clinical outcome was reported, particularly towards a better functional outcome in terms of NIHSS
when decompressive surgery was combined with and Barthel scores with the combination of
moderate hypothermia.64–67 hemicraniectomy and hypothermia than with
The encouraging findings from animal studies of a hemicraniectomy alone. A larger prospective multicentre
decrease in mortality were supported by clinical trial on the possible benefits of this treatment combination
investigations. Although mainly retrospective and of an is therefore warranted.
observational design, more than 80 reports have analysed Several risk factors that predict mortality and poor
the possible efficacy of hemicraniectomy in routine functional outcome have been identified, age being the
clinical settings with regard to mortality, functional strongest one (identified in a meta-analysis by Gupta and
outcome, and quality of life.26,68–82 Results from most of colleagues79), followed by a low Glasgow coma scale score
these studies have provided evidence for reduced on admission, involvement of territories other than the
mortality in patients who underwent decompressive MCA area, anisocoria, early clinical deterioration,
surgery. However, the control patients used in some coronary artery disease, and internal carotid artery
studies were poorly matched, as they were substantially occlusion.26,68,75,79,84–87 There are few studies on the long-term
older, had more severe comorbidities, or had been treated outcome and quality of life of patients who have received
months or years before the study patients. The findings hemicraniectomy.70–72,82,88 The available data indicate that
of functional outcome and quality of life are inconclusive. the average quality of life after malignant MCA infarction
Combined therapy with decompressive surgery and is acceptable, and retrospective agreement to hemi-

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 Review
A B
60
50
Intracranial pressure (mm Hg)
40
30
20
10
0 0
Craniotomy Opening of the dura
Figure 3: Decompressive surgery and intracranial pressure
(A) Intra-operative multi-slice CT. Bone window three-dimensional reconstruction after removal of the bone flap
during hemicraniectomy. Image courtesy of Alfred Aschoff, Department of Neurosurgery, University of Heidelberg,
Germany. (B) Curve of intracranial pressure (red) and brain tissue oxygenation (PBR O2; blue). Note that the essential
decrease in intracranial pressure and elevation in brain tissue oxygenation partly occurs after craniotomy, and to a
greater extent after opening of the dura. Adapted from Gruber and colleagues,61 with permission from
Krause & Pachernegg.
craniectomy is high in both patients and their relatives.5,72
However, depression is commonly present in surviving
patients.71,80 This finding was confirmed in the recently
published HAMLET (Hemicraniectomy After Middle
cerebral artery infarction with Life-threatening Edema
Trial) study (n=32); patients who underwent surgical
decompression as well as those who were treated
conservatively showed symptoms of depression. A higher
number of patients in the hemicraniectomy group had a
score of 7 or more on the Montgomery and Asberg
depression rating scale than did those who were treated
conservatively, although the difference was not statistically
significant (18 vs 7; p=0·22).5
Randomised clinical trials
Following on from the promising results of experimental,
observational, and non-randomised studies, there have
been five randomised controlled trials initiated since
2000, of which three European trials and their pooled
analyses have been published over the past 3 years.5,11–13
Official data from the American HeADDFIRST study
(Hemicraniectomy and Durotomy Upon Deterioration
From Infarction Related Swelling Trial) and the Philippine
HeMMI trial (Hemicraniectomy For Malignant Middle
Cerebral Artery Infarcts) are awaited; HeADDFIRST has
been completed but not yet published officially, and
HeMMI is still recruiting patients.89 The European trials
were DECIMAL (DEcompressive Craniectomy In
MALignant middle cerebral-artery infarcts),11 DESTINY
(DEcompressive Surgery for the Treatment of malignant
INfarction of the middle cerebral arterY),12 and
HAMLET.5
The French DECIMAL trial11 was an open, prospective,
randomised, multicentre study with blinded evaluation
of the primary endpoint. DECIMAL started enrolment in
2001 and included patients who were diagnosed within
952
24 h of symptom onset and who were younger than
20
55 years of age. The primary endpoint in this trial was
functional outcome after 6 and 12 months based on the
modified Rankin scale (mRS) score, which was
15 dichotomised between 0–3 and 4–6, and interim analyses
were done after every four patients. Secondary endpoints
PBR O2 (mm Hg)
included survival and mRS at 6 and 12 months. Surgery
10
had to be undertaken within 30 h after symptom onset.
After randomisation of 38 patients, the data safety
5 monitoring committee recommended discontinuation of
the study because of a planned pooled analysis with the
other European trials (see below). At that time, there was
a significant difference in survival: five of 20 patients who
received hemicraniectomy died compared with 14 of
18 patients treated conservatively (p<0·01), with an
absolute risk reduction of more than 52%. The functional
outcome analysis did not reach significance both at the
6-month (mRS ≤3 in 5 patients who received hemi-
craniectomy vs 1 patient who was treated conservatively;
p=0·18) and 12-month (mRS ≤3 in 10 vs 4; p=0·10) follow-
up examinations.11
The German DESTINY trial12 was an open, controlled,
prospective, randomised, multicentre study that included
patients with a malignant MCA infarction who were
diagnosed within 36 h of symptom onset and who were
younger than 60 years of age. Patients were randomised
to receive either surgical plus best medical treatment or
best conservative treatment alone, including hypothermia.
However, the option of hypothermia was not used in any
of the included patients. DESTINY was based on a
sequential design: mortality after 30 days was assessed as
a first endpoint, and randomisation was planned to
continue until statistical significance for this endpoint
was reached. Enrolment of patients would then be
interrupted until data on the primary endpoint (6-month
functional outcome based on dichotomised mRS scores
of 0–3 vs 4–6) had been analysed. Depending on the
observed difference in functional outcome, the final
sample size would be recalculated for a second explorative
trial stage. As a secondary endpoint, dichotomisation of
patients into those who had a score of mRS 0–4 after
1 year versus those who had an mRS score of 5 or 6 was
planned. A significant difference in mortality was seen
after inclusion of 32 patients. The intention-to-treat
analysis revealed that after 30 days, two of 17 patients in
the hemicraniectomy arm and eight of 15 patients in the
conservative treatment group had died (p=0·02). The
consecutive functional outcome analysis did not show
significant differences (eight patients in the surgical arm
versus four in the conservative treatment group had an
mRS score of 0–3; p=0·23). The secondary outcome
comparison revealed a significant difference in favour of
surgical treatment (13 in the surgical arm versus five
conservatively treated patients had an mRS score of 0–4;
p=0·01), as did the distribution of the mRS scores
(p=0·04) at 12 months. After calculation of the sample
size needed for attaining the primary endpoint (at least
www.thelancet.com/neurology Vol 8 October 2009

188 randomised patients), DESTINY was stopped because
of ethical concerns.12
The Dutch HAMLET trial5 included patients who were
diagnosed within 96 h after symptom onset and who
were younger than 60 years of age. The primary endpoint
was the functional outcome after 12 months, dichotomised
according to mRS scores (0–3 vs 4–6). Among other
secondary endpoints, case fatality and a dichotomised
functional outcome analysis (mRS 0–4 vs 5 or 6) were
used. After obtaining the 1-year follow-up outcome data
for 50 patients (at that time 64 patients had been
recruited), the data monitoring committee recommended
discontinuation of the trial because it seemed unlikely
that a statistically significant difference between the
treatment groups would be seen for the primary outcome
measure. Additionally, for the secondary outcome
measure of function on the mRS, scores were not
significantly different between the two groups. However,
surgical decompression was associated with a decrease
in mortality (seven vs 19; p=0·002), with an absolute risk
reduction of 38%.5
Pooled analyses and meta-analyses of DECIMAL,
DESTINY, and HAMLET
In 2007, the results of a pooled analysis of the three
European trials (DESTINY, DECIMAL, and 23 patients
from the then-ongoing HAMLET trial who had received
surgery within 48 h after symptom onset) were
published.13 For this pooled analysis, a maximum time
window of 48 h from stroke onset to treatment was
adopted. Given the different outcome data of the
three trials, as shown by the wide distribution of scores
on the mRS (figure 4),5,11,12 the importance of the
collaboration of the European groups becomes clear: this
pooled analysis had been prospectively planned at a time
when each of the studies was still ongoing and, therefore,
this analysis could provide strong evidence of reduced
mortality at a very early stage.13,90 Otherwise, if the
investigators had waited until the end of enrolment for
each study, the final results might have been less certain
or new problems might have emerged (see below).5,14,90
Different treatment algorithms for conservatively treated
patients might have contributed to the varying outcome
findings of the three trials (eg, the control group in
HAMLET received conservative management on stroke
units, whereas best medical treatment was provided on
neurocritical care units in DESTINY).
The outcome measures of this pooled analysis were
mortality and functional outcome (mRS) at 1 year,
dichotomised into mRS scores of 0–3 versus 4–6
(mortality) and 0–4 versus 5 or 6 (functional outcome).13
Of the 93 patients included, 51 had received
hemicraniectomy and 42 had been assigned to receive
conservative treatment. There was a significantly lower
case fatality rate in the surgical group than in the
conservative treatment arm (29% vs 78%; p<0·01), with
an absolute risk reduction of 50%. With regard to the
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Review
functional outcome, the pooled analysis indicated that
patients who underwent decompressive surgery more
often had mRS scores of 3 or less (43% vs 21%; p=0·014;
absolute risk reduction of 23%) and mRS scores of 4 or
less (75% vs 24%; p<0·01; absolute risk reduction of
51%). These data formed the basis of a calculation of
the numbers needed to treat (NNT) with hemi-
craniectomy to achieve a successful outcome. The NNT
for survival was two, irrespective of functional outcome,
four for an mRS score of 3 or less, and two for an mRS
score of 4 or less. Moreover, this positive effect of
surgery was highly consistent across the three trials.
However, there was no difference in the benefit of
surgery for any of the predefined subgroup analyses for
age (older or younger than 50 years), presence of
aphasia, and time to randomisation (within or beyond
24 h).13
After completion of HAMLET in 2009, an updated
meta-analysis, which included all patients from DESTINY,
DECIMAL, and HAMLET who were randomised within
48 h after stroke onset, focused on case fatality rate and
functional outcome after 12 months.5 Of the 109 patients
analysed, 58 had been assigned to receive surgery and 51
to receive conservative treatment. With regard to
mortality, the absolute risk reduction with surgical
decompression compared with conservative treatment
mRS=2 mRS=3 mRS=4 mRS=5 Death
A DECIMAL11
Conservative treatment (n=18) 4 14
Decompressive surgery <30 h (n=20) 3 7 5 5
B DESTINY12
Conservative treatment (n=15) 1 3 1 2 8
Decompressive surgery <36 h (n=17) 4 4 5 1 3
C HAMLET5
Conservative treatment (n=32) 3 5 5 19
Decompressive surgery <96 h (n=32) 1 7 11 6 7
D Meta-analysis13
Conservative treatment (n=42) 1 8 1 2 30
Decompressive surgery <48 h (n=51) 7 15 16 2 11
0 20 40 60 80 100
Patients (%)
Figure 4: Comparison of outcome data 12 months after malignant MCA infarction as distributions of scores
on the mRS (best medical treatment versus hemicraniectomy)
Results of the DECIMAL trial11 (A), DESTINY trial12 (B), HAMLET trial5 (C), and a pooled analysis of patients from
these trials* who received surgery within 48 h after symptom onset (D).13 For interpretation see text. *23 patients
from HAMLET. DECIMAL=DEcompressive Craniectomy In MALignant middle cerebral-artery infarcts.
DESTINY=DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY.
HAMLET=Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial. MCA=middle
cerebral artery. mRS=modified Rankin scale. Subparts A and B are adapted from Vahedi et al11 and Jüttler et al,12
with permission from Lippincott Williams & Wilkins.
953
 Review
alone was 49·9% (95% CI 33·9–65·9), confirming the
previously reported NNT of two for prevention of death.
There was an absolute risk reduction of 41·9%
(25·2–58·6) for an outcome measure of more than 4 on
the mRS when treated with hemicraniectomy, indicating
an NNT of two. However, the analysis of functional out-
come revealed a non-significant benefit of surgical
decompression: 23 of 58 patients who received hemi-
craniectomy versus 12 of 51 who received conservative
treatment had an mRS score of 3 or less (absolute risk
reduction of 16·3%; 95% CI –0·1 to 33·1; NNT of six).
Open questions and future perspectives
Functional outcome
The above randomised controlled trials and their pooled
analyses have provided clear evidence that the survival
rate after malignant MCA infarction was substantially
higher in patients who received surgical decompression
instead of conservative treatment. There is no doubt
that this finding is of major importance and has
changed, and will further affect, routine management of
malignant MCA infarction. However, interpretation of
the data on functional outcome, measured as mRS
scores below or above 3 or 4, is more difficult. One of
the key questions is whether an mRS score of 4 is
considered to be a favourable outcome (while an mRS
score of 5 is seen as unfavourable). One could even
argue that the decreased mortality after hemicraniectomy
is achieved at the expense of functionality for surviving
patients (figure 4). In other words, while the few patients
who survive a malignant MCA infarction and who
receive conservative treatment have a good functional
outcome, the many more survivors who receive
decompressive surgery are more likely to have functional
dependency with impaired quality of life and commonly
have depression.91
Therefore, whether an mRS score of 4 (moderately
severe disability; unable to walk without assistance and
unable to attend to own bodily needs without assistance)
can be interpreted as a favourable outcome is of great
importance. This question should probably be answered
only by the individual patients and their caregivers. One
of the main irresolvable problems is that many patients
in the acute situation cannot state their preferences and
cannot be adequately advised of treatment options.
Moreover, the rehabilitation potential of those patients—
which, if known, would probably influence whether to
operate or not—is linked to their social, familial, and
economic support. To obtain data that would aid decision
making, future research on decompressive surgery
should concentrate on identifying predisposing factors
for survival with a poor outcome (mRS of 4 or 5).
The mRS mainly reflects motor function and
dependency, a general categorisation of outcome.
Whether the mRS is the appropriate score (rather than
quality of life as a primary outcome measure) is arguable
because, in principle, a patient with a poor outcome (ie,
954
mRS ≥4) who is intellectually able and who, for example,
can experience his child growing up in a sound family
environment might subjectively interpret this clinical
status as more favourable than a patient with aphasia and
depression who reached an mRS score of 3 or less. The
discussion of functional outcome in terms of what is
ethical or not is important in light of the possibilities of
hemicraniectomy. Before surgical decompression was
available, malignant MCA infarction was a disorder with
a high mortality rate. As this life-saving procedure results
in about 40% of survivors becoming disabled, there are
likely to be differences in opinion among clinicians,
patients, and their families as to the value of this
treatment.
Timing of surgery
One of the most urgent questions regarding surgical
decompression for treatment of malignant MCA
infarction concerns the optimum time-point for surgery.
In principle, there are two contrary approaches: either to
operate as soon as diagnosis of a complete MCA infarction
is made or to wait until a possible development occurs
such as further clinical deterioration, midline shift on
brain imaging, increased intracranial pressure values, or
even signs of herniation.92 In light of a variable clinical
course (some patients develop fatal brain oedema early,
whereas other patients do not show severe brain swelling
for several days), identification of those patients who are
at risk of developing an early malignant course must be
done as soon as possible. However, more research is
needed to understand the factors that promote or protect
against malignant brain oedema formation.1,60 Further
experimental studies on reperfusion, free radicals,
prostaglandins, arachidonic acid, and leukotrienes,9,10,27,40,93
and with novel imaging approaches, including MRI,
might be helpful in this regard.28,36,37
Published data about the timing of hemicraniectomy
are derived mainly from contradictory observational
studies (the three European trials did not satisfactorily
address this matter). For example, Mori and colleagues75
and Woertgen and co-workers70 retrospectively compared
mortality and outcome of patients who received
hemicraniectomy either early after diagnosis of complete
MCA infarction or at a delayed point when additional
symptoms of brain swelling occurred. Both studies
concluded that there were benefits of early surgery with
regard to decreased mortality (4·8% vs 17·2% after
1 month, 19·1% vs 27·6% after 6 months,75 and 16% vs
39% after a mean follow-up time of 30 months70); however,
the data on functional outcome were inconclusive. The
finding of a reduced mortality was also reported by Schwab
and colleagues,68 who compared early surgery (within
24 h) with delayed hemicraniectomy (after 48 h): as well as
a reduced case fatality rate (16% vs 34%), there was a trend
towards a better clinical outcome in patients who had early
surgery (p=0·06).68 Very early surgery, within 6 h of
symptom onset, has even been shown to result in lower
www.thelancet.com/neurology Vol 8 October 2009

mortality rates (1 of 12; 8·3%),94 and complications such as
postoperative hydrocephalus might be reduced with the
early timing of this procedure.95 The studies that indicated
a benefit of early surgery, however, were only suggestive,
and selection bias might have undermined the strength of
the conclusions. By contrast, a meta-analysis published in
2004 by Gupta and colleagues,79 which included all data
reported from patients up to that date, did not confirm
that delayed surgical decompression resulted in an
increased case fatality rate and poorer outcome.
The pooled analysis from 2007 also did not adequately
answer the question of whether surgery should be done
within 24 h or later as there was no difference in outcome
among both groups (treated <24 h or >24 h), as measured
on mRS scores; however, all included patients were
treated within 48 h.13 Only the recently published
HAMLET trial allowed delayed surgery up to 96 h after
symptom onset.5 In secondary outcome analyses, results
from HAMLET revealed that surgical decompression
done within 48 h reduced the probability of having a poor
outcome (defined as an mRS score of ≥5), whereas
delayed hemicraniectomy after 48 h did not affect
outcome. However, only 11 of the 64 patients received
delayed surgery, so no final conclusions on possible
benefits of hemicraniectomy beyond the 48-h time
window can be made as yet.5,92 Nevertheless, on the basis
of the available data from the randomised trials, and in
the absence of trials that truly compare early versus
delayed intervention, early decompression seems to be
beneficial.5,11,12
Age limit of surgery
All the randomised trials of hemicraniectomy have
enrolled only patients younger than 60 years of age. As
about 40% of patients with malignant MCA infarction
are older than 60 years,4,26,78 whether these patients might
also benefit from surgery remains unclear.92 Observational
data indicate reduced case fatality but poor outcome with
functional dependency if patients older than 60 years
receive decompressive surgery,26,78,86,87,96,97 and the
meta-analysis of 2004 indicated that age was the main
factor to affect outcome.79 The pooled analysis of 2007 did
not reveal differences in outcome (mRS 0–4 vs 5 or 6)
between patients younger and older than 50 years.13 The
HAMLET trial, however, indicated that patients with an
age of 51–60 years were more likely to benefit from
surgery than were younger patients.5 On the basis of the
available data, a conclusion regarding an age limit for
hemicraniectomy cannot be made. The planned
DESTINY-II trial98 will study patients older than 60 years
of age and will hopefully provide more information to
answer this controversial question.
Treatment of dominant versus non-dominant hemisphere
infarction
The controversy of whether to treat or not treat patients
with dominant MCA infarction emerged from the
www.thelancet.com/neurology Vol 8 October 2009
Review
hypothesis that patients with aphasia might have a poorer
outcome after hemicraniectomy because of a loss of
ability to communicate.99 However, the handicap caused
by aphasia, which only infrequently seems to remain
complete even after malignant MCA infarction,70,73,77
might be no less disabling than the neuropsychological
deficits seen in patients with infarction of the
non-dominant hemisphere (eg, severe attention deficits
and depression).81,82,96,100,101 Taking the meta-analyses and
prospective trials into account, mortality, functional
outcome, or quality of life do not seem to depend on
which hemisphere is affected.5,11–13,79 Nonetheless, a
definite conclusion is premature until more suitable data
are available.92 In summary, there is no indication at
present that patients with dominant malignant infarctions
do not benefit from surgery.
Quality of life and depression after surgery
Overall, both quality of life and depression seem to be
similar after surgery and conservative treatment.71,72,81
Although the retrospective agreement to decompressive
surgery was high in the trials done so far, the decision
about whether to operate on patients with a malignant
MCA infarction should be made on an individual basis
at present. Quality of life is the most important outcome
variable; however, its assessment is hindered as
questionnaires are often completed by close relatives or
by patients who can be influenced by the perception of
their relatives regarding their clinical status.72 The
prospective trials and pooled analyses did not provide
conclusive results on quality of life and extent of
depression in patients who survived because of
surgery,5,11–13 and the benefit of a decrease in mortality
from hemicraniectomy might be outweighed by a high
number of severely disabled survivors.91 Because of the
findings of reduced mortality after surgery, there will be
a reluctance to undertake trials that randomise patients
to receive conservative treatment for malignant MCA
infarction in the future; therefore, a control group
would not be available for questions on quality of life to
resolve this important matter. Only a few patients in the
trials done so far survived malignant MCA infarction
after conservative treatment (24 of 65 patients in the
pooled analysis13), and further analyses on quality of
life, including long-term evaluation of patients included
in these randomised trials, will be necessary.
Conclusions
Malignant MCA infarction was associated with high
mortality for many years. The three European prospective
randomised trials and the pooled analyses have revealed
a substantial increase in survival with decompressive
surgery. However, there are several clinical and ethical
questions that need to be resolved in future studies.
These questions regard the timing of surgery (before or
after the 48-h time window), particularly as oedema
formation often peaks after this time; the definition of a
955
 Review
Search strategy and selection criteria
References for this Review were identified through searches
of PubMed with the search terms “hemicraniectomy”,
“malignant MCA infarction”, and “decompressive surgery”
from 1970 until July, 2009. References selected were limited
to core clinical journals. Articles were also identified through
searches of the authors’ own files. Only papers published in
English or German were reviewed.
potential cut-off age, after which the effect of comorbidities
might undermine the positive effects of surgery; the
possible benefits of surgery on dominant versus
non-dominant malignant MCA infarction; and the
analysis of long-term benefits on quality of life and
depression in survivors after surgery versus those who
receive conservative treatment.92 Resolving these
questions should be a main goal for future international
prospective studies in the field of stroke management.
Contributors
HBH and SS both undertook the literature search, wrote the paper, and
approved the final version.
Conflicts of interest
We have no conflicts of interest.
Acknowledgments
We thank Alfred Aschoff (Department of Neurosurgery, University of
Heidelberg, Germany), Gerald Suttner (Department of Psychiatry,
University of Erlangen, Germany), and the Department of
Neuroradiology, University of Erlangen, Germany, for providing images
and graphical assistance. We thank Martin Köhrmann (Department of
Neurology, University of Erlangen, Germany) and Eric Jüttler
(Department of Neurology, Charité, University of Berlin, Germany) for
constructive criticism on the contents of the paper. Finally, we thank
Inken Martin (Molecular Cardiology, Victor Chang Cardiac Research
Institute, Australia) for language editing of the Review.
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