COPINION Malignant middle cerebral artery infarction

REVIEW

COURRENT Malignant middle cerebral artery infarction
PINION

Katja E. Wartenberg

Purpose of review
This review will report on the new aspects of management of ‘malignant’ middle cerebral artery (MCA)
infarctions.

Recent findings
Large MCA infarctions have been associated with high death rates for years. The most reliable predictors
of a ‘malignant’ course are hypodensity in more than 50% of the MCA territory on computed tomography
as well as stroke volume greater than 145 ml on diffusion-weighted imaging. Real-time neuromonitoring
may be helpful in the detection of development of cerebral edema. The attempt of recanalization of the
affected artery utilizing a combination of intravenous and intra-arterial thrombolysis and mechanical
thrombectomy is crucial. Monitoring of intracranial pressure has not been proven helpful. Decompressive
surgery within 48 h after symptom onset in patients less than 60 years old reduces mortality and severe
disability. The quality of life perceived by the survivors is variable and deserves further study. The
neuroprotective effect of hypothermia requires additional investigation.

Summary
The era of decompressive hemicraniectomy has changed the prospects of patients with large infarctions in
the MCA or internal carotid artery territory who are at risk of development of ‘malignant’ cerebral edema.
Timing of surgery and appropriate patient selection based on age and other criteria need to be refined.

Keywords
cerebral edema, decompression, hemicraniectomy, malignant MCA infarction, malignant stroke

INTRODUCTION infarction may include the anterior and/or posterior
territory as well [10,11].
Large hemispheric infarctions because of middle
cerebral artery (MCA) or internal carotid artery Most patients have risk factors for vascular
(ICA) occlusion constitute a major cause of severe disease such as hypertension, diabetes, hypercholes-
morbidity and mortality. Neurological deterioration teremia, tobacco abuse, history of transient ische-
occurs as a consequence of space-occupying cerebral mic attacks or ischemic strokes, congestive heart
edema in approximately 10% of all hemispheric failure, and coronary artery disease. Atrial fibrilla-
strokes and 5% of all ischemic strokes which led tion is more frequent in patients with MCA and ICA
to the term ‘malignant MCA infarction’ [1–3]. territory strokes compared to the remaining stroke
Mortality ranges between 41 and 79% with conser- population [1–3,12]. ICA dissection is a significant
vative treatment in the intensive care unit [1–5]. cause of large territory infarctions in younger
However, the new era of decompressive craniectomy patients (12%) [12].
resulted in a dramatic decrease of mortality and
severe disability [6–9]. The patients present with hemiparesis, hemi-
plegia, hemisensory loss, homonymous hemianopia
The patients affected are generally 10 years contralateral to the site of infarction, partial and
younger (56 Æ 9.4 years) than the average stroke
patient [1]. The incidence ranges between 10 and Neurointensive Care Unit, Martin-Luther-University, Halle-Wittenberg,
20 per 100 000 per year [1]. Halle, Germany

Large hemispheric infarctions occur as a Correspondence to Katja E. Wartenberg, MD, PhD, Neurointensive Care
consequence of a thrombotic or embolic occlusion Unit, Martin-Luther-University, Halle-Wittenberg, Ernst-Grube-Strasse
of the distal ICA or the proximal MCA trunk without 40, 06120 Halle, Germany. Tel: +49 345 557 2934; fax: +49 345
sufficient collateral flow (Figs 1 and 2). Depending 557 2935; e-mail: [email protected]
on the presence of sufficient collaterals, mainly
leptomeningeal arteries, or anatomic variants, the Curr Opin Crit Care 2012, 18:152–163

DOI:10.1097/MCC.0b013e32835075c5

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Malignant middle cerebral artery infarction Wartenberg

KEY POINTS

The most reliable predictors of a ‘malignant’ course of
large hemispheric strokes are infarction of more than
50% of the MCA territory and a perfusion deficit of
more than 66% on CT as well as stroke volume in
diffusion-weighted imaging of greater than 145 ml
within 14 h and greater than 82 ml within 6 h of
symptom onset.

Close neuromonitoring with continuous EEG,
intracortical electrodes, microdialysis, and brain tissue
oxygenation may be helpful in early detection of
development of cerebral edema.

Recanalization of the affected artery utilizing a
combination of intravenous and intra-arterial
thrombolysis and/or mechanical thrombectomy within
3–6 h, as early as possible, should be attempted.

Monitoring of intracranial pressure has not been proven
helpful. ICP can be normal in the setting of herniation.

Decompressive surgery within 48 h after symptom onset
in patients less than 60 years old reduces mortality,
moderate (mRS 3) and severe disability (mRS 4).
The number needed to treat (NNT) for survival and
severe disability is 2, the NNT for moderate disability
equals 6.

fixed gaze palsy towards the nonaffected hemi- FIGURE 2. Cerebral angiography with right internal carotid
sphere, and depressed level of awareness. Non- injection showing occlusion of the M1 segment of the right
dominant hemispheric infarctions are associated middle cerebral artery.
with visual, motor, and sensory neglect. Language
disturbance such as fluent, nonfluent, and mostly edema include nausea and emesis, decreasing level
global aphasia are typical for infarctions localized to of consciousness to coma, increasing pupillary size
the dominant hemisphere [1,12]. ipsilateral to the infarct, hemiparesis ipsilateral to
the infarct, unilateral or bilateral flexor or extensor
Neurological decline starts mostly within the posturing, altered breathing pattern, respiratory
first 48 h [1,3], in 36% within 24 h, and 68% within failure, bradycardia, and hypertension (Cushing
48 h [3]. Clinical signs for development of cerebral response) [1,3,4]. The first sign is drowsiness
followed by pupillary asymmetry, periodic breath-
FIGURE 1. Magnetic resonance angiogram time-of-flight ing, and extensor plantar response ipsilateral to the
image showing distal occlusion of the left internal carotid site of infarction [13].
artery (carotid T occlusion).
Death occurs within 5 days [1,3,4] as a result
of brain death in the majority of patients, cardiac
arrhythmias and arrest, sepsis, recurrent stroke,
and pneumonia [1–3]. Hemispheric brain swelling
leads to brain tissue shifts with subsequent brain
stem distortion, bihemispheric dysfunction through
mechanical displacement, vascular compression,
uncal and transtentorial herniation. The global intra-
cranial pressure (ICP) is usually not elevated in large

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hemispheric infarctions; cerebral hypoperfusion is and functional outcome at discharge [44&]. Cortical
not the cause for early neurological deterioration spreading depression and peri-infarct depolariz-
brain death [1,14,15&]. ations were seen on cortical EEG strips inserted
during hemicraniectomy procedures in all patients
PREDICTORS OF MALIGNANT MIDDLE with electrodes placed correctly in areas adjacent
CEREBRAL ARTERY INFARCTION to infarcted tissue. The time for the EEG to recover
was longer after clusters of cortical-spreading
With increasing availability of decompressive depressions indicating progressive deterioration of
craniectomy as an aggressive treatment option, the metabolic or hemodynamic status in peri-infarct
identification of predictors of a malignant course tissue [45].
of the MCA or ICA infarction is exceedingly import-
ant. Several clinical and radiological predictors of MANAGEMENT OF ACUTE ISCHEMIC
development of brain swelling and poor outcome INFARCTION
are summarized in Table 1 [2,11,16–40]. The meta-
analysis by Hofmeijer et al. [41] included 23 studies Successful recanalization of the hypoperfused
and found involvement of more than 50% of the or occluded MCA or ICA within a narrow time
MCA territory (Fig. 3) and a perfusion deficit of window of 3–4.5 h can be lifesaving and decrease
more than 66% on computed tomography (CT) to the size of infarction, thereby preventing the devel-
be the most reliable predictors of edema formation. opment of malignant brain edema [46–49]. Intra-
Other associated predictors with moderate effect venous recombinant tissue plasminogen activator
size were early mass effect, involvement of other (rtPA) administered within 3 h of onset of the first
vascular territories, higher body temperature, stroke symptom is the only approved acute stroke
ICA occlusion, and mechanical ventilation. A head treatment [46,49,50]. Extension of the time window
CT showing ischemic infarction of more than two- up to 4.5 h has been demonstrated to be safe and
thirds of the MCA territory with either involvement efficacious [48]. However, intravenous thrombolysis
of the basal ganglia or evidence of developing is less likely to reperfuse large cerebral artery occlu-
cerebral edema was also chosen as inclusion sions such as in ‘malignant’ MCA infarctions [51&].
criterion in two randomized hemicraniectomy trials The PROACT trials investigated safety and feasibility
[6,7]. Utilizing magnetic resonance tomography of intra-arterially administered recombinant pro-
with diffusion-weighted imaging (DWI), stroke urokinase within 6 h of stroke onset. The recanali-
volumes of greater than 145 ml within 14 h of zation rate was 66% with a 10% risk of intracerebral
symptom onset [19] and of greater than 82 ml hemorrhage [52,53]. A meta-analysis including
within 6 h [27] were found to be reliable predictors 395 patients from five trials showed a rate of partial
of a malignant course. or complete vessel recanalization of 46.8% with
intra-arterial fibrinolysis with 14.8% good and
More recently, multimodality monitoring 13.0% excellent outcomes. The discrepancy
including brain tissue oxygenation, cerebral meta- between recanalization rates and outcomes may
bolites by microdialysis, continuous and intra- be explained by prolonged times from stroke onset
cortical electroencephalography (EEG) revealed to procedure [54]. In the meantime, several devices
new insights into the development of malignant for mechanical recanalization have become avail-
brain edema [38–40,42,43]. An increase in peri- able: the Mechanical Embolus Removal in Cerebral
infarct extracellular glutamate, glycerin, and lactate Ischemia (MERCI; Concentric Medical, Inc., Moun-
concentration, and an augmentation of the lactate/ tainview, California, USA, see Fig. 4), a corkscrew-
pyruvate ratio was thought to reflect developing shaped device to pull the thrombus into an
brain edema with subsequent secondary neuronal extracranial guide catheter under active suction;
ischemia, as those changes of neurochemicals the Penumbra stroke system (Penumbra, Inc.,
preceded an increase in ICP [39,43]. Impaired auto- Alameda, California, USA) for clot aspiration and
regulation, decreased brain tissue oxygenation, and extraction with catheter position proximal to the
low cerebral perfusion pressure (CPP) were shown occlusion; Solitaire (Covidien/eV3, Maple Grove,
surrounding the infarct [38,40]. Bosche et al. [42] Minnesota, USA), or Trevo (Concentric Medical,
found significantly lower nontransmitter amino Inc., Mountainview, California, USA) which are
acid concentrations in the areas adjacent to the combined removable stent and clot retriever devices
infarct in patients who developed malignant brain [51&]. None of these devices have been evaluated in a
edema. The presence of a peak of faster EEG activity randomized controlled trial regarding their effect on
(5–7 Hz) in EEG power spectra obtained from con- long-term outcome. Acute stenting and angioplasty
tinuous EEG monitoring after hemicraniectomy was of intracranial stenosis with the Wingspan stent
correlated with an improved level of consciousness

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Malignant middle cerebral artery infarction Wartenberg

Table 1. Clinical and radiological predictors of a malignant course of infarctions in the middle cerebral or
internal carotid artery territories

Predictor Number Odds ratio or sensitivity/specificity Study
of patients

Demographic and clinical predictors 192 OR 0.4, 95% CI 0.3–0.6, P < 0.0001 Jaramillo et al., Neurology 2006 [11]
Younger age 192 OR 8.2, 95% CI 2.7–25.2, P ¼ 0.0003 Jaramillo et al., Neurology, 2006 [11]
Female sex 24 72 vs. 20% Maramattom et al., Neurology 2004 [16]
192 OR 0.2, 95% CI 0.05–0.7, P ¼ 0.01 Jaramillo et al., Neurology 2006 [11]
No previous ischemic infarctions 135 OR 4.2, 95% CI 1.4–12.9, P ¼ 0.01 Krieger et al., Stroke 1999 [17]
12 h systolic BP !180 mmHg 201 OR 3.0, 95% CI 1.2–7.6, P ¼ 0.02 Kasner et al., Stroke 2001 [2]
History of hypertension 201 OR 2.1, 95% CI 1.5–3.0, P ¼ 0.001 Kasner et al., Stroke 2001 [2]
History of congestive heart failure 62 OR 8.5, 95% CI 1.4–50.8, P ¼ 0.02 Wang et al., Eur J Neurology 2006 [18]
Coronary artery disease 201 OR 1.08 per 1000 white blood cells/ml, Kasner et al., Stroke 2001 [2]
High white blood cell count
95% CI 1.01–1.14, P ¼ 0.02 Oppenheim et al., Stroke 2000 [19]
Severe clinical deficit on admission 28 100% sensitivity, 78% specificity
NIHSS >20 Thomalla et al., Stroke 2003 [20]
37 96% sensitivity, 72% specificity Wang et al., Eur J Neurology 2006 [18]
NIHSS !19 62 OR 0.6, 95% CI 0.4–0.9, P ¼ 0.006 Krieger et al., Stroke 1999 [17]
OR 5.1, 95% CI 1.7–15.3, P ¼ 0.003 Foerch et al., Stroke 2004 [21]
Total Glasgow Coma Scale score
75% sensitivity, 80% specificity Serena et al., Stroke 2005 [22]
Nausea and vomiting within 24 h 135 94% sensitivity, 83% specificity
90% sensitivity, 100% specificity Krieger et al., Stroke 1999 [17]
Protein S-100 51 64% sensitivity, 88% specificity Kasner et al., Stroke 2001 [2]
>0.35 mg/l at 12 h Manno et al., Mayo Clin Proc 2003 [23]
>1.03 mg/l at 24 h OR 6.1, 95% CI 2.3–16.6, P ¼ 0.0004 Pullicino et al., Neurology 1997 [24]
OR 6.3, 95% CI 3.5–11.6, P ¼ 0.001
Cellular fibronectin !16.6 mg/ml 40 OR 14.0, 95% CI 1.04–189.4, P ¼ 0.047 Moulin et al., Neurology 1996 [25]
Matrix metalloproteinase 9 !140 ng/ml 46% sensitivity, 89% specificity
Kucinski et al., AJNR 1998 [26]
Radiological predictors – computed tomography OR 5.3, 95% CI 1.7–16.2, P ¼ 0.01 Thomalla et al., Stroke 2003 [20]
64% sensitivity, 85% specificity Thomalla et al., Ann Neurol 2010 [27]
Hypodensity in MCA territory 135 OR 5.4, 95% CI 1.6–18.7, P ¼ 0.008 Kasner et al., Stroke 2001 [2]
on initial CT >50% 201 OR 3.3, 95% CI 1.2–9.4, P ¼ 0.02 Maramattom et al., Neurology 2004 [16]
36 72 vs. 0%
Haring et al., Stroke 1999 [28]
Horizontal pineal displacement >4 mm 127 71% sensitivity, 84% specificity Manno et al., Mayo Clin Proc 2003 [23]
on CT within 48 h of stroke onset 100 OR 21.6, 95% CI 3.5–130.0, P < 0.001 Haring et al., Stroke 1999 [28]
87% sensitivity, 97% specificity
Attenuation of the lentiform nucleus, 74 Lee et al., Arch Neurol 2004 [29]
loss of the insular ribbon, 37 91% sensitivity, 94% specificity
or hemispheric sulcal effacement Ryoo et al., J Comput Assist Tomogr
85% sensitivity, 78% specificity 2004 [30]
Internal carotid T occlusion
85% sensitivity, 74% specificity Dittrich et al., J Neurol 2008 [31]
Combined ICA and MCA occlusion 140 95% sensitivity, 72% specificity
Bektas et al., Stroke 2010 [32]
Involvement of additional vascular 201 96% sensitivity, 96% specificity
territories (ACA, PCA, anterior 24 Minnerup et al., Stroke 2011 [33]
choroidal)
62 Limburg et al., Stroke 1990 [34]
Hyperdense MCA sign 36

Attenuated corticomedullary contrast 62
within 18 h of symptom onset 31

Perfusion deficit >50% of MCA 27
territory on CT within 6 h of stroke
onset

Perfusion deficit >66% of MCA territory
on CT within 6 h of stroke onset

Infarction core on cerebral blood flow 106
maps >27.9%

Cerebral blood volume maps >22.8%

Time to peak maps >39.9% of the 122
hemisphere on perfusion CT (median 52
2 h after stroke onset) 26

Increased infarct permeability area on
perfusion CT on average within 6 h
after symptom onset

Cerebral blood volume to cerebrospinal
fluid volume ratio >0.92 on perfusion
CT within 6 h after symptom onset

Single-photon emission CT flow deficit

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Table 1 (Continued)

Predictor Number Odds ratio or sensitivity/specificity Study
of patients Mean CBF 8.6 ml/100 g/min Firlik et al., J Neurosurg 1998 [35]
Berrouschot et al., Stroke 1998 [36]
Xenon-enhanced CT within 6 h of stroke 20 correlated with herniation
onset 82% sensitivity, 99% specificity Lampl et al., Brain Res 2006 [37]

99mTc-ECD SPECT deficit in the entire 108 Significant correlation with Oppenheim et al., Stroke 2000 [19]
MCA territory within 6 h of stroke 25 herniation Thomalla et al., Stroke 2003 [20]
onset Thomalla et al., Ann Neurol 2010 [27]
100% sensitivity, 94% specificity Thomalla et al., Stroke 2003 [20]
99mTc-DTPA SPECT DTPA disruption 87% sensitivity, 91% specificity
index within 36 h after stroke onset 52% sensitivity, 98% specificity Dohmen et al., Stroke 2003 [38]
83% sensitivity, 75% specificity
Radiological predictors – magnetic resonance imaging Dohmen et al., Stroke 2003 [38]
99% sensitivity, 86% specificity Dohmen et al., Stroke 2003 [38]
DWI volume >145 ml within 14 h 28 Schneweiss et al., Stroke 2001 [39]
of stroke onset 94% sensitivity, 100% specificity Dohmen et al., Stroke 2003 [38]
95% sensitivity, 100% specificity Dohmen et al., Stroke 2007 [40]
ADC<80% lesion volume >82 ml 37
within 6 h of stroke onset

DWI volume >82 ml within 6 h of 140
symptom onset

TTP lesion volume >162 ml 37

Other radiological predictors

PET mean cerebral blood flow in 34
infarction core <25.5% within
24 h after stroke

Multimodality monitoring

pbtO2 <10.5 mmHg 34
CPP <56 mmHg 34

Increase in glutamate, lactate– 10
pyruvate ratios, and glycerol 34
(microdialysis)
15
Impaired cerebral perfusion pressure-
oxygen reactivity index and correlation
coefficient of cerebral perfusion
pressure and tissue oxygen pressure
at 24 and 72 h after stroke

99mTc-DTPA SPECT, 99m technetium-diethylenetriaminepenta-acetic acid single-photon emission computed tomography; 99mTc-ECD SPECT, 99m technetium-ethyl-
cysteinate-dimer single-photon emission CT; ACA, anterior cerebral artery; ADC, apparent diffusion coefficient; BP, blood pressure; CI, confidence interval; CPP,
cerebral perfusion pressure; CT, computed tomography; DWI, diffusion-weighted imaging; MCA, middle cerebral artery; NIHSS, National Institute of Health
Stroke Scale; pbtO2, partial brain tissue oxygen pressure; OR, odds ratio; PCA, posterior cerebral artery; PET, positron emission tomography; TTP, time to peak
on magnetic resonance imaging perfusion maps.

system (Stryker/Target, Fremont, California, USA) !5 mm at the level of septum pellucidum, uncal
increased the risk of recurrent stroke at 30 days [55]. herniation, cisternal effacement by CT, or anisoco-
ria by clinical examination [15&].
Several other methods are currently under
investigation, such as bridging of intravenous with Medical management of cerebral edema consists
intra-arterial rtPA and/or mechanical thrombus of head of bed elevation (308), osmotherapy
removal (Interventional Management of Stroke Trial with mannitol or hypertonic saline, sedation, and
3, IMS3). hypothermia. None of these treatments has been
studied in a randomized controlled trial [57]. Bolus
INTENSIVE CARE MANAGEMENT administration of 23.4% hypertonic saline led
to rapid reversal of transtentorial herniation in
Patients with ‘malignant’ MCA strokes are best 75% of 68 patients including eight patients with
managed in a neuroscience intensive care unit. Most ischemic stroke [58]. Direct comparison of equios-
patients require intubation, mechanical ventilation, molar doses of 20% mannitol and 23.4% hypertonic
and sedation for prophylaxis of aspiration or pro- saline in nine patients with ‘malignant’ MCA stroke
cedures if not for respiratory failure [56]. with greater than 2 mm midline shift at the pineal
gland or septum pellucidum level demonstrated
Monitoring of ICP has not been proven to be comparable minimal effects on cerebral blood
more helpful than neurological examination and flow (CBF) utilizing positron emission tomography
repeated CT scanning. Twelve of 19 patients with at normal blood pressures. When the blood pressure
ICP monitors did not present with ICP rise by was elevated, the agents led to a rise in CBF in the
monitor, despite increases in midline shift at least

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Malignant middle cerebral artery infarction Wartenberg

FIGURE 3. Computed tomography showing hypoattenuation hemisphere not affected. Cerebral blood volume
of more than 50% of the territory of the left middle remained unchanged after administration of both
cerebral artery including the head of the caudate, globus therapies [59]. After administration of hypertonic
pallidus, and putamen with loss of sulci and grey–white saline, hydroxyethyl starch solution ICP decreased
matter differentiation, effacement of the left lateral ventricle, by 34% 16 times at 15 min compared to 17% with
and minimal midline shift at the level of the septum mannitol during 30 episodes of ICP crisis in patients
pellucidum. with space-occupying infarctions [60]. A recent
meta-analysis including 112 patients from five
FIGURE 4. Cerebral angiogram demonstrating an attempt to trials showed a greater benefit for ICP control with
remove the thrombus from the right middle cerebral artery hypertonic saline compared to mannitol (odds ratio
with the MERCI retriever. 1.16, 95% confidence interval 1.00–1.33), with a
mean difference in ICP of 2 mmHg [61&]. In general,
most neurointensivists favor the use of hypertonic
saline (55% vs. mannitol 45%) for a reduced
frequency of rebound edema, a longer duration of
effect, desired volume expansion, and lack of
systemic side-effects [62].

Systemic hypothermia (target temperature 33–
358C) for ICP control can be achieved with ice packs,
intravenous cold saline solutions, cooling blankets,
surface and intravascular cooling devices. There are
a few safety trials, but no efficacy studies, despite
reliable demonstrations of reduced infarct size with
variable levels and duration of hypothermia after
ischemic stroke in animal models [63]. In one safety
trial, 25 patients with large MCA territory infarcts
underwent moderate hypothermia (338C) after an
interval of 14 Æ 7 h after stroke onset. Hypothermia
was maintained for 48–72 h. ICP was reduced, but
the patients were subjected to passive rewarming
(17–24 h) which resulted in a continuous rise of
ICP with subsequent herniation and death in nine
patients (44% mortality). Complications of hypo-
thermia encompassed shivering, cardiac arrhyth-
mias including prolongation of the PR and QT
interval, ventricular ectopy and fibrillation, sepsis,
pneumonia, thrombocytopenia, as well as augmen-
tation of serum amylase and lipase with unknown
clinical significance [64]. Controlled rewarming
at 0.1–0.28C over 2–4 h correlated with a gradual
increase of ICP, decrease of CPP, and improved
cerebral cellular and metabolic compensation
mechanisms [65]. In a large prospective trial of
50 patients treated with moderate hypothermia
(32–338C) for 72 h after large hemispheric infarc-
tion, ICP was significantly reduced. Passive rewarm-
ing within 16 h was associated with a pronounced
rise in ICP compared to controlled rewarming over a
longer period of time (>16 h). The most common
side-effects of hypothermia in this study were
cardiac arrhythmias (sinus bradycardia, prolonged
PR and QT intervals), arterial hypotension, pneumo-
nia, decreased serum potassium, thrombocytopenia,
and coagulopathy. Mortality was 38% overall.
All patients received midazolam and propofol for
sedation, morphine and fentanyl for analgesia, and

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neuromuscular blockade with vecuronium and FIGURE 5. Computed tomography showing an infarction of
atracurium during hypothermia and rewarming the entire right middle cerebral artery territory with
[66]. In another study, 36 patients with space-occu- hemorrhagic transformation, treated with decompressive
pying MCA infarction were treated with moderate hemicraniectomy, with expansion of cerebral infarct edema
hypothermia (338C) if the dominant hemisphere beyond the calvarial compartment.
was affected (19 patients) and compared to patients
with nondominant hemispheric infarctions treated removed down to the middle fossa. An increase in
with hemicraniectomy (17 patients). Mortality was the anterior–posterior diameter from 12 to 14 cm
47% in the hypothermia group (hemicraniectomy results in an increase of potential volume by
group 12%): one patient died of sepsis and three of 76%. A small diameter hemicraniectomy leads
rebound intracranial hypertension after rewarming. to compression and kinking of bridging veins, or
The application of hypothermia led to a prolonged mushroom-like herniation of the brain with shear-
application of higher doses of vasopressors to treat ing distortion and additional ischemic lesions [70&]
hypotension [67]. A case series reports 12 patients (Fig. 5). A new method to maximally enlarge the
treated with moderate hypothermia (32–338C) surface covered by the craniectomy encompasses
24 h after stroke onset until evidence of resolution five keyholes: below the crossing of the superior
of mass effect by CT, followed by slow rewarming temporal line with the frontozygomatic suture,
over 2–5 days. Most common side-effects encom- 1 cm above the zygomatic root, 4 cm above the
passed systemic hypotension, thrombocytopenia, ipsilateral mid-pupil, 1.5 cm lateral to the midline,
and hyperfibrinogenemia. Five patients died of and 4 cm lateral and 6 cm above the inion [71]. After
herniation before and after the rewarming phase resection of the temporal bone to the skull base,
[68]. Moderate hypothermia (358C) was introduced the dura is opened, adjusted, and a biconvex dural
after hemicraniectomy in 12 of 25 patients for 48 h. patch is placed into the incision (duroplasty) to
There was no difference in mortality, but a trend to prevent leakage of cerebrospinal fluid. Resection
better functional outcome was done using National of the infarction is not advisable as the margins
Institute of Health Stroke Scale (NIHSS) and Barthel between infarct and penumbra are poorly defined.
Index at 6 months in the group treated with hemi- The bone flap can be conserved in the abdominal
craniectomy and hypothermia [69]. In summary, subcutaneous tissue or in a cooled sterile isotonic
the use of hypothermia for control of cerebral edema solution. Reimplantation of the bone flap is possible
in large hemispheric infarction is well tolerated 6–12 weeks up to 6 months after removal, once the
and feasible, its efficacy needs to be evaluated in swelling has resolved. Decompressive craniectomy
randomized clinical trials. The DEcompressive was found to be well tolerated after intra-arterial
surgery Plus hypothermia in Space-Occupying thrombolysis [72]. Potential periprocedural compli-
Stroke (DEPTH-SOS) study, a randomized trial cations include intracranial, wound and bone flap
of moderate hypothermia after hemicraniectomy,
is currently ongoing.

DECOMPRESSIVE SURGERY

Horizontal and vertical tissue shifts, ventricular and
vascular compression by massive brain edema are
relieved by removal of the bone flap over the frontal,
temporal, and parietal lobe at the infarct site.
This allows the edematous brain to expand extrac-
ranially, improves CPP and retrograde flow in
the MCA, preserves CBF, and may prevent further
ongoing ischemia. An adequate craniectomy
needs to cover a large surface area, ideally beyond
the margins of the infarction in all directions.
Beginning with an appropriate scalp incision, the
bone flap includes frontal, temporal, and parietal
bone. The limiting factor is its anterior–posterior
diameter, as the vertical diameter cannot exceed
9–10 cm from the floor of the middle fossa to the
sagittal sinus. The target diameter should be 14 cm
anterior–posterior, temporal bone needs to be

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Malignant middle cerebral artery infarction Wartenberg

infection (5–10%), subdural and epidural hema- outcome [78–83]. Although many clinicians are
toma, contralateral subdural effusions, and hypo- reluctant to offer hemicraniectomy to patients
tension with the risk of additional infarction with dominant hemisphere infarcts, a meta-analysis
[70&,73]. Late complications such as sinking skin found no difference in functional outcome
flap syndrome (26%), extra-axial fluid collections, comparing left vs. right-sided [79]. Five randomized
hydrocephalus, chronic pain, and subdural hema- controlled trials comparing decompressive hemicra-
tomas have become more frequent with the appli- niectomy have started in the past decade. The results
cation of hemicraniectomy in daily clinical practice of the four completed trials and a subsequent pooled
[70&,74,75&,76,77]. Sinking skin flap syndrome analysis are listed below [6–9,84]. The Philippine
(see Fig. 6) presents with orthostatic headaches, HeMMI (Hemicraniectomy for Malignant Middle
focal signs, or seizures. The presumed cause is the cerebral artery Infarcts) trial is still ongoing.
pressure gradient between the atmosphere and
the intracranial vault. Those patients tend to have The North American Hemicraniectomy and
a smaller surface of the craniectomy with larger Durotomy for Deterioration From Infarction Related
lesion size which leads to increased areas of atrophy, Swelling Trial (HeaDDFIRST) enrolled 26 patients.
a longer delay to reinsertion of the bone flap or Inclusion criteria were age 18–75 years and evidence
cranioplasty, and a larger baseline stroke volume. of complete MCA/ICA infarction (>50% MCA
They are generally older. Death may occur from territory, >90 ml volume by CT). The patients were
‘paradoxical herniation’. Treatment includes place- first managed in the intensive care unit with defined
ment in supine position, epidural blood patch, and protocols including glucose and fever control,
cranioplasty as soon as possible [74,75&]. did not receive prophylactic ICP treatment, and
got a follow-up CT. Randomization to decompres-
Multiple case series, clinical trials, and a meta- sive surgery within the next 4 h or to medical
analysis suggest that timing of hemicraniectomy management was allowed if the CT scan revealed
and age of the patients are crucial factors in a septal shift greater than 7.5 mm and/or pineal shift
determining outcome. Early surgery has a greater greater than 4 mm. The results are shown in Table 2.
impact on reduction of mortality, and young There was one crossover from the surgical to the
patients (<50, 52, and 60 years) tend to have a better medical arm. Short-term and long-term mortality
as well as discharge status at 1 year did not
differ between the groups. The trial has not been
published [84].

The German Decompressive Surgery for the
Treatment of Malignant Infarction of the Middle
Cerebral Artery (DESTINY) study included 32
patients, aged 18–60 years who presented with a
NIHSS of 18 for nondominant and 20 for dominant
hemisphere infarctions. Two-thirds of MCA territory
and at least part of the basal ganglia had to be
involved on CT. Randomization to surgical or
medical management and treatment took place
within 12–36 h. The study had a sequential design:
a 40% difference of mortality was assumed between
the groups and was therefore terminated when
short term mortality reached a significant difference
(P ¼ 0.019). However, functional outcome at 6 and
12 months was not statistically different (Table 3).
There were more dominant infarctions with higher

Table 2. Results of the HeADDFIRST trial [84]

n ¼ 26 Surgical arm Medical arm

FIGURE 6. Computed tomography 3 months after the initial Mortality at 21 days 20% 40%
event demonstrating the ‘sinking skin flap syndrome’ after Mortality at 90 days 36% 40%
decompressive hemicraniectomy for right MCA territory Mortality at 180 days 35.5% 40%
infarction. Home at 1 year 38.5% 40%

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Table 3. Results of the DESTINY trial [7] Table 5. Results of the HAMLET trial [6]

Surgical arm Medical arm n ¼ 64 Surgical arm Medical arm
(n ¼ 17) (n ¼ 15)
n ¼ 32 56%
53% P < 0.0001
P ¼ 0.03 14-day mortality 16%
75%
Mortality at 1 year 18% 27% 59%
NS
mRS 2–3 at 180 days 47% mRS 4–6 at 12 months 75%
27% mRS 5–6 at 12 months 41%
NS
mRS 2–3 at 1 year 48% mRS, modified Rankin Scale.

mRS, modified Rankin Scale.

NIHSS scores in the medical group, and 80% of the quality of life (Table 5). For patients treated within
patients were enrolled at two centers only [7]. 48 h, hemicraniectomy provided better outcomes.
However, the study was terminated early because a
The French Decompressive Craniectomy difference in functional outcome seemed unlikely
in Malignant Middle Cerebral Artery Infarction [6].
(DECIMAL) trial was stopped after enrollment of
38 patients less than 55 years old with a NIHSS The pooled analysis of the DESTINY, DECIMAL,
greater than 16 and altered level of consciousness and HAMLET trials initially included 93 patients,
because of the dramatic difference in mortality at 18–60 years of age, with a NIHSS greater than 15
30 days (Table 4). The radiological inclusion and MCA infarctions greater than two-thirds of
criterion was stroke volume greater than 145 ml the MCA territory on CT or a volume greater than
on DWI. The patients were randomized to decom- 145 ml on DWI, who were randomized to decom-
pressive surgery vs. best medical management pressive surgery or medical management within
within 30 h of infarction. The mean time to decom- 48 h of symptom onset. The results are shown in
pression was 20 h. Significantly more patients had Table 6. The number needed to treat (NNT) for
better outcomes at 6 and 12 months. Younger age survival with severe disability [inability to walk or
correlated with better outcome, and an infarct to attend bodily needs, modified Rankin Scale (mRS)
volume greater than 200 ml was the greatest predic-
tor of mortality [9]. 4] at 1 year was 2. To achieve moderate disability
with the ability to walk with assistance (mRS 3),
The Dutch Hemicraniectomy After Middle the NNT was 4. There were no differences in chosen
cerebral artery infarction with Life-threatening subgroups older than 50 years, patients with apha-
Edema Trial (HAMLET) studied 64 patients with sia, or patients randomized and treated within 24 h
18–60 years of age and a stroke covering more than [8]. This analysis was repeated after the completion
two-thirds of the MCA territory and evidence of of HAMLET with 109 patients. Decompressive
space-occupying edema on CT. The patients were surgery resulted in an absolute risk reduction of
randomized to decompression or medical therapy 50% for mortality, 42% for mRS 4, and 16%
within 96 h of symptom onset. There were no differ- for mRS 3. For mortality and severe disability
ences in functional outcomes between the groups (mRS 4), the NNT remained 2, to achieve moderate
including Barthel index, depression scales, and disability (mRS 3) it increased to 6 [73]. On the
basis of these trials and analysis, treatment of space-
occupying infarction with hemicraniectomy within
48 h of MCA or ICA stroke in patients younger than

Table 4. Results of the DECIMAL trial [9] Table 6. Results of the pooled analysis of DESTINY,
DECIMAL, and HAMLET [8]

n ¼ 38 Surgical arm Medical arm n ¼ 93 Surgical arm Medical arm

Mortality at 30 days 25% 78% Survival at 12 months 78% 29%
P < 0.0001 mRS 0–4 at 12 months 75% P < 0.0001
mRS 2–3 at 6 months 25% mRS 0–3 at 12 months 43%
5.6% 24%
mRS 2–3 at 12 months 50% P ¼ 0.01 P < 0.0001
22.2%
P ¼ 0.0024 23%
P ¼ 0.014

mRS, modified Rankin Scale. mRS, modified Rankin Scale.

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Malignant middle cerebral artery infarction Wartenberg

60 years received a level I recommendation in the MCA infarctions, DESTINY-R, and a question-
guidelines [47]. naire to patients, families, and physicians about
their expectations from a treatment with
However, according to the criteria of the clinical hemicraniectomy after space-occupying infarc-
trials, only 0.3% of a cohort of 2227 patients with tion and acceptable outcomes, DESTINY-S will
ischemic stroke were eligible for hemicraniectomy continue to illuminate this issue.
within the defined time window [5].
CONCLUSION
More questions remained: (1) The earlier the
better? (2) Up to what age? and (3) What about Space-occupying edema after large hemispheric
the quality of life after hemicraniectomy? infarctions is difficult to control with conservative
intensive medical management. Decompressive
(1) The mortality benefit was greater if surgery was hemicraniectomy can save lives after large
performed within 24 h compared to more than hemispheric infarction; most patients live with
24 h (16 vs. 34%; 37 vs. 80%) in two series moderate-to-severe disability. The perceived quality
[78,81]. Within 6 h of stroke onset, mortality of life and neuropsychological deficits after hemi-
was reduced to 9% [78]. There was no benefit for craniectomy need further investigation, so does
mortality and severe disability if hemicraniec- the timing for surgery and appropriate age limits.
tomy was undertaken beyond 48 h in HAMLET The correct patient selection for hemicraniectomy is
[6]. The pooled analysis did not demonstrate of utmost importance to limit risks and provide
any difference in outcome if surgery was done maximum benefit. The only valid predictor of a
less or greater than 24 h after symptom onset [8]. malignant course seems to be the size of infarction,
Selection of patients for hemicraniectomy greater than 50% of MCA territory on CT and greater
too early after symptom onset may lead to than 145 ml volume on DWI within 14 h of stroke
unnecessary surgical procedures, whereas if onset (>82 ml on ADC or DWI within 6 h). Further
hemicraniectomy is carried out after the point investigation of multimodality monitoring with
of herniation it was certainly too late. probes inserted adjacent to the infarct may refine
the selection of patients who develop cerebral
(2) About 40% of patients with ‘malignant’ MCA edema. Hypothermia is a promising additional
infarction are older than 60 years [1,83]. tool for control of cerebral edema with a beneficial
The HAMLET study suggested that patients aged neuroprotective effect that requires further investi-
51–60 years may benefit more from surgical gation.
decompression than patients 50 years old and
younger [6]. The ongoing DESTINY II study Acknowledgements
includes patients older than 60 years who are
randomized to hemicraniectomy or medical None.
management within 48 h of symptom onset
[85]. Conflicts of interest

(3) An important question not addressed by the The author has no conflicts of interest and no financial
larger randomized trials is: What level of func- support to disclose.
tional outcome is acceptable to individual
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