1. No category

Journal of Clinical Neuroscience 20 (2013) 6–12
Contents lists available at SciVerse ScienceDirect
Journal of Clinical Neuroscience
journal homepage: www.elsevier.com/locate/jocn
Review
Hemicraniectomy in the management of space-occupying ischemic stroke
Julia Flechsenhar a, Johannes Woitzik b, Klaus Zweckberger c, Hemasse Amiri d, Werner Hacke d,
Eric Jüttler a,d,⇑
a
Center for Stroke Research Berlin (CSB), Charité-University Medicine Berlin, Berlin, Germany
Department of Neurosurgery, Charité-University Medicine Berlin, Berlin, Germany
c
Department of Neurosurgery, University of Heidelberg, Heidelberg, Germany
d
Department of Neurology, University of Heidelberg, Heidelberg, Germany
b
a r t i c l e
i n f o
Article history:
Received 31 December 2011
Accepted 13 February 2012
Keywords:
Decompressive hemicraniectomy
Ischemic stroke
Malignant infarction
a b s t r a c t
A space-occupying mass effect is a common finding in several stroke subtypes. A large, intracranial mass
is a potentially life-threatening complication, irrespective of its underlying origin, with transtentorial or
transforaminal herniation being the common endpoint and often the cause of death. Prompt and
adequate intervention is therefore required. Although sufficient data on the management of large
haematomas are lacking, there is good evidence from randomized trials that in younger patients with
life-threatening, space-occupying, so-called ‘‘malignant’’ middle cerebral artery (MCA) infarctions, early
hemicraniectomy decreases mortality without increasing the number of severely disabled survivors. Yet
many questions concerning hemicraniectomy in malignant MCA infarction remain open: the definition of
a malignant MCA infarct within the first hours, optimal timing of surgery, quality of life and acceptance of
remaining disability, the role of aphasia in patients with dominant hemispheric infarcts, the effect of age,
and the influence of the pre-morbid status on decision making. The joint efforts of neurologists, neurosurgeons, intensive care physicians, and rehabilitation physicians are needed to design and conduct studies that might answer these questions.
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction and definition
Regardless of the underlying pathology, all types of stroke are
associated with accompanying brain edema, which is classified traditionally into three subtypes: vasogenic, cytotoxic and interstitial.
In severe ischemic stroke, a combination is always found, with
cytotoxic brain edema having the leading role.1–4 In most patients,
accompanying brain edema does not lead to a relevant mass effect,
but between 1% and 10% of supratentorial ischemic infarctions are
associated with serious brain swelling, which usually manifests between 2 days and 5 days after stroke. Clinically, the formation of
serious brain edema after MCA infarction follows a uniform course
beginning with compression of the ventricular system, subsequent
brain tissue shift, usually to the contralateral side, compression of
formerly healthy brain structures, and later a critical increase of
intracranial pressure (ICP) with subsequent complications such
as compromised cerebral blood flow, and finally transtentorial or
transforaminal herniation and death. Under standard care up to
80% of patients meet this fate within the first week after symptom
⇑ Corresponding author. Present address: Department of Neurology, Rehabilitation and University Hospitals Ulm, Oberer Eselsberg 45, D-89081 Ulm, Germany.
Tel.: +49 731 177 5263; fax: +49 731 177 1202.
E-mail address: eric.juettler@rku.de (E. Jüttler).
0967-5868/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jocn.2012.02.019
onset.5–12 The term ‘‘malignant MCA infarction’’ was coined5 for
these catastrophic infarctions (Fig. 1).
2. Diagnosis
Early diagnosis and prediction of a malignant course are important for the timely identification of patients who may require
closer monitoring and may profit from more aggressive intervention.13 Although the term ‘‘malignant MCA infarction’’ was introduced in 1996, there is still no generally accepted definition of
this condition, especially early after symptom onset.5 This lack of
a clear definition has been superseded by the uniform inclusion
criteria of several trials, defining a population in whom particular
interventions were deployed.14–18 Based on the inclusion and
exclusion criteria of these trials, the diagnosis of a ‘‘malignant
MCA infarction’’ can be made by assessing clinical presentation
at stroke onset, the clinical course, and neuroimaging findings.
At presentation patients suffering from a malignant MCA infarction show dense hemiplegia, head and eye deviation, unilateral
severe hypaesthesia or anaesthesia, often hemianopsia and always
a multimodal neglect syndrome and global aphasia (when the
dominant hemisphere is affected). The National Institutes of Health
Stroke Scale (NIHSS) score is typically > 15.13–16 The NIHSS
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J. Flechsenhar et al. / Journal of Clinical Neuroscience 20 (2013) 6–12
Fig. 1. Axial CT scans (left to right: 24, 36, 72 and 96 hours after symptom onset) showing the natural course of malignant middle cerebral artery infarction. Massive spaceoccupying edema with brain tissue shift resulted in transtentorial herniation. (Reproduced from Future Neurology, May 2008, Vol. 3, No. 3, Pages 251–6438 with the
permission of Future Medicine Ltd.).
score, however, underestimates the severity of a non-dominant
infarction.13
The typical clinical course of patients with a malignant MCA
infarction starts with a very early impaired level of consciousness
(score of P1 in item 1a of the NIHSS or <14 on the Glasgow Coma
Scale [GCS]), often even at first presentation or within the first few
hours, followed by a progressive deterioration over the next
24 hours to 48 hours, regularly associated with a reduced ventilatory drive, usually requiring mechanical ventilation.5,13,14,17
On neuroimaging, the relative and absolute infarction size, as
viewed on CT scans or MRI, seems to be major determinant for
the development of life-threatening edema after MCA infarction.
If at least 2/3 of the MCA territory or > 82 mL on diffusionweighted imaging (DWI) is involved, the infarct size has a positive
and negative predictive value of about 90%, especially when combined with MCA plus internal carotid artery occlusion.14,15,18–21
between patients, so body and head positioning should be tested
individually and adapted continuously by monitoring ICP and
CPP in different positions and taking into account ventilation and
blood flow in the jugular veins.
As an example of a specific conservative intervention, the antiedematous effect of osmotic substances is, at least from a physiological point of view, based on the integrity of the blood–brain barrier, which, however, is largely disrupted in the infarcted territory.
Therefore, osmotic therapy seems of little pathophysiological value. Most other intensive care measures aim to lower ICP, but significant increases in ICP usually occur late, when local mass effect
has already led to severe destruction of vital brain structures.
Sometimes herniation may even occur before significant increases
in ICP.29
3. Treatment options
In contrast to the rather complex and poorly understood pathophysiological theories underlying conservative treatments, the
benefits of decompressive surgery are based on purely mechanical
effects. In malignant MCA infarction, ipsilateral hemicraniectomy
(‘‘external decompressive surgery’’) is the procedure most widely
recommended and frequently followed. Additional removal of necrotic tissue, usually temporal lobectomy (‘‘internal decompression’’) is more controversial.30–32
Serious complications from hemicraniectomy seem uncommon,
although no reliable data are available so far. Wound and bone
infections, epidural or subdural hematomas, hygroma, hydrocephalus or the sinking skin flap syndrome and paradoxical herniation
have been reported.30,33–36
A far more common and widely underestimated complication
arises when hemicraniectomy is insufficient and leads to local
shear stress and venous insufficiency at the bone margins, and at
worst, to herniation through the craniectomy defect.37 A sufficient
diameter is critical, not only to prevent these complications but
also for the craniectomy to be effective: The volume of brain tissue
shifting out of the skull is directly correlated to the diameter of the
bone flap removed. The following formula is based on the assumption of a globus and a circular bone flap, but may be used to estimate the volume gain (for definitions of the variables see Fig. 2):
The therapeutic goal of any treatment in malignant MCA infarction is to interrupt the vicious cycle of brain swelling, mass effect,
increased intracranial pressure (ICP), reduced cerebral perfusion
and energy supply, further brain tissue damage, subsequent edema
formation, and finally, herniation.
3.1. Conservative therapy
Basic conservative therapy is not different from that applied for
stroke in general and aims to optimize cerebral perfusion and energy supply and to minimize cerebral metabolic demands by general measures such as adequate oxygen supply, maintenance of
adequate blood pressure, normothermia, and optimal body and
head positioning. Specific conservative interventions in malignant
MCA infarction may include deep sedation, barbiturates, buffers,
hypothermia, osmotic therapy, steroids, and controlled hyperventilation.22,23 To our knowledge, there is no adequate evidence to
support any of these therapies in malignant MCA infarction.22–24
The results from randomized trials indicate that these measures
may not be much better than palliative care, and several reports
suggest that some are not only largely ineffective but may be even
harmful.6,14,15,17,18,22–28
There are various possible explanations why these therapies often fail. For example, upright body positioning for basic management is often recommended and is said to lower ICP through
improved venous drainage. However, the effect of body positioning
on ICP and cerebral perfusion pressure (CPP) differs greatly
3.2. Surgical intervention
Additional volume ¼
p h22
3
ð3 r2 h2 Þ p h21
3
ð3 r1 h1 Þ
Malignant MCA infarctions usually require an additional volume of P 80 mL to 100 mL, so the diameter of the craniectomy
should be at least 12 cm to be effective (Fig. 2).38
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J. Flechsenhar et al. / Journal of Clinical Neuroscience 20 (2013) 6–12
Fig. 2. (a) Diagram of a hemicraniectomy in a malignant middle cerebral artery infarction showing the parameters used to calculate the relationship between the diameter of
the craniotomy and volume gain. (Reproduced from Future Neurology, May 2008, Vol. 3, No. 3, Pages 251–6438 with the permission of Future Medicine Ltd.) (b) Graph showing
the relationship between the diameter of the hemicraneictomy and the volume gain. r = radius, h = the distance from the thin white line joining the edges of the craniectomy
defect to the dura.
3.3. Clinical experience
Dating back to at least 1935,39 hemicraniectomy in space-occupying stroke is by no means new. A continuously growing body of
evidence from observational and comparative studies and parallel
findings in animal studies provides evidence for the benefits of
hemicraniectomy in lowering mortality and improving functional
outcome in survivors of malignant MCA infarction, yet the procedure
remains an intensely debated issue in neurointensive care.14,40–45
Between 2000 and 2009 seven randomized and controlled trials
were initiated:
(i) The American Hemicraniectomy And Durotomy Upon
Deterioration From Infarction Related Swelling Trial
(HeADDFIRST);
(ii) the German DEcompressive Surgery for the Treatment of
malignant INfarction of the middle cerebral arterY (DESTINY) trial;
(iii) the French DEcompressive Craniectomy In MALignant middle cerebral artery infarcts (DECIMAL) trial;
(iv) the Dutch Hemicraniectomy After Middle cerebral artery
infarction with Life-threatening Edema Trial (HAMLET);
(v) the Philippine HEmicraniectomy for Malignant Middle cerebral artery Infarcts (HeMMI) trial;
(vi) the Turkish DEcompressive surgery for the treatment of
Malignant Infarction of the middle cerebral artery in a TURkish population (DEMITUR) trial; and
(vii) the Decompressive Hemicraniectomy in Malignant Middle
Cerebral Artery Infarction: a Randomized Controlled Trial
Enrolling a Group of Patients Older than 60 Years of
Age.14,17,18,46–49
Results are available from DESTINY, DECIMAL, HAMLET, and a
pooled analysis of these three trials.16 All three trials had similar
inclusion and exclusion criteria including clinical signs of infarction in the territory of the MCA, a decrease in the level of consciousness, a pre-existing modified Rankin Scale (mRS) score of 0
or 1, and life expectancy of at least 3 years in each trial. DECIMAL
included patients 18 years to 55 years of age, whereas HAMLET and
DESTINY included patients aged 18 years to 60 years of age. In
DECIMAL a score on the National Institutes of Health Stroke Scale
(NIHSS) of >15 was an inclusion criterion for patients with infarctions of the dominant or non-dominant hemispheres. HAMLET and
DESTINY used different criteria for the NIHSS scores depending on
the affected hemisphere: >15 in HAMLET and >18 in DESTINY for
infarctions of the non-dominant hemisphere, and >20 for infarctions of the dominant hemisphere.
Inclusion criteria on neuroimaging also differed between the
three trials: In HAMLET and DESTINY, at least two-thirds of the
MCA territory, and in DESTINY, at least part of the basal ganglia
needed to be involved, whereas in DECIMAL more than 50% with
a volume of at least 145 mL in DWI needed to be involved. In HAMLET patients with infarctions of the complete hemisphere were
excluded, whereas in DECIMAL and DESTINY, patients with additional anterior and/or posterior cerebral artery infarctions could
enter the study. For differences in time to treatment, see Table 1.
The primary outcome measure in DECIMAL and DESTINY was the
mRS score dichotomized into 0–3 compared to 4–6 after 6 months,
whereas in HAMLET this same primary endpoint was assessed after
1 year. DESTINY and DECIMAL assessed mRS scores after 1 year as a
secondary endpoint. All three trials used a 1:1 randomization to
either hemicraniectomy or conservative treatment. Treatment protocols were broadly similar.
All three trials were stopped prematurely: DECIMAL was designed to include a maximum of 60 patients based on interim analyses. Recruitment was stopped in March 2006, however, after only
38 patients had been enrolled between December 2001 and
November 2005, because of the slow enrolment, because there
9
J. Flechsenhar et al. / Journal of Clinical Neuroscience 20 (2013) 6–12
Table 1
DECIMAL, DESTINY and HAMLET trials on the effect of decompressive hemicraniectomy (DHC) in the management of space-occupying ischemic stroke
Trial and treatment type
DESTINY
DHC
Conservative
DECIMAL
DHC
Conservative
HAMLET
DHC
Conservative
HAMLET
DHC
Conservative
Time to treatment (hours)
Mortality after 1 year (%)
Absolute risk reduction (%)
<36
18
53
35
<43
25
78
53
<51
19
78
59
51–99
27
36
8
DECIMAL = the French DEcompressive Craniectomy In MALignant middle cerebral artery infarcts trial, DESTINY = the German DEcompressive Surgery for the Treatment of
malignant INfarction of the middle cerebral artery, HAMLET = the Dutch Hemicraniectomy After Middle cerebral artery infarction with Life-threatening Edema Trial.
was a significant difference in mortality favoring decompressive
surgery, and because the opportunity arose for a pooled analysis
of the three trials. A total of 112 patients were to have been enrolled in HAMLET but recruitment was stopped in February 2008
on the advice of the data monitoring committee after an interim
analysis of the primary endpoint of 50 patients made it highly unlikely that a statistically significant difference would be seen at the
end of the trial. At that time, 64 patients had been enrolled between November 2002 and October 2007. A maximum of 68 patients were to have been enrolled DESTINY using a sequential
trial design based on mortality after 30 days. Recruitment was
temporarily stopped in November 2005 after a planned interim
analysis showed a significant benefit of surgery based on 30-day
mortality. At this time 32 patients had been enrolled between February 2004 and October 2005. The trial was then stopped after a
recalculation of the sample size projection based on the primary
endpoint indicated that 188 patients would be needed to show a
significant difference14,15,18
Fig. 3 and Table 1 show the results of DESTINY, DECIMAL and
HAMLET and pooled data of these trials. Surgical treatment is
subdivided in patients operated within and beyond 48 hours after
symptom onset.
None of the three trials showed a statistically significant difference between the two treatment groups for the mRS score dichotomized into 0–1 compared to 4–6, thereby missing their primary
endpoints. Detailed comparative results of the three trials are provided in Table 2. Most deaths occurred early (DECIMAL: 100% within 4 weeks, DESTINY: 90% within 8 days, HAMLET: 91% within
14 days) and were due to transtentorial herniation, thereby contradicting the results of larger case series indicating that a considerable number of deaths occur after discharge.35 Interestingly, in
patients treated early, mortality rates under conservative treatment in HAMLET and DECIMAL were much higher than in DESTINY: 78% compared to 53%. Comparatively low mortality rates
in conservatively treated patients have also been reported in
HeADDFIRST (46%). One explanation may be that most patients
in DESTINY and HeADDFIRST were treated in an experienced neurocritical care unit including maximum invasive neuromonitoring
and treatment, whereas in HAMLET and DECIMAL these patients
were usually referred to a stroke unit14,15,18,47
Fig. 3. The pooled data showing functional outcome after 1 year of the French DEcompressive Craniectomy In MALignant middle cerebral artery infarcts trial (DECIMAL), the
German DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY trial (DESTINY), and the Dutch Hemicraniectomy After Middle
cerebral artery infarction with Life-threatening Edema Trial (HAMLET). Cons = conservative treatment, DHC = decompressive hemicraniectomy, mRS = modified Rankin Scale
score.
10
J. Flechsenhar et al. / Journal of Clinical Neuroscience 20 (2013) 6–12
Table 2
Comparative results of primary and secondary endpoints of DESTINY, DECIMAL and HAMLET trials on the effect of decompressive hemicraniectomy in the management of spaceoccupying ischemic stroke
Outcome at 30 days
Mortality
Outcome at 6 months
mRS 63
mRS 64
DESTINY
DECIMAL
HAMLET
*
N.A.
N.A.
N.S. (PE)
N.S. (PE)
*
**
N.A.
N.A.
N.A.
mRS (non-dichotomized)
Barthel Index
NIHSS
Mortality
Outcome at 12 months
mRS 63
mRS 64
mRS (non-dichotomized)
Barthel Index
NIHSS
Mortality
SIS
SF-36
MADRS
Retrospective ‘‘agreement to treatment’’
‘‘Life worth living on follow-up’’
’’Satisfied with treatment’’
*
*
N.S.
N.A.
N.A.
*
*
**
N.S.
N.S.
*
**
*
**
N.A.
N.A.
N.A.
N.A.
N.S. (PE)
N.S.
N.D.
N.S.
N.A.
N.S.
N.S.
N.S.
N.S.
*
**
**
N.A.
N.A.
N.D.
N.A.
N.A.
Patients:
Surgical: 100%
Medical: 100%
N.A.
Patients:
Surgical: 100%
Medical: 100%
N.A.
Physical domain: #
Mental domain: N.S.
N.S.
Patients:
Surgical: 100%
Medical: 92%
Caregivers:
Surgical: 90%
Medical: 92%
MADRS = Montgomery and Asperg Depression Rating Scale, mRS = modified Rankin scale, N.A. = not assessed, N.D. = not determined (no statistical analysis), NIHSS = National
Institutes of Health Stroke Scale, N.S. = no statistically significant difference, PE = primary endpoint, SF-36 = Short Form-36 Questionnaire; SIS = Stroke Impact Scale.
*
p < 0.05 – a statistically significant difference between surgically and medically treated patients in favor of surgery.
**
p<0.01 – a highly significant statistical difference between surgically and medically treated patients in favor of surgery; # p < 0.05 – a statistically significant difference
between surgically and medically treated patients in favor of medical treatment.
Before these trials were completed, a prospectively planned
pooled analysis including all patients from DECIMAL and DESTINY
and 23 patients from HAMLET was performed, based on a protocol
with uniform inclusion and exclusion criteria. This pooled analysis
forms the basis of most current guidelines and recommendations
for acute stroke treatment concerning surgical treatment of malignant MCA infarction:50–53 93 patients treated within 48 hours after
symptom onset were included (51 treated by hemicraniectomy and
42 treated conservatively). Mortality at 1 year was significantly
decreased from 71.4% in the conservative group to 21.6% in the
surgery group (absolute risk reduction 49.8%). More patients in
the group treated surgically had an mRS score 64 (74.5% compared
to 23.8%) and an mRS score 63 (43.1% compared to 21.4%). The
numbers needed to treat (NNT) were: two patients for survival with
an mRS score 64; four for survival with an mRS score 63; and two
for survival irrespective of functional outcome. Very severe disability (mRS score 5) was not increased (4% after surgery compared to
5% after conservative treatment). The number of moderately to
severely disabled patients (mRS score 4) increased from 2.4% after
conservative treatment to 31.4% after hemicraniectomy.16
4. Open questions and future perspectives
Although hemicraniectomy is a standard procedure in neurosurgery worldwide, there is no one standardized operative
procedure.54 Opinions differ deeply regarding the diameter of
craniectomy and the mode of duraplasty. Facts about the impact
of these aspects on outcome are not available38 and they are still
being researched.55
Another important aspect is the timing of hemicraniectomy.
The randomized trials indicate that it benefits patients only when
performed early, at least within 48 hours of symptom onset.
However, the number of patients in these trials who were treated
within 48 hours is still very small, and a valid comparison with patients who have been treated later is not possible.14,16 As described
in Section 3.3, the results from HAMLET are not helpful in this
regard. Some studies suggest an improved outcome when hemicraniectomy is performed very early compared to delayed treatment.31,56 However, in other case series and non-randomized
studies, the time to treatment had no influence on outcome.57,58
More data are needed from larger prospective registries to estimate the effect of early treatment as a possible basis for future
trials. As long as these data are unavailable, hemicraniectomy
should be performed as soon as possible.
As in other diseases, but particularly in stroke, older patients
with malignant MCA infarctions have a poorer outcome than do
younger patients. There are several studies on hemicraniectomy
in these patients that suggest age limits of 50 years, 55 years, or
60 years.35,58–69 Interpretation of these findings is limited by older
patients undergoing surgery significantly later in most of studies
and being treated less aggressively than younger patients. The subgroup analyses of the randomized trials did not indicate poorer
outcome in patients P50 years of age compared to younger patients, but were not powered to detect such differences.14,16 Furthermore, the age limit for inclusion in these trials was 60 years,
and so far there are no data from randomized trials on patients older than 60 years. To further assess the question of how to treat older patients, DESTINY II is ongoing and has already enrolled more
than 100 patients.70 Until the results are available, the choice of
treatment in older patients with malignant MCA infarction is a difficult decision that should be made on an individual basis.70–73
Treatment of patients with malignant MCA infarction of the dominant hemisphere is another controversial issue. In the past, in
many centres, decompressive surgery was not considered. From
the randomized trials and larger prospective case series there is
no indication that patients with dominant malignant infarctions
J. Flechsenhar et al. / Journal of Clinical Neuroscience 20 (2013) 6–12
do not profit from surgical treatment.14,16 Neither mortality nor
functional outcome seems dependent on the side of the lesion in
any of the larger prospective studies.61 Indeed, the handicap
caused by aphasia may be balanced by the neuropsychological deficits (that is, the severe attention deficit, apraxia and anosognosia
in patients with infarction of the non-dominant hemisphere).74,75
In addition, in the long term, aphasia in dominant malignant
MCA infarction is rarely complete and shows remarkable improvement.30,33,62,74,76 Only a few studies suggest a more severe impairment in dominant malignant MCA infarction.77
Much criticism has been directed to the assessment strategies
of functional outcome in studies and trials on malignant MCA
infarction. It is often criticised that standard outcome measures
such as the Barthel Index, Glasgow Outcome Scale and mRS, with
their emphasis on motor abilities, may not account for all relevant
remaining deficits. Especially controversial is the dichotomization
between favorable and unfavorable outcomes in a condition with
a high mortality rate under conservative treatment and such severe primary disablement. It may be questioned as to whether
the terms ‘‘favorable’’ and ‘‘unfavorable’’ apply here or whether
they should be replaced by ‘‘acceptable’’ and ‘‘unacceptable’’ for
the patients.
To answer this question more data on the quality of life of
patients after malignant MCA infarction are needed. Available
studies have come to divergent results, although most of these
small studies suggest that survivors of malignant MCA infarction
have an average quality of life compared to other stroke
patients.57,59,74,76,78 Only one trial revealed a more profound reduction in the quality of life.60 Interpretation of these findings is
limited as there are insufficient data on quality of life after conservative treatment.
The joint efforts of neurologists, neurosurgeons, intensive care
physicians, and rehabilitation physicians are needed to design
and conduct studies that might answer these questions.
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