1. health and fitness
2. disease

Management of Large Hemispheric Infarction
K. E. Wartenberg and S. A. Mayer
z Introduction: Natural History of Large Hemispheric Infarction
Large hemispheric infarctions due to middle cerebral artery (MCA) or internal carotid artery (ICA) occlusion are an important cause of morbidity and mortality in
the neurological intensive care unit (ICU). Neurological deterioration occurs as a
consequence of malignant cerebral edema in approximately 5±10% of hemispheric
ischemic strokes [1±3], but in over two-thirds of patients when the complete MCA
territory is infarcted [1, 3]. The reported mortality of these `malignant' hemispheric
infarctions varies between 42 and 80% [1±5].
Patients with complete MCA infarction are generally 10 years younger (mean age
56 years) than the average stroke patient [1]. The initial presentation usually includes contralateral conjugate gaze paresis, hemineglect, and reduced level of consciousness in addition to the expected sensorimotor and language deficits [1, 6, 7].
Most patients experience neurological decline within 48 hours [1, 3]. Of those
who deteriorate, worsening occurs within 24 hours in 36% and within 48 hours in
68% [3]. The first sign of transtentorial herniation is usually drowsiness, followed
by pupillary asymmetry, hyperventilation, and contralateral motor posturing [8, 9].
Autonomic abnormalities may include hyper- or hypoventilation, bradycardia, and
sustained hypertension or blood pressure lability [1, 3, 5, 7]. Bilateral motor posturing and lower extremity rigidity then follows as the midbrain and diencephalon
are subjected to physical distortion and compression [8]. Without life support,
death typically occurs within five days [1, 3, 5] as a result of brain death, respiratory failure, cardiac arrhythmia, or pneumonia [1±3].
Infarction of the brain parenchyma and the vasculature results in a delayed
break down of the blood brain barrier with extravasation of serum proteases and
worsening of brain edema 24 to 72 hours after the initial infarct signs [9]. Hemispheric brain swelling leads to brain tissue shifting with subsequent brain stem
distortion, bihemispheric dysfunction through mechanical displacement, vascular
compression, uncal and transtentorial herniation (Fig. 1). Intracranial pressure
(ICP) is usually not elevated early in the process of transtentorial hermiation from
large hemispheric infarction, but increases later as severe cytotoxic edema ensues.
Ongoing ischemia is usually not the cause of neurological deterioration beyond 24
hours of onset, but this can result from vascular compression of the anterior and
posterior cerebral arteries against the falx or tentorium, and is a universal finding
in patients who become brain dead [4].
648
K. E. Wartenberg and S. A. Mayer
Fig. 1. Schematic diagram of the importance of tissue shifts and hypothetical significance of pressure differentials in clinical worsening from large hemispheric infarction with edema. P1 represents the pressure
in the injured hemisphere and P2 the pressure in the uninjured hemisphere. As edema ensues, pressure
differentials occur and accentuate, leading to tissue shifts and clinical worsening. From [4] with permission
z Etiology of Large Hemispheric Infarctions
Large hemispheric infarctions occur as the consequence of an occlusion of the distal ICA or proximal MCA trunk without sufficient collateral flow (Figs. 2 and 3).
Total ICA occlusions lead to infarction of the anterior cerebral artery (ACA) and
MCA territories [7].
Most patients have risk factors for vascular disease such as hypertension, diabetes, hypercholesteremia, tobacco abuse, history of transient ischemic attacks or
ischemic strokes, congestive heart failure (CHF), and coronary artery disease. Atrial
fibrillation is more frequent in patients with MCA and ICA territory strokes compared to the remaining stroke population [1±3, 6]. ICA dissection is a significant
cause of large territory infarctions in younger patients (12%) [6]. In one series of
610 patients with large hemispheric strokes 42% were attributed to focal or general
atherosclerosis and 33% to a cardioembolic source [6].
z Diagnosis of Early MCA Infarction
Computed tomography (CT) of the brain obtained within 6 hours of symptom onset has a sensitivity of 82% for ischemic hemispheric infarctions [10]. Early infarct
signs on CT include:
z Hyperdense MCA sign (high contrast in the MCA that is brighter than the adjacent brain tissue and other intracranial arteries in the absence of calcification)
(Fig. 4)
Management of Large Hemispheric Infarction
Fig. 2. a ICA occlusion after the bifurcation demonstrated by cerebral angiography with a common carotid artery injection. b MR Angiogram of the Circle of Willis shows no flow signal in the left ICA and crossfilling of the left MCA via the anterior communicating artery
z Hyperdense ICA sign distinguishable from the opposite ICA and the surrounding bone
z Obscuration of the lentiform nucleus defined by decreased density compared to
the contralateral nucleus
z Effacement of the sylvian fissure with loss of grey-white matter distinction compared to the contralateral side
z Involvement of other vascular territories seen as hypodensity in the ACA, anterior choroidal and posterior cerebral arteries (PCA)
z Complete sylvian fissure obscuration and extensive effacement of the hemisphere
as well as compression of the lateral ventricle demonstrating mass effect
z Midline shift at the level of the pineal gland and the septum pellucidum (anteroseptal shift) [2, 10]
z Predictors of Fatal Deterioration
Several studies have identified risk factors for secondary fatal neurological deterioration after MCA infarction. A multivariate analysis of 201 patients with large
hemispheric strokes [2] identified the following predictors of fatal brain swelling:
z History of hypertension
z History of CHF
z An elevated white blood count (WBC)
649
650
K. E. Wartenberg and S. A. Mayer
Fig. 3. MCA main stem occlusion by cerebral angiogram
with left common carotid injection
z CT involvement of > 50% of MCA territory (Fig. 5), and
z CT involvement of additional territories [1, 2, 10, 11].
In a series of 37 patients with MCA stroke and proximal vessel occlusion a National
Institute of Health Stroke Scale (NIHSS) on admission of 19 or greater was found
to be highly predictive of severe neurological deterioration (sensitivity 96%, specificity 72%) [12].
Several studies have found that radiographic evidence of a large initial infarction
volume can reliably identify those at greatest risk for neurological deterioration. In
a case control study of 31 patients studied with contrast CT, attenuated corticomedullary contrast enhancement involving the entire MCA territory within 18 hours
of onset was found to be the most reliable neuroradiological predictor of neurological deterioration, with a sensitivity of 87% and specificity of 97% [13]. In another
study horizontal pineal displacement greater than 4 mm on CT performed within
48 hours of stroke onset was highly predictive of mortality with a specificity of
89% and a sensitivity of 46% in 127 patients [14]. In an analysis of magnetic resonance imaging (MRI) predictors, a reduction in the apparent diffusion coefficient
(ADC) of greater than 82 ml was the most accurate predictor of deterioration, with
Management of Large Hemispheric Infarction
Fig. 4. a Hyperdense MCA sign (right) on CT surrounded by hypoattenuation in the right frontal and temporal regions with loss of sulci and grey-white matter differention. b The Fluid Attenuated Inversion Recovery (FLAIR) sequence reveals high signal in the right MCA consistent with a thrombus
a sensitivity of 87% and specificity of 91% [12]. This finding is supported by a retrospective analysis that identified a diffusion weighted imaging (DWI) lesion volume exceeding 145 ml within 14 hours of symptom onset as the best predictor of a
malignant clinical course, with a sensitivity and specificity of 100% in a multivariate model [15].
Krieger et al. identified nausea and vomiting within 24 hours of stroke onset,
systolic blood pressure (SBP) > 180 mmHg after 12 hours, and involvement of
> 50% of the MCA territory on CT as independent predictors of fatal brain swelling
in a multivariate analysis of 135 patients [16]. Carotid ªTº occlusion was significantly associated with a fatal outcome in 74 MCA infarction patients with acute
carotid artery distribution stroke [17]. Severe cerebral blood flow (CBF) reductions
in the MCA territory, detected by Xenon-CT (mean CBF 8.6 ml/100 gm/minute)
[18] or single photon emission CT (SPECT) [19] can also identify patients at risk
for fatal brain edema.
Neurochemical monitoring with cerebral microdialysis is another interesting tool
to monitor the course of MCA infarction. An increase in extracellular glutamate,
glycerin and lactate concentration and an augmentation of the lactate/pyruvate ratio in peri-infarct areas was thought to reflect developing brain edema with subsequent secondary neuronal ischemia as those changes of neurochemicals preceded
an increase in ICP [20±22]. Bosche et al. found significantly lower non-transmitter
amino acid concentrations in the areas adjacent to the infarct in patients who developed malignant brain edema [23].
In summary, the CT criteria involvement of > 50% of the MCA territory and
other vascular territories, and the presence of a midline shift at the level of the
pineal gland of septum pellucidum represent the most reliable predictors of fatal
neurological deterioration.
651
652
K. E. Wartenberg and S. A. Mayer
Fig. 5. a CT showing hypoattenuation in the total right MCA and ACA territory with effacement of the adjacent sulci and loss of the grey-white matter distinction. b Left: Diffusion-weighted MRI sequence (DWI)
demonstrating restricted diffusion in the right MCA territory compatible with early acute ischemia. Right:
Effacement of the sulci, loss of grey-white matter differentiation and local mass effect on the right lateral
ventricle on the FLAIR sequence corresponding to panel on the left. c DWI (left) and T2-weighted (right)
MRI sequence revealing significant cerebral edema from a left MCA territory infarction seen as hyperintense
signal with effacement of the lateral ventricle and > 2 cm midline shift at the level of the septum pellucidum
Management of Large Hemispheric Infarction
z Acute Management
The mainstay of supportive care for large hemispheric infarction is endotracheal
intubation and mechanical ventilation for airway protection and depressed level of
consciousness. The costs of critical care management of stroke patients treated with
mechanical ventilation has been calculated to be (1996 USD) $ 89 400 for every patient discharged alive, and $ 174 200 for each quality-adjusted life year saved. The
functional status of most survivors is poor, with over 50% left severely disabled
and completely dependent [24]. For this reason, aggressive efforts to attain reperfusion within an early time window or to minimize brain injury are justified. Intravenous recombinant tissue plasminogen activator (rt-PA) administered within 3 hours
of onset of the first stroke symptom is the only FDA approved acute stroke treatment [25]. The PROACT trials demonstrated safety and efficacy of intra-arterially
administered recombinant pro-urokinase within 6 hours of stroke onset. The recanalization rate was 66% with a 10% risk of intracerebral hemorrhage, and the likelihood of survival with a good outcome was significantly increased [26, 27]. Several
other methods to potentially salvage hypoperfused but not yet infarcted brain tissue are currently under investigation, such as bridging of intravenous and intra-arterial t-PA, mechanical thrombus removal, intra-arterial abciximab, stenting, and
angioplasty. Induced hypertension with norepinephrine or phenylephrine augments
cerebral perfusion pressure (CPP) and mean flow velocity and may improve perfusion in areas at risk for further infarction (e.g. the ischemic penumbra) [28]. One
preliminary prospective clinical report indicates that a trial of induced hypertension can result in clinical improvement of neurological signs in 54% of patients,
usually within 20 minutes [29].
z Intensive Care Management
Patients with large hemispheric strokes are best managed in an ICU. The mainstays
of treatment for massive cerebal edema include osmotherapy and hyperventilation
[7, 30]. The goal of osmotherapy is to reduce brain volume by creating an osmotic
gradient between the intracellular and extracellular compartment [7].
Mannitol infusion leads to a reduction in brain water content first by creating an
osmotic gradient between the interstitial and intracellular compartments and the
intravascular space across the semipermeable blood brain barrier. Mannitol also reduces blood viscosity and improves microvascular CBF, which may result in reflex
vasoconstriction and reduced cerebral blood volume, and has free radical scavenger
properties. It has a fast onset of action, which is helpful in cases of impending
transtentorial herniation. The recommended dose is 0.5±1.5 g/kg i.v. every 1 to 6
hours. Complications may include transient intravascular fluid overload, secondary
volume contraction or hypokalemia resulting from the diuretic effect of repeated
doses over longer intervals [7, 30]. In a series of seven patients with large hemispheric infarction the administration of a bolus of 1.5 g/kg mannitol did not have
any effect on midline shift measured by MRI or neurological status [31]. It has also
been suggested that mannitol might have a greater effect on normal rather than infarcted tissue due to a disruption of the blood brain barrier [4]. At least theoretically, this might result in worsening of midline shift as mannitol extravasates in the
infarcted tissue and dehydrates the normal contralateral hemisphere. In clinical
653
654
K. E. Wartenberg and S. A. Mayer
practice, however, this does not occur, and there are animal studies demonstrating
that mannitol dehydrates infarcted tissue at least as effectively as normal brain tissue [32].
Hypertonic saline solutions improve microvascular perfusion and CPP by causing volume expansion, increases in cardiac output and systemic blood pressure,
and decreased production of cerebrospinal fluid (CSF). Hypertonic saline also can
modify inflammatory responses, interact with the neuroendocrine system and expand intracranial elastance. We use continuous infusion of 3% saline solution or
23.4% saline boluses for ICP control in our neurocritical ICU. There are only a few
prospective clinical trials that have investigated the effect of hypertonic saline in
fatal large hemispheric infarctions with conflicting results, and none of these
studies have evaluated functional outcome [30]. In one study, hypertonic saline
hydroxyethyl starch solution successfully decreased elevated ICP by 34% within
15 minutes in patients with space-occupying infarctions [33]. In general, the
administration of hypertonic saline over a longer period seems to be safe in the
absence of renal failure and CHF, though careful monitoring of central venous pressure (CVP) and fluid balance is prudent.
There is no evidence supporting the use of glucocorticoids for the treatment of
brain edema from acute stroke [30]. Barbiturates decrease the cerebral metabolic
rate, resulting in diminished CBF and blood volume with reduction of cerebral
edema formation. The neuroprotective properties (free radical scavenging) of barbiturates make them attractive for the treatment of brain swelling related to ischemia
on a theoretical basis [30], but practical experience suggests that barbiturates may
in fact be harmful when used to control ICP in patients with MCA infarction. Of
60 patients with large hemispheric infarctions who were subjected to barbiturate
coma with thiopental (3±5 mg/kg bolus followed by continuous infusion) to achieve
burst suppression pattern on a continuous electroencephalogram (EEG) for 48
hours, only 5 patients (8%) survived. Thiopental infusion resulted in a decrease of
ICP, which was not sustained and was complicated by arterial hypotension requiring vasopressors, pneumonia, sepsis and hepatic dysfunction [34]. Hypotension in
this setting may have been provoked by previous dehydration from osmotherapy
[7].
Hyperventilation has long been considered a mainstay of management for increased ICP and cerebral edema. Decreased PCO2 (30±35 mmHg) is achieved by increasing the ventilation rate, leading to vasoconstriction, diminished cerebral blood
volume, and lower ICP. This effect is rapid ± a reduction in ICP usually occurs
within 30 minutes ± but may be limited by excessive vasoconstriction resulting in
further cerebral ischemia if the patient is excessively hyperventilated. Normocapnia
should be reinstituted slowly because of a possible rebound effect [7, 30]. Hyperventilation is a useful tool for the acute stabilization of impending herniation, but
is often not effective over longer periods of time.
z Decompressive Surgery
Hemicraniectomy for large hemispheric infarction was first reported in 1935. Horizontal and vertical tissue shifts, and 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 ex-
Management of Large Hemispheric Infarction
tracranially, improves CPP and retrograde flow in the MCA, preserves CBF, and
may prevent further ongoing ischemia. The diameter of the craniectomy should be
at least 12 cm (14 to 15 cm anterior-posterior, and 10 to 12 cm from the temporal
base to the vertex is recommended) [7]. A small diameter hemicraniectomy can result in compression and kinking of bridging veins, or mushroom-like herniation of
the brain with shearing distortion and additional ischemic lesions (Fig. 6) [35].
Fig. 6. CT of a 35 year old woman with left MCA infarction (day 0) who deteriorated clinically and developed additional left ACA territory infarction and significant midline shift to the right on day 2. After decompressive hemicraniectomy the CT showed slight improvement of the midline shift on day 3. On day 5
she proceeded to infarct the left PCA territory because the diameter of the hemicraniectomy was too
small
655
656
K. E. Wartenberg and S. A. Mayer
After resection of the temporal bone to the skull base the dura is opened, adjusted,
and a biconvex dural patch is placed into the incision (duroplasty). Resection of
the infarction is not advisable as the margins between infarct and penumbra are
poorly defined. The bone flap can be conserved in the abdominal subcutaneous tissue or in a cooled sterile isotonic solution. Reimplantation of the bone flap is possible 6 to 12 weeks after removal, once the swelling has resolved. Potential complications include intracranial, wound and bone flap infection, subdural and epidural
hematoma, subdural CSF hygroma, paradoxical herniation after the swelling period
and hydrocephalus [7, 30, 35, 36].
The first prospective but uncontrolled clinical trial of hemicraniectomy included
32 patients with a midline shift of more than 10 mm at the septum pellucidum
level. Most of the patients who underwent decompressive surgery at a mean time of
39 hours after stroke onset suffered a non-dominant MCA territory infarction and
did not have any medical complications. The mortality rate in the surgical group
was 34%. The control group encompassed patients with more severe medical comorbidities and inability to consent and had a mortality rate of 76% [36]. The next
prospective, uncontrolled trial included 31 patients undergoing hemicraniectomy
considerably earlier in the course (within the first 24 hours of symptom onset),
with a mortality rate of 16% [37]. In another prospective, non-randomized series
of 34 patients, mortality at 3 months was 67% in the conservatively managed group
and 16% in the group receiving surgery immediately after the onset of neurological
deterioration [38]. Ultra-early hemicraniectomy performed within 6 hours of stroke
onset in 12 patients resulted in a mortality of 8% compared to 36% in 30 patients
undergoing surgery after 6 hours of symptom onset and 80% in 10 patients managed with maximal medical therapy [39].
Hemicraniectomy is clearly a life-saving procedure. However, analysis of functional outcome of patients after hemicraniectomy has revealed conflicting results.
Multiple case series, clinical trials and a metaanalysis suggest that timing of hemicraniectomy and age of the patients are crucial factors in determining outcome:
Early surgery has a greater impact on reduction of mortality, and young patients
(< 50 years) tend to have a better outcome [37±41]. Although many clinicians are
reluctant to offer hemicraniectomy to patients with dominant hemisphere infarcts,
a meta-analysis found no difference in functional outcome comparing left versus
right-sided [40]. A retrospective analysis of 188 patients identified age 50 years and
involvement of more than one vascular territory as predictors of death among patients undergoing hemicraniectomy [42]. In another analysis of long-term outcomes, none of 36 patients who had a hemicraniectomy attained an independent
outcome at a 6-month follow-up [43].
The HeaDDFIRST (Hemicraniectomy and Durotomy for Deterioration From Infarction Related Swelling Trial) was the first multicenter, prospective, randomized
trial that investigated mortality and functional outcome in patients undergoing
hemicraniectomy versus comprehensive standardized medical therapy. Enrollment
in this study was limited to 26 randomized patients. Mortality was reduced from 46
to 27%, but this reduction was not statistically significant [44]. Two multicenter,
prospective randomized trials comparing hemicraniectomy and medical management are still ongoing:
z DESTINY (Decompressive Surgery for the Treatment of Malignant Infarction of
the Middle Cerebral Artery) and
z HAMLET (Hemicraniectomy After MCA infarction with Life-threatening Edema
Trial).
Management of Large Hemispheric Infarction
z Hypothermia
Mild systemic hypothermia (33±36 8C) can be achieved with surface and intravascular cooling devices. Cooling decreases cerebral metabolism, preserves the blood
brain barrier, and reduces inflammatory responses as well as excitotoxic neurotransmitter release [7, 30]. In 25 patients with large MCA territory infarcts hypothermia (33 8C) was started after an interval of 14 hours after stroke onset and
maintained for 48±72 hours, which significantly reduced the ICP. The patients were
subjected to passive rewarming (17 to 24 hours) which resulted in a continuous rise
in ICP with subsequent herniation and death in 9 patients thought to be attributable to a hypermetabolic response (44% mortality). Complications of hypothermia
included shivering, sepsis, pneumonia, thrombocytopenia, coagulopathy, and elevation of serum amylase and lipase levels. Cardiac arrhythmias, including prolongation of the PR and QT interval, ventricular ectopy and fibrillation, are adverse effects that limit cooling to levels below 32 8C [7, 45].
More gradual controlled rewarming appears to be safer than passive or active rewarming. In one series of MCA infarction patients treated with hypothermia, a
mean temperature increase of 0.1 to 0.2 8C over 2 to 4 hours correlated with a more
gradual increase in ICP and improved cerebral cellular and metabolic compensation
mechanisms [46]. In a large prospective uncontrolled trial of 50 patients undergoing mild-to-moderate hypothermia (32±33 8C) for 72 hours after large hemispheric infarction ICP was significantly reduced [47]. In this study, passive rewarming within 16 hours was associated with a pronounced rise in ICP compared
to controlled rewarming over a longer period of time (> 16 hours) (Fig. 7).
The most common side effects of hypothermia in this study were arrhythmia
(sinus bradycardia, prolonged PR and QT intervals), arterial hypotension, pneumonia, decreased serum potassium, decreased platelet count, and coagulopathy. Mortality was 38% overall. All patients received midazolam and propofol for sedation,
morphine and fentanyl for analgesia, and neuromuscular blockade with vecuronium
and atracurium during hypothermia and rewarming [47].
In summary, the use of hypothermia for control of cerebral edema in large
hemispheric infarction is feasible, but the risks are prominent. It seems most likely
that cooling shows greater promise as an acute intervention designed to reduce infarct volume, than a primary form of treatment for malignant brain edema.
Fig. 7. ICP levels after rewarming of different durations (> 16 and < 16 hours). From [47] with permission
657
658
K. E. Wartenberg and S. A. Mayer
z Conclusion
Space-occupying edema after large hemispheric infarctions is difficult to control
with conservative intensive medical management including osmotherapy, hyperventilation and barbiturate coma. It is of major importance to predict which patients
may experience severe neurological deterioration from tissue shifts and edema expansion.
Decompressive surgery is extremely effective in decreasing mortality, especially
when performed early in the course, but the quality of life of those who survive
may be poor, particularly if the patient is older than 50 years. Hypothermia is a
promising additional tool for short-term ICP control but our experience suggests
that it is not as robust as hemicraniectomy as a life-saving procedure for patients
with malignant edema.
Additional research is needed to develop ICU treatment strategies that minimize
brain edema and the need for hemicraniectomy among victims of large hemispheric infarction.
References
1. Hacke W, Schwab S, Horn M, Spranger M, De Georgia M, von Kummer R (1996) `Malignant' middle cerebral artery territory infarction: Clinical course and prognostic signs. Arch
Neurol 53:309±315
2. Kasner SE, Demchuk AM, Berrouschot J, et al (2001) Predictors of fatal brain edema in
massive hemispheric ischemic stroke. Stroke 32:2117±2123
3. Qureshi AI, Suarez JI, Abutaher MY, et al (2003) Timing of neurologic deterioration in massive middle cerebral artery infarction: A multicenter review. Crit Care Med 31:272±277
4. Frank JI (1995) Large hemispheric infarction, deterioration, and intracranial pressure. Neurology 45:1286±1290
5. Berrouschot J, Sterker M, Bettin S, Kæster J, Schneider D (1998) Mortality of space-occupying (`malignant') middle cerebral artery infarction under conservative intensive care. Intensive Care Med 24:620±623
6. Heinsius T, Bogousslavsky J, Van Melle G (1998) Large infarcts in the middle cerebral artery
territory: Etiology and outcome patterns. Neurology 50:341±350
7. Steiner T, Ringleb P, Hacke W (2001) Treatment options for large hemispheric stroke. Neurology 57 (Suppl 2):S61±S68
8. Ropper AH, Shafran B (1984) Brain edema after stroke. Clinical outcome and intracranial
pressure. Arch Neurol 41:26±29
9. Ayata C, Ropper AH (2002) Ischaemic brain oedema. J Clin Neurosci 9:113±124
10. Von Kummer R, Nolte PN, Schnittger H, Thron A, Ringelstein EB (1996) Detectability of
cerebral hemisphere ischaemic infarcts by CT within 6 h of stroke. Neuroradiology 38:31±33
11. Moulin T, Cattin F, Crepin-Leblond T, et al (1996) Early CT signs in acute middle cerebral
artery infarction: Predictive value for subsequent infarct locations and outcome. Neurology
47:366±375
12. Thomalla GT, Kucinski T, Schoder V, et al (2003) Prediction of malignant middle cerebral
artery infarction by early perfusion- and diffusion-weighted magnetic resonance imaging.
Stroke 34:1892±1900
13. Haring HP, Dilitz E, Pallua A, et al (1999) Attenuated corticomedullary contrast: An early
cerebral computed tomography sign indicating malignant middle cerebral artery infarction.
A case control study. Stroke 30:1076±1082
14. Pullicino PA, Alexandrov AV, Shelton JA, Alexandrova NA, Smurawska LT, Norris JW (1997)
Mass effect and death from severe acute stroke. Neurology 49:1090±1095
15. Oppenheim C, Samson Y, Mana R (2000) Prediction of malignant middle cerebral artery infarction by diffusion-weighted imaging. Stroke 31:2175±2181
Management of Large Hemispheric Infarction
16. Krieger DW, Demchuk AM, Kasner SE, Jauss M, Hantson L (1999) Early clinical and radiological predictors of fatal brain swelling in ischemic stroke. Stroke 30:287±292
17. Kucinski T, Koch C, Gryzska U, Freitag HJ, Kræmer H, Zeumer H (1998) The predictive
value of early CT and angiography for fatal hemispheric swelling in acute stroke. Am J
Neuroradiol 19:839±846
18. Firlik AD, Yonas H, Kaufmann AM, et al (1998) Relationship between cerebral blood flow
and the development of swelling and life-threatening herniation in acute stroke. J Neurosurg
89:243±249
19. Berrouschot J, Barthel H, von Kummer R, Knapp WH, Hesse S, Schneider D (1998) 99m
technetium-ethyl-cysteinate-dimer single-photon emission CT can predict fatal ischemic
brain edema. Stroke 29:2556±2562
20. Schneweis S, Grond M, Staub F, et al (2001) Predictive value of neurochemical monitoring
in large middle cerebral artery infarction. Stroke 32:1863±1867
21. Berger C, Annecke A, Aschoff A, Spranger M, Schwab S (1999) Neurochemical monitoring
of fatal middle cerebral artery infarction. Stroke 30:460±463
22. Heiss WD, Dohmen C, Sobesky J, et al (2003) Identification of malignant brain edema after
hemispheric stroke by PET-imaging and microdialysis. Acta Neurochir 86:237±240
23. Bosche B, Dohmen C, Graf R, et al (2003) Extracellular concentrations of non-transmitter
amino acids in peri-infarct tissue of patients predict malignant middle cerebral artery infarction. Stroke 34:2908±2915
24. Mayer SA, Copeland D, Bernardini GL, et al (2000) Cost and outcome of mechanical ventilation for life-threatening stroke. Stroke 31:2346±2353
25. The National Institute of Neurological Disorders, and Stroke rt-PA Study Group (1995) Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 333:1581±1587
26. Del Zoppo GJ, Higashida RT, Furlan AJ, et al (1998) PROACT: A phase II randomized trial
of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery
stroke. Stroke 29:4±11
27. Furlan AJ, Higashida RT, Wechsler LR (1999) Intra-arterial prourokinase for acute ischemic
stroke: The PROACT study: A randomized controlled trial. JAMA 282: 2003±2011
28. Schwarz S, Georgiadis D, Aschoff A, Schwab S (2002) Effects of induced hypertension on intracranial pressure and flow velocities of the middle cerebral arteries in patients with large
hemispheric stroke. Stroke 33:998±1004
29. Rordorf G, Koroshetz WJ, Ezzeddine MA, Segal AZ, Buonnanno FS (2001) A pilot study of
drug-induced hypertension for treatment of acute stroke. Neurology 56:1210±1213
30. Hofmeijer J, van der Worp B, Kappelle J (2003) Treatment of space-occupying cerebral infarction. Crit Care Med 31:617±625
31. Manno EM, Adams RE, Derdeyn CP, Powers WJ, Diringer MN (1999) The effects of mannitol on cerebral edema after large hemispheric cerebral infarct. Neurology 52: 583±587
32. Paczynski RP, He YY, Diringer MN, Hsu CY (1997) Mulitple-dose mannitol reduces brain
water content in a rat model of cortical infarction. Stroke 28:1437±1443
33. Schwarz S, Schwab S, Bertram M, Aschoff A, Hacke W (1998) Effects of hypertonic saline
hydroxyethyl starch solution and mannitol in patients with increased intracranial pressure
after stroke. Stroke 29:1550±1555
34. Schwab S, Spranger M, Schwarz S, Hacke W (1997) Barbiturate coma in severe hemispheric
stroke: useful or obsolete? Neurology 48:1608±1613
35. Wagner S, Schnippering H, Aschoff A, Koziol JA, Schwab S, Steiner T (2001) Suboptimum
hemicraniectomy as a cause of additional cerebral lesions in patients with malignant infarction of the middle cerebral artery. J Neurosurg 94:693±696
36. Rieke K, Schwab S, Krieger D, et al (1995) Decompressive surgery in space-occupying hemispheric infarction: Results of a open, prospective trial. Crit Care Med 23:1576±1587
37. Schwab S, Steiner T, Aschoff A, et al (1998) Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke 29:1888±1893
38. Mori K, Aoki A, Yamamoto N, Horinaka N, Maeda M (2001) Aggressive decompressive surgery in patients with massive hemispheric embolic cerebral infarction associated with severe brain swelling. Acta Neurochir (Wien) 143:483±492
39. Cho DY, Chen TC, Lee HC (2003) Ultra-early decompressive craniectomy for malignant
middle cerebral artery infarction. Surg Neurol 60:227±233
659
660
K. E. Wartenberg and S. A. Mayer: Management of Large Hemispheric Infarction
40. Gupta R, Connolly ES, Mayer SA, Elkind MSV (2004) Hemicraniectomy for massive middle
cerebral artery territory infarction: A systematic review. Stroke 35:539±543
41. Walz B, Zimmermann C, Bættger S, Haberl RL (2002) Prognosis of patients after hemicraniectomy in malignant middle cerebral artery infarction. J Neurol 249:1183±1190
42. Uhl E, Kreth FW, Elias B, et al (2004) Outcome and prognostic factors of hemicraniectomy
for space occupying cerebral infarction. J Neurol Neurosurg Psychiatry 75:270±274
43. Foerch C, Lang JM, Krause J, et al (2004) Functional impairment, disability, and quality of
life outcome after decompressive hemicraniectomy in malignant middle cerebral artery infarction. J Neurosurg 101:248±254
44. Frank JI, Chyatte D, Thisted R, et al (2003) Hemicraniectomy and durotomy upon deterioration from infarction related swelling trial (HeADDFIRST): First public presentation of the
primary study findings. Neurology 60 (Suppl 1):S52.004
45. Schwab S, Schwarz S, Spranger M, Keller E, Bertram M, Hacke W (1998) Moderate hypothermia in the treatment of patients with severe middle cerebral artery infarction. Stroke
29:2461±2466
46. Steiner T, Friede T, Aschoff A, Schellinger PD, Schwab S, Hacke W (2001) Effect and feasibility of controlled rewarming after moderate hypothermia in stroke patients with malignant infarction of the middle cerebral artery. Stroke 32: 2833±2835
47. Schwab S, Georgiadis D, Berrouschot J, Schellinger PD, Graffagnino C, Mayer SA (2001)
Feasibility and safety of moderate hypothermia after massive hemispheric infarction. Stroke
32:2033±2035