Review Hemicraniectomy for malignant middle cerebral artery infarction: Current status and future directions Hermann Neugebauer* and Eric Jüttler Malignant middle cerebral artery infarction is a lifethreatening sub-type of ischemic stroke that may only be survived at the expense of permanent disability. Decompressive hemicraniectomy is an effective surgical therapy to reduce mortality and improve functional outcome without promoting most severe disability. Evidence derives from three European randomized controlled trials in patients up to 60 years. The recently finished DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY – II trial gives now high-level evidence for the effectiveness of decompressive hemicraniectomy in patients older than 60 years. Nevertheless, pressing issues persist that need to be answered in future clinical trials, e.g. the acceptable degree of disability in survivors of malignant middle cerebral artery infarction, the importance of aphasia, and the best timing for decompressive hemicraniectomy. This review provides an overview of the current diagnosis and treatment of malignant middle cerebral artery infarction with a focus on decompressive hemicraniectomy and outlines future perspectives. Key words: decompressive surgery, hemicraniectomy, malignant, middle cerebral artery infarction, space-occupying
Introduction Malignant middle cerebral artery infarction (MMI) has an estimated yearly incidence of 10–20/100·000 (1). Most often, thrombotic or embolic occlusion of the internal carotid artery or the proximal middle cerebral artery (MCA) results in sub-total or complete infarction of the MCA territory. Depending on the intracranial vascular status and collateralization, the territories of the anterior cerebral artery (ACA) and/or posterior cerebral artery are additionally involved (2,3). Occlusion of the ACA and anterior choroidal artery, ipsilateral abnormalities of the circle of Willis, and the combined involvement of the superficial and deep MCA territory are more frequently associated with malignant infarction, whereas the presence of a prominent anterior temporal artery is considered to be associated with smaller infarcts (3–5). Malignant middle cerebral artery infarction represents a devastating sub-group of severe ischemic stroke that is usually fatal under medical treatment and, in the case of survival, always associated with long-term disability (1). The hallmark of MMI is the relentless formation of early cytotoxic and late vasogenic and interstitial space-occupying edema (6). Maximal brain swelling Correspondence: Hermann Neugebauer*, Department of Neurology, RKU – University and Rehabilitation Hospitals Ulm, Oberer Eselsberg 45, Ulm 89081, Germany. E-mail: [email protected] Department of Neurology, RKU – University and Rehabilitation Hospitals, Ulm, Germany Received: 30 July 2013; Accepted: 8 September 2013; Published online 11 April 2014 Conflict of interest: None declared. DOI: 10.1111/ijs.12211
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may occur early but generally peaks around the second and fifth day after stroke onset (2). In contrast to the general belief, extensive edema formation in MMI is not accompanied by a critical increase in global intracranial pressure (ICP) in the majority of cases (7). Death results from transtentorial and transforaminal herniation in up to 80% of patients under standard and under intensive medical care within the first week of onset (1,2). Conservative and intensive care treatment such as ICP lowering therapy, deep sedation, body positioning, controlled hyperventilation, and even therapeutic hypothermia (TH) fail to substantially lower this high mortality rate (8–11). So far, only early decompressive hemicraniectomy (DHC) within 48 h of stroke onset has been shown to be effective in lowering mortality and improving outcome in randomized controlled trials. As a result, utilization of DHC increased steadily in the last years, but the total numbers of procedures remained low (0·15–0·3%) (12–15). According to clinicopathological and epidemiological studies, patients with MMI are about 10 years younger than the average ischemic stroke patient (56 ± 9·4 years, 66 ± 17 years, 71·0 years range 46·0–92·0) (1,3,13). At the same time, at least 28–40% of patients with MMI are older than 60 years (16). Only patients up to 60 years of age were included in the randomized trials on DHC (9–11,17,18). Higher age was found to be associated with much poorer outcome in observational studies and is the major reason why older patients are considered ineligible for DHC (4,15,19,20). Nevertheless, 30% of all hemicraniectomy procedures are currently performed in this age group (14), although uncertainty on the effectiveness remains because of the lack of data from randomized controlled trials. Therefore, the results of the most recently published DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY – II (DESTINY-II) trial in patients older than 60 years were eagerly awaited (21). In this review, we outline the current status of diagnosis and treatment of MMI, as well as perspectives on future directions.
Diagnosis and early prediction of malignant MCA infarction The term ‘malignant MCA infarction’ was already introduced in 1996 describing a severe MCA syndrome with typical clinical symptoms, following a uniform clinical course, and ending in herniation (1). However, early after symptom onset and before signs of herniation occur, there is no generally accepted definition of this condition. This lack of a clear definition is somehow superseded by the uniform inclusion criteria of the three European randomized controlled trials on hemicraniectomy: DEcompresssive Craniectomy In MALignant middle cerebral artery infarcts (DECIMAL), the Dutch Hemicraniectomy After Middle cerebral Artery infarction with Life-threatening Edema Trial (HAMLET), and the German DEcompressive Surgery for the Treatment of © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
H. Neugebauer and E. Jüttler malignant INfarction of the middle cerebral artery trial (DESTINY) (9–11). Based on the inclusion and exclusion criteria of these trials, the diagnosis of a ‘malignant MCA infarction’ is currently made by assessing clinical presentation at stroke onset, the clinical course, and neuroimaging findings. These include: 1. clinical signs of a severe unilateral MCA infarction, including eye and head deviation, contralateral hemiplegia and hypo- or anesthesia, frequent hemianopia, always multimodal neglect, and global aphasia in case of dominant hemispheric infarction; 2. decreased level of consciousness: either from the beginning or progressively deteriorating over the first 24–48 h (a score of ≥1 as assessed in item 1a of the National Institutes of Health Stroke Scale [NIHSS], or a score of 15 (DECIMAL), or >20 (DESTINY, HAMLET); NIHSS score (in infarctions of the nondominant hemisphere): >15 (DECIMAL, HAMLET), >18 (DESTINY); 4. infarction of the MCA territory of ≥50% (DECIMAL), or >2/3 (DESTINY, HAMLET), or infarct volume on diffusion-weighted imaging (DWI) of >145 ml (DECIMAL); and 5. involvement of the basal ganglia (DESTINY). The effectiveness of early DHC within 48 h of stroke onset has raised interest in finding other reliable, more specific, and more sensitive early predictors of MMI to enable early selection of patients who may benefit from DHC. Hofmeijer et al. provide a comprehensive overview on the value of clinical parameters and neuroimaging: Infarct size of more than 50% and perfusion deficit larger than 66% of the MCA territory are the major early determinants of MMI. From a clinical point of view, the need for mechanical ventilation strongly predicts extensive edema. However, none of these factors provide sufficient positive predictive values (PPVs) to reliably select patients for DHC (22). Compared with computed tomography (CT), magnetic resonance imaging (MRI) seems to allow a more accurate prediction of MMI. Two retrospective studies reported high predictive values for infarct sizes larger than 145 ml on DWI and 82 ml on apparent diffusion coefficient maps (23,24). The latter finding was reproduced in a prospective multicenter study with a high PPV but low sensitivity (0·88 vs. 0·52). Of note, DWI volume is more accurate in the early prediction of MMI than multivariate models including vessel status and stroke severity (0·89 vs. 0·88) (25). In contrast, after 24 h from stroke onset, stroke severity (NIHSS scores of >21) enhances the predictive value of DWI (0·93 vs. 0·79) (26). Concerning the lack of sensitivity of DWI-lesion size in predicting MMI, a recent positron emission tomography study suggested that edema formation is not only a function of the size of the perfusion deficit but also of its severity. The specific sub-volumes of areas with severely reduced cerebral blood flow (CBF) identified patients with MMI in 100%. The severity of CBF reduction is thought to determine the extent of blood–brain barrier (BBB) breakdown, which correlates to the extent of vasogenic edema (27). Likewise, increased serum levels of molecular markers of BBB disruption, i.e. cellular-fibronectin and matrix metalloproteinase-9 are associated with MMI (28–30). A different approach in predicting MMI is based on evaluating the intracra© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
Review nial volume reserve (cerebrospinal fluid) in addition to the infarct volume with perfusion CT (96·2% sensitivity and PPV) (31). However, the promising results of this retrospective single-center analysis need to be validated in larger prospective studies. The retrospective single-center experience is also the major drawback of electrophysiological studies on electroencephalogram (EEG), evoked potentials (EPs), and autonomic function that found moderate predictive values of the coexistence of background slowing on EEG, pathological brainstem auditory EP, and a decreased baroreflex sensitivity (32,33). Studies investigating multimodal neuro-biochemical monitoring, EEG power spectrum, and cortical spreading depolarization require invasive procedures and are not available in many centers in clinical routine or outside an experienced intensive care unit.
DHC in the treatment of malignant MCA infarction DHC as surgical procedure The rational behind early DHC is to create external space for the expanding edema before compression of formerly healthy brain tissue occurs. The diameter of craniectomy should measure at least 12 cm corresponding to an additional edema volume of 80–100 ml (34). Smaller craniotomies are insufficient and may lead to venous infarction at the bone margins, hemorrhages, and herniation through the craniotomy (35). Delayed complications despite sufficient craniotomy include the sinking skin flap syndrome, extra-axial fluid collections, hydrocephalus, epi- or subdural hematomas, infections, and skin or muscle necrosis (36). In addition to external DHC, some authors advocate for an internal decompression by removing infarcted, nonviable tissue (strokectomy) especially the resection of the temporal lobe (37). However, as long as the safety and efficacy of internal decompression has not been proven in prospective trials, external decompression is recommended as the treatment of choice (38). It should be emphasized that DHC is safe after intravenous/intra-arterial (IA) thrombolysis and/or IA thrombectomy and that bleeding complications are rather associated with prior antiplatelet therapy (39–41). DHC: treatment goals Given that MMI is a fatal disease that can only be survived at the expense of permanent disability, the aims of any treatment can only be: first, to safe the patient’s life [modified Rankin score (mRS) 0–5]; second, without the price of survival with very severe disability or inacceptable clinical status (mRS 0–4); third, if possible, to improve functional outcome and reduce severe dependency (mRS 0–3). DHC: randomized controlled trials Meanwhile, seven randomized controlled trials were successfully performed between 2000 and 2013 comparing DHC to standard intensive care [Hemicraniectomy And Durotomy upon Deterioration From Infarction Related Swelling Trial (HeADDFIRST); DEcompressive surgery for the treatment of Malignant Infarction of the middle cerebral artery: a randomized, controlled trial in a TURkish population (DEMITUR TRIAL); DECIMAL; HAMLET; DESTINY; DESTINY-II and Decompressive hemicraniectomy in malignant middle cerebral artery infarct: a randomized controlled Vol 9, June 2014, 460–467
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Review trial enrolling patients up to 80 years old], five of which have officially been published (9–11,21,42). The Chinese study by Zhao et al. was not prospectively registered and end-points, sample size calculation, outcome assessment, sub-groups, and statistical analysis are not prespecified. Sub-group analyses were not powered to show statistical significant differences in outcome, and the study is critical from an ethical point of view, because it was started almost exactly copying the protocol of HAMLET and DESTINY when these trials were already published and the treatment effect was known (42). The HeADDFIRST trial and the DEMITUR TRIAL were completed but not officially published so far.* Data are available from conferences or via Internet. The Hemicraniectomy for Malignant Middle cerebral artery Infarction (HEMMI) trial is still ongoing (see Table 1). DHC in patients 18–60 years of age DECIMAL and DESTINY were stopped prematurely because of a marked difference in mortality and the possibility to perform a prospectively planned pooled analysis including data from the ongoing HAMLET trial (9–11). This prospective pooled analysis provides class one evidence for DHC in patients up to 60 years (17): The number needed to treat (NNT) to avoid death (mRS score 6) is 2, to avoid death, or most severe, dependency (mRS score 5 or 6) is 2, and to avoid death most severe and moderately severe disability (mRS 4–6) is 4. The results of the randomized controlled trials are consistent with comparative data from nonrandomized studies and could be reproduced in a medical center without previous experience with DHC in all day clinical practice (19,34,43,44). After the final publication of HAMLET, two metaanalyses including different sets of patients from HAMLET were published. Both meta-analyses were post hoc and not stratified by time since stroke onset. Furthermore, mortality rates in patients treated before and after 48 h of stroke onset in HAMLET differed significantly (11,18). In contrast, pooled data from DESTINY and DECIMAL show the same significant reduction of mortality (mRS 0–5: NNT 2), most severe disability (mRS 0–4: NNT 2), and severe disability at 12 months (mRS 0–3: NNT 4) as the prospective pooled analysis (9,10,17). DHC in patients older than 60 years In the past several nonrandomized case series, retrospective studies and systematic reviews suggested that higher age is an important predictor of unfavorable outcome in MMI with proposed upper age limits between 50 and 60 years (4,19). In the pooled analysis of DECIMAL, HAMLET, and DESTINY, no significantly reduced effectiveness of DHC was observed in patients between 50 and 60 years of age. However, the studies were underpowered to detect such a difference (9–11,17). The study by Zhao et al. showed significantly reduced mortality and most severe disability also in patients older than 60 years. However, these data come from an underpowered sub-group analysis of patients, which was not predefined, comparing 16 patients treated with *HeADDFIRST was finally published in the March 2014 issue of Stroke (Frank JI1, Schumm LP, Wroblewski K, et al. Hemicraniectomy and durotomy upon deterioration from infarction-related swelling trial: randomized pilot clinical trial. Stroke 2014;45:781–7).
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H. Neugebauer and E. Jüttler DHC vs. 13 patients treated conservatively, of whom two-thirds were 61–70 years old (42). To adequately assess the possible benefits of DHC in patients older than 60 years, the DESTINY-II trial, a randomized controlled trial with independent end-point assessment and a sequential interim analysis design, was conducted (21). The inclusion criteria paralleled those of the DESTINY trial. In accordance with the pooled analysis of DECIMAL, HAMLET, and DESTINY, the primary end-point was functional outcome on the mRS dichotomized into 0–4 vs. 5–6 after six-months. Secondary outcome measures were mRS 0–3 vs. 4–6 at 12 months, mortality, time of survival, health outcome, quality of life, retrospective consent, and rate of depression. The trial was stopped after assessment of the primary end-point of the 82nd patient on the basis of the six-months outcomes. Meanwhile, another 30 patients had been included, and data from 112 patients were evaluated in the final analysis. DESTINY-II met its primary endpoint: early DHC within 48 h of stroke onset in patients older than 60 years with MMI is associated with a significant increase in survival without most severe disability (mRS 38% vs. 18%, NNT 5) particularly because of a significant reduction in mortality. The high number of patients with most severe disability (mRS 5) at 6 months was reduced to 19% at 12 months mainly because some of these patients deceased. Nevertheless, one-third of the survivors suffered from this state of complete dependency. About one-half of the survivors suffered from moderately severe disability (mRS score of 4). Only 6% of the survivors were moderately disabled (mRS score of 3), and no patient achieved independency. There were no differences between the treatment groups with regard to the secondary outcome measures in a survivor-based analysis. Retrospective consent to treatment was high in both treatment groups (63% vs. 53%). However, 60% of survivors could not adequately answer this question. The results of DESTINY-II show that DHC is a life-saving procedure also in patients older than 60 years and increases the chance to survive without complete dependency. However, whereas case fatality among older patients is comparable with younger patients under intensive care treatment, outcome after DHC is clearly worse.
Controversies and future directions in DHC for malignant MCA infarction Functional outcome Immediately after the publication of the pooled analysis of DECIMAL, HAMLET, and DESTINY, the scientific community initiated a debate as to whether an mRS of 4 – unable to walk and unable to attend to own bodily needs without assistance – may be called ‘favorable’ (45). With the results from the DESTINY-II trial, this discussion will revive. In the light of a devastating disease such as MMI, where the choice is between permanent moderate to severe disability and death, the definition of favorable outcome on the basis of the mRS, done by healthy academics, may probably not sufficiently address the issue. The mRS has a strong focus on motor abilities and has a neglect for neuropsychological functions and quality of life (46). It is also well known that disabled people indicate a higher quality of life compared with healthy subjects who are asked to imagine comparable situations and that the © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
02/2004–10/2005
12/2000–11/2005
09/2002–10/2007
DESTINY9
DECIMAL10
HAMLET11
09/2002–10/2007
09/2002-recruiting
HeMMI
– HAMLET
01/2003–12/2007
DEMITUR TRIAL
09/2002–10/2007
05/2000–03/2003
HeADDFIRST
– HAMLET
Duration
Trial/Analysis
18–80 NIHSS > 16/18# 2/3 MCA+ 18–65 MCA stroke and GCS < 6–14/5–9# or NIHSS Item 1a > 0 18–60 y NIHSS > 18/20# & Item 1a > 0 >2/3 MCA+ 18–55 y NIHSS > 15 & Item 1a > 0 >1/2 MCA & DWI > 145 ml 18–60 y NIHSS > 15/20# GCS < 14/10# >2/3 MCA 18–60 y NIHSS > 15/20# >2/3 MCA 18–60 y NIHSS > 15/20# >2/3 MCA
18–75 y NIHSS > 17 Item 1a < 2 > 1/2 MCA w/i 5 h or 3/3 MCA w/i 48 h
Eligibility Criteria
25
39
12 h–2/3 MCA & edema formation >60 y NIHSS > 15/20# >2/3 MCA+
48 h
DESTINY n = 32 DECIMAL n = 38 HAMLET n = 23 DESTINY n = 32 DECIMAL n = 38 HAMLET n = 39 DESTINY n = 32 DECIMAL n = 38 HAMLET n = 64 DESTINY n = 32 DECIMAL n = 28
48 h
48 h
43 h
99 h
48 h
Tx w/i
Eligibility Criteria
112
47
70
134
109
93
(n)
mRS 0–4 vs. 5–6 at 6 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–4 vs. 5–6 at 12 months
mRS 0–4 vs. 5–6 at 6 months mRS 0–3 vs. 4–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
Primary/ Secondary Endpoint
38 38
75
67 25
51 76
38 68
40 75
43 75
DHC
18 16
13
17 9
23 27
25 34
24 33
21 24
Conservative
Functional Outcome (%)
20* 22*
62*
49* 16
29* 48*
13 34*
16 42*
23* 51*
ARR (%)
43
17
23
22
21
22
DHC
76
70
63
63
71
71
Conservative
Mortality at 12 mo (%)
33*
53*
40*
41*
50*
50*
ARR (%)
Randomized controlled trials and pooled/meta-analyses are listed by content. Data from the HAMLET trial are additionally subdivides into data from patients treated before/after 48 hours. Number of patients from the HAMLET trial included in the different analyses and primary study endpoints are printed in bold letters. Data in brackets have not officially been published in peer-reviewed journals: Results of the HeADDFIRST trial were presented at the 55th Annual AAN Meeting in 2003 [HeADDFIRST was finally published in the March 2014 issue of Stroke (Frank et al. Stroke 2014;45:781–7)], results of the DEMITUR TRIAL are reported on www.strokecenter.org/trial/clinicalstudies. Abbreviations: HeADDFIRST = Hemicraniectomy And Durotomy upon Deterioration From Infarction Related Swelling Trial, DEMITUR TRIAL = DEcompressive surgery for the treatment of Malignant Infarction of the middle cerebral artery in a TURkish population, HeMMI = Hemicraniectomy for Malignant Middle cerebral artery Infarction, DECIMAL = the French DEcompresssive Craniectomy In MALignant middle cerebral artery infarcts, DESTINY = the German DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral artery trial, HAMLET = the Dutch Hemicraniectomy After Middle cerebral Artery infarction with Life-threatening Edema Trial, NIHSS = National Institute for Health Stroke Scale, MCA = middle cerebral artery, DWI = diffusion weighted imaging, Tx w/i = Treatment within, mo = months, mRS = modified Rankin Scale, DHC = decompressive hemicraniectomy, ARR = absolute risk reduction; #non-dominant/dominant hemisphere, +at least partial involvement of the basal ganglia, *statistical significant.
DESTINY-II
2009
Meta-Analysis HAMLET11 (retrospective) Meta-Analysis Mitchel P et al.18 (retrospective) Pooled Analysis (DESTINY and DECIMAL) Zhao et al. 201242
21
2007
Pooled Analysis17 (prospective)
2009
Duration
Trial/Analysis
Table 1 Continued
Review H. Neugebauer and E. Jüttler
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Review
H. Neugebauer and E. Jüttler
involved in the treatment of MMI and of important relevance in treatment decision.
capacity to cope with a life-changing experience is generally underestimated (47,48). The more adequate question instead of defining favorable vs. unfavorable outcome may therefore be: what degree of disability is ‘still acceptable’ for the individual survivor of MMI. A systemic review on quality of life and outcome satisfaction of survivors after DHC reported that the majority of survivors and caregivers (76·6%) expressed satisfaction with life despite moderate severe disability (mRS = 4) or most severe disability (mRS = 5) in more than 50% of those patients (49). These results are congruent with what is seen in the DESTINY-II trial. Given the high rate of retrospective consent, at least some patients who survived with a mRS of 5 must retrospectively have agreed to their treatment. In younger patients, DHC is associated with more qualityadjusted life-years than medical treatment (50). The reason for the obvious discrepancy of functional disability and satisfaction with treatment is most likely because psychosocial functions such as the premorbid personality, cultural background and lifestyle of the patient, the presence of a strong social and/or family support, and the absence of poststroke depression are important factors in perceiving life worth living (46,51,52). Psychosocial functions are less impaired after malignant MCA infarction than physical functions and successful coping and external support seem to correlate with quality of life and treatment satisfaction (46,49,51–54). In this connection special attention should be made to poststroke depression. It is common in survivors of malignant MCA infarction (56·1%, range 20–81·8%), correlated with impaired healthrelated quality of life and functional outcome, associated with lower rates of retrospective consent, and unfortunately still not treated sufficiently in many survivors of MMI (49,52,55). It has to be noted that most data on quality of life after MMI were derived from heterogeneous, retrospective, and uncontrolled case series. The ongoing DESTINY-R study – an international, multicenter, prospective ‘Registry’ – aims to collect data on functional outcome, retrospective consent, quality of life, and risk factors for predicting outcome, but first results are not to be expected until 2015 (56). Until then, data on quality of life and treatment satisfaction should be presented in addition to rates of disability and mortality in an unbiased way to patients and/or their surrogates, who should outweigh risks and benefits of DHC and make their own decision accordingly.
Summary
Side of infarction The side of the infarction is a common surrogate for the presence of aphasia (dominant hemisphere), and it is of intuitive sense to consider the loss of communication skills in treatment decisions after MMI. Data from the randomized controlled trials including DESTINY-II, systematic reviews, and case series do not find differences in functional outcome, retrospective consent, or quality of life between patients with dominant and nondominant hemispheric infarction (4,9–11,17,19,42). Aphasia frequently improves over time and rarely remains complete after MMI (53,57). In contrast, neuropsychological deficits and depression are common also in nondominant hemispheric infarction and impact negatively on recovery and rehabilitation (52,53,58). Nevertheless, the presence of aphasia is still of special concern among physicians
Decompressive hemicraniectomy is increasingly utilized in the treatment of MMI even though absolute numbers of procedures remain low. Latest neuroradiological studies suggest a reliable early prediction of MMI by infarct size in MRI, severity of perfusion deficit, and intracranial reserve volume. The effectiveness of DHC in the treatment of younger patients with MMI could be reproduced in older patients by the DESTINY-II trial, although the treatment effect is much smaller. With older patients suffering a worse outcome after DHC, the debate as to which degree of functional outcome is still acceptable in survivors is brought back to the fore. It is hoped that ongoing and future trials will answer further questions such as long-term quality of life, the importance of aphasia, the best timing of DHC, and the further reduction of early mortality.
© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
Early mortality Although DCH is considered a live-saving procedure, still more than 20% of younger and more than 40% of older patients die despite surgery (17). This clearly calls for improved intensive care treatment of these patients. TH is an antiedematous and neuroprotective therapy with proven efficacy in global hypoxia. Data from observational studies suggest that TH may also be effective in MMI, reducing early mortality to about 40% (59). The obvious consequence may be the combination of DHC and TH, which has been tested in smaller studies showing promising results (60). To further test this approach, the DEcompressive surgery Plus hypoTHermia for Space-Occupying Stroke (DEPTH-SOS), a multicenter randomized controlled phase II trial, is currently recruiting patients (61). Results are expected for 2015. Timing of surgery There is some evidence from nonrandomized prospective studies that early DHC within 24 h (vs. 48 h) and/or ultra-early DHC within six-hours from symptom onset may further reduce mortality in MMI (62,63). Other case series find no difference in early vs. delayed DHC (4,19). The randomized controlled trials on DHC and the pooled analyses only provide evidence for early treatment of patients with MMI, i.e. within 48 h from symptom onset (9–11). In the HAMLET trial, patients could be treated up to 96 h of symptom onset (11). In these patients, no benefit of DHC was observed, which is often misinterpreted as the ineffectiveness of delayed DHC. However, the lack of an effect in the late time window in HAMLET is rather due to the low mortality rates in the control group of 36% as compared with 78% in patients randomized within 48 h. This points to a bias in the selection of patients in the later time window in HAMLET and does not justify dismissing delayed DHC as ineffective. As long as there are no randomized comparative data, the effect of delayed DHC remains uncertain. Because early DHC is effective, there is currently no indication for a wait-and-see strategy (i.e. waiting for midline shift or further clinical deterioration) once the diagnosis of MMI has been made.
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H. Neugebauer and E. Jüttler 22 Hofmeijer J, Algra A, Kappelle LJ, van der Worp HB. Predictors of life-threatening brain edema in middle cerebral artery infarction. Cerebrovasc Dis 2008; 25:176–84. 23 Oppenheim C, Samson Y, Manaï R et al. Prediction of malignant middle cerebral artery infarction by diffusion-weighted imaging. Stroke 2000; 31:2175–81. 24 Thomalla GJ, Kucinski T, Schoder V et al. Prediction of malignant middle cerebral artery infarction by early perfusion- and diffusionweighted magnetic resonance imaging. Stroke 2003; 34:1892–9. 25 Thomalla G, Hartmann F, Juettler E et al. Prediction of malignant middle cerebral artery infarction by magnetic resonance imaging within 6 hours of symptom onset: a prospective multicenter observational study. Ann Neurol 2010; 68:435–45. 26 Kruetzelmann A, Hartmann F, Beck C et al. Combining magnetic resonance imaging within six-hours of symptom onset with clinical follow-up at 24 h improves prediction of ‘malignant’ middle cerebral artery infarction. Int J Stroke 2013; doi: 10.1111/ijs.12060. [Epub ahead of print]. 27 Dohmen C, Galldiks N, Bosche B, Kracht L, Graf R. The severity of ischemia determines and predicts malignant brain edema in patients with large middle cerebral artery infarction. Cerebrovasc Dis 2012; 33:1–7. 28 Bektas H, Wu TC, Kasam M et al. Increased blood-brain barrier permeability on perfusion CT might predict malignant middle cerebral artery infarction. Stroke 2010; 41:2539–44. 29 Bang OY, Saver JL, Alger JR et al. Patterns and predictors of bloodbrain barrier permeability derangements in acute ischemic stroke. Stroke 2009; 40:454–61. 30 Serena J, Blanco M, Castellanos M et al. The prediction of malignant cerebral infarction by molecular brain barrier disruption markers. Stroke 2005; 36:1921–6. 31 Minnerup J, Wersching H, Ringelstein EB et al. Prediction of malignant middle cerebral artery infarction using computed tomography-based intracranial volume reserve measurements. Stroke 2011; 42:3403–9. 32 Burghaus L, Liu WC, Dohmen C, Haupt WF, Fink GR, Eggers C. Prognostic value of electroencephalography and evoked potentials in the early course of malignant middle cerebral artery infarction. Neurol Sci 2013; 34:671–8. doi: 10.1007/s10072-012-1102-1. [Epub 2012 Apr 27]. 33 Sykora M, Steiner T, Rocco A, Turcani P, Hacke W, Diedler J. Baroreflex sensitivity to predict malignant middle cerebral artery infarction. Stroke 2012; 43:714–9. 34 Jüttler E, Köhrmann M, Aschoff A, Huttner HB, Hacke W, Schwab S. Hemicraniectomy for space-occupying supratentorial ischemic stroke. Future Neurol 2008; 3:251–64. 35 Wagner S, Schnippering H, Aschoff A, Koziol JA, Schwab S, Steiner T. Suboptimum hemicraniectomy as a cause of additional cerebral lesions in patients with malignant infarction of the middle cerebral artery. J Neurosurg 2001; 94:693–6. 36 Staykov D, Gupta R. Hemicraniectomy in malignant middle cerebral artery infarction. Stroke 2011; 42:513–6. 37 Kostov DB, Singleton RH, Panczykowski D et al. Decompressive hemicraniectomy, strokectomy, or both in the treatment of malignant middle cerebral artery syndrome. World Neurosurg 2012; 78:480–6. 38 Unterberg A, Juettler E. The role of surgery in ischemic stroke: decompressive surgery. Curr Opin Crit Care 2007; 13:175–9. 39 Fischer U, Taussky P, Gralla J et al. Decompressive craniectomy after intra-arterial thrombolysis: safety and outcome. J Neurol Neurosurg Psychiatry 2011; 82:885–7. 40 Takeuchi S, Wada K, Nawashiro H et al. Decompressive craniectomy after intravenous tissue plasminogen activator administration for stroke. Clin Neurol Neurosurg 2012; 114:1312–5. 41 Schuss P, Borger V, Vatter H, Singer OC, Seifert V, Güresir E. Antiplatelet therapy, but not intravenous thrombolytic therapy, is associated with postoperative bleeding complications after decompressive craniectomy for stroke. J Neurol 2013; 260:2149–55. doi: 10.1007/ s00415-013-6950-y. [Epub 2013 May 28]. © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
H. Neugebauer and E. Jüttler 42 Zhao J, Su YY, Zhang Y et al. Decompressive hemicraniectomy in malignant middle cerebral artery infarct: a randomized controlled trial enrolling patients up to 80 years old. Neurocrit Care 2012; 17:161– 71. 43 McKenna A, Wilson CF, Caldwell SB, Curran D. Functional outcomes of decompressive hemicraniectomy following malignant middle cerebral artery infarctions: a systematic review. Br J Neurosurg 2012; 26:310–5. 44 Lucas C, Thines L, Dumont F et al. Decompressive surgery for malignant middle cerebral artery infarcts: the results of randomized trials can be reproduced in daily practice. Eur Neurol 2012; 68:145–9. 45 Puetz V, Campos CR, Eliasziw M, Hill MD, Demchuk AM. Calgary Stroke Program: assessing the benefits of hemicraniectomy: what is a favourable outcome? Lancet Neurol 2007; 6:580–1. 46 World Health Organization. International Classification of Functioning. Geneva, Disability and Health (ICF), 2003. 47 Albrecht GL, Devlieger PJ. The disability paradox: high quality of life against all odds. Soc Sci Med 1999; 48:977–88. 48 Creutzfeldt CJ, Holloway RG. Treatment decisions after severe stroke: uncertainty and biases. Stroke 2012; 43:3405–8. 49 Rahme R, Zuccarello M, Kleindorfer D, Adeoye OM, Ringer AJ. Decompressive hemicraniectomy for malignant middle cerebral artery territory infarction: is life worth living? J Neurosurg 2012; 117:749–54. 50 Kelly AG, Holloway RG. Health state preferences and decision-making after malignant middle cerebral artery infarctions. Neurology 2010; 75:682–7. 51 Weil AG, Rahme R, Moumdjian R, Bouthillier A, Bojanowski MW. Quality of life following hemicraniectomy for malignant MCA territory infarction. Can J Neurol Sci 2011; 38:434–8. 52 von Sarnowski B, Kleist-Welch Guerra W, Kohlmann T et al. Longterm health-related quality of life after decompressive hemicraniectomy in stroke patients with life-threatening space-occupying brain edema. Clin Neurol Neurosurg 2012; 114:627–33. 53 Walz B, Zimmermann C, Böttger S, Haberl RL. Prognosis of patients after hemicraniectomy in malignant middle cerebral artery infarction. J Neurol 2002; 249:1183–90.
© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
Review 54 Hofmeijer J, van der Worp HB, Kappelle LJ, Amelink GJ, Algra A, van Zandvoort MJ. Cognitive outcome of survivors of space-occupying hemispheric infarction. J Neurol 2013; 260:1396–403. 55 Schmidt H, Heinemann T, Elster J et al. Cognition after malignant media infarction and decompressive hemicraniectomy – a retrospective observational study. BMC Neurol 2011; 11:77. doi: 10.1186/14712377-11-77. 56 Neugebauer H, Heuschmann PU, Jüttler E. DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY – Registry (DESTINY-R): design and protocols. BMC Neurol 2012; 12:115. 57 Kastrau F, Wolter M, Huber W, Block F. Recovery from aphasia after hemicraniectomy for infarction of the speech-dominant hemisphere. Stroke 2005; 36:825–9. 58 Parikh RM, Robinson RG, Lipsey JR, Starkstein SE, Fedoroff JP, Price TR. The impact of poststroke depression on recovery in activities of daily living over a 2-year follow-up. Arch Neurol 1990; 47:785–9. 59 Van der Worp HB, Macleod MR, Kollmar R. European Stroke Research Network for Hypothermia (EuroHYP). Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials? J Cereb Blood Flow Metab 2010; 30:1079–93. 60 Els T, Oehm E, Voigt S, Klisch J, Hetzel A, Kassubek J. Safety and therapeutical benefit of hemicraniectomy combined with mild hypothermia in comparison with hemicraniectomy alone in patients with malignant ischemic stroke. Cerebrovasc Dis 2006; 21:79–85. 61 Neugebauer H, Kollmar R, Niesen WD et al. DEcompressive surgery Plus hypoTHermia for Space-Occupying Stroke (DEPTH-SOS): a protocol of a multicenter randomized controlled clinical trial and a literature review. Int J Stroke 2013; 8:383–7. 62 Schwab S, Steiner T, Aschoff A et al. Early hemicraniectomy in patients with complete middle cerebral artery infarction. Stroke 1998; 29:1888– 93. 63 Cho DY, Chen TC, Lee HC. Ultra-early decompressive craniectomy for malignant middle cerebral artery infarction. Surg Neurol 2003; 60:227–32.
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Introduction Malignant middle cerebral artery infarction (MMI) has an estimated yearly incidence of 10–20/100·000 (1). Most often, thrombotic or embolic occlusion of the internal carotid artery or the proximal middle cerebral artery (MCA) results in sub-total or complete infarction of the MCA territory. Depending on the intracranial vascular status and collateralization, the territories of the anterior cerebral artery (ACA) and/or posterior cerebral artery are additionally involved (2,3). Occlusion of the ACA and anterior choroidal artery, ipsilateral abnormalities of the circle of Willis, and the combined involvement of the superficial and deep MCA territory are more frequently associated with malignant infarction, whereas the presence of a prominent anterior temporal artery is considered to be associated with smaller infarcts (3–5). Malignant middle cerebral artery infarction represents a devastating sub-group of severe ischemic stroke that is usually fatal under medical treatment and, in the case of survival, always associated with long-term disability (1). The hallmark of MMI is the relentless formation of early cytotoxic and late vasogenic and interstitial space-occupying edema (6). Maximal brain swelling Correspondence: Hermann Neugebauer*, Department of Neurology, RKU – University and Rehabilitation Hospitals Ulm, Oberer Eselsberg 45, Ulm 89081, Germany. E-mail: [email protected] Department of Neurology, RKU – University and Rehabilitation Hospitals, Ulm, Germany Received: 30 July 2013; Accepted: 8 September 2013; Published online 11 April 2014 Conflict of interest: None declared. DOI: 10.1111/ijs.12211
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may occur early but generally peaks around the second and fifth day after stroke onset (2). In contrast to the general belief, extensive edema formation in MMI is not accompanied by a critical increase in global intracranial pressure (ICP) in the majority of cases (7). Death results from transtentorial and transforaminal herniation in up to 80% of patients under standard and under intensive medical care within the first week of onset (1,2). Conservative and intensive care treatment such as ICP lowering therapy, deep sedation, body positioning, controlled hyperventilation, and even therapeutic hypothermia (TH) fail to substantially lower this high mortality rate (8–11). So far, only early decompressive hemicraniectomy (DHC) within 48 h of stroke onset has been shown to be effective in lowering mortality and improving outcome in randomized controlled trials. As a result, utilization of DHC increased steadily in the last years, but the total numbers of procedures remained low (0·15–0·3%) (12–15). According to clinicopathological and epidemiological studies, patients with MMI are about 10 years younger than the average ischemic stroke patient (56 ± 9·4 years, 66 ± 17 years, 71·0 years range 46·0–92·0) (1,3,13). At the same time, at least 28–40% of patients with MMI are older than 60 years (16). Only patients up to 60 years of age were included in the randomized trials on DHC (9–11,17,18). Higher age was found to be associated with much poorer outcome in observational studies and is the major reason why older patients are considered ineligible for DHC (4,15,19,20). Nevertheless, 30% of all hemicraniectomy procedures are currently performed in this age group (14), although uncertainty on the effectiveness remains because of the lack of data from randomized controlled trials. Therefore, the results of the most recently published DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral arterY – II (DESTINY-II) trial in patients older than 60 years were eagerly awaited (21). In this review, we outline the current status of diagnosis and treatment of MMI, as well as perspectives on future directions.
Diagnosis and early prediction of malignant MCA infarction The term ‘malignant MCA infarction’ was already introduced in 1996 describing a severe MCA syndrome with typical clinical symptoms, following a uniform clinical course, and ending in herniation (1). However, early after symptom onset and before signs of herniation occur, there is no generally accepted definition of this condition. This lack of a clear definition is somehow superseded by the uniform inclusion criteria of the three European randomized controlled trials on hemicraniectomy: DEcompresssive Craniectomy In MALignant middle cerebral artery infarcts (DECIMAL), the Dutch Hemicraniectomy After Middle cerebral Artery infarction with Life-threatening Edema Trial (HAMLET), and the German DEcompressive Surgery for the Treatment of © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
H. Neugebauer and E. Jüttler malignant INfarction of the middle cerebral artery trial (DESTINY) (9–11). Based on the inclusion and exclusion criteria of these trials, the diagnosis of a ‘malignant MCA infarction’ is currently made by assessing clinical presentation at stroke onset, the clinical course, and neuroimaging findings. These include: 1. clinical signs of a severe unilateral MCA infarction, including eye and head deviation, contralateral hemiplegia and hypo- or anesthesia, frequent hemianopia, always multimodal neglect, and global aphasia in case of dominant hemispheric infarction; 2. decreased level of consciousness: either from the beginning or progressively deteriorating over the first 24–48 h (a score of ≥1 as assessed in item 1a of the National Institutes of Health Stroke Scale [NIHSS], or a score of 15 (DECIMAL), or >20 (DESTINY, HAMLET); NIHSS score (in infarctions of the nondominant hemisphere): >15 (DECIMAL, HAMLET), >18 (DESTINY); 4. infarction of the MCA territory of ≥50% (DECIMAL), or >2/3 (DESTINY, HAMLET), or infarct volume on diffusion-weighted imaging (DWI) of >145 ml (DECIMAL); and 5. involvement of the basal ganglia (DESTINY). The effectiveness of early DHC within 48 h of stroke onset has raised interest in finding other reliable, more specific, and more sensitive early predictors of MMI to enable early selection of patients who may benefit from DHC. Hofmeijer et al. provide a comprehensive overview on the value of clinical parameters and neuroimaging: Infarct size of more than 50% and perfusion deficit larger than 66% of the MCA territory are the major early determinants of MMI. From a clinical point of view, the need for mechanical ventilation strongly predicts extensive edema. However, none of these factors provide sufficient positive predictive values (PPVs) to reliably select patients for DHC (22). Compared with computed tomography (CT), magnetic resonance imaging (MRI) seems to allow a more accurate prediction of MMI. Two retrospective studies reported high predictive values for infarct sizes larger than 145 ml on DWI and 82 ml on apparent diffusion coefficient maps (23,24). The latter finding was reproduced in a prospective multicenter study with a high PPV but low sensitivity (0·88 vs. 0·52). Of note, DWI volume is more accurate in the early prediction of MMI than multivariate models including vessel status and stroke severity (0·89 vs. 0·88) (25). In contrast, after 24 h from stroke onset, stroke severity (NIHSS scores of >21) enhances the predictive value of DWI (0·93 vs. 0·79) (26). Concerning the lack of sensitivity of DWI-lesion size in predicting MMI, a recent positron emission tomography study suggested that edema formation is not only a function of the size of the perfusion deficit but also of its severity. The specific sub-volumes of areas with severely reduced cerebral blood flow (CBF) identified patients with MMI in 100%. The severity of CBF reduction is thought to determine the extent of blood–brain barrier (BBB) breakdown, which correlates to the extent of vasogenic edema (27). Likewise, increased serum levels of molecular markers of BBB disruption, i.e. cellular-fibronectin and matrix metalloproteinase-9 are associated with MMI (28–30). A different approach in predicting MMI is based on evaluating the intracra© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
Review nial volume reserve (cerebrospinal fluid) in addition to the infarct volume with perfusion CT (96·2% sensitivity and PPV) (31). However, the promising results of this retrospective single-center analysis need to be validated in larger prospective studies. The retrospective single-center experience is also the major drawback of electrophysiological studies on electroencephalogram (EEG), evoked potentials (EPs), and autonomic function that found moderate predictive values of the coexistence of background slowing on EEG, pathological brainstem auditory EP, and a decreased baroreflex sensitivity (32,33). Studies investigating multimodal neuro-biochemical monitoring, EEG power spectrum, and cortical spreading depolarization require invasive procedures and are not available in many centers in clinical routine or outside an experienced intensive care unit.
DHC in the treatment of malignant MCA infarction DHC as surgical procedure The rational behind early DHC is to create external space for the expanding edema before compression of formerly healthy brain tissue occurs. The diameter of craniectomy should measure at least 12 cm corresponding to an additional edema volume of 80–100 ml (34). Smaller craniotomies are insufficient and may lead to venous infarction at the bone margins, hemorrhages, and herniation through the craniotomy (35). Delayed complications despite sufficient craniotomy include the sinking skin flap syndrome, extra-axial fluid collections, hydrocephalus, epi- or subdural hematomas, infections, and skin or muscle necrosis (36). In addition to external DHC, some authors advocate for an internal decompression by removing infarcted, nonviable tissue (strokectomy) especially the resection of the temporal lobe (37). However, as long as the safety and efficacy of internal decompression has not been proven in prospective trials, external decompression is recommended as the treatment of choice (38). It should be emphasized that DHC is safe after intravenous/intra-arterial (IA) thrombolysis and/or IA thrombectomy and that bleeding complications are rather associated with prior antiplatelet therapy (39–41). DHC: treatment goals Given that MMI is a fatal disease that can only be survived at the expense of permanent disability, the aims of any treatment can only be: first, to safe the patient’s life [modified Rankin score (mRS) 0–5]; second, without the price of survival with very severe disability or inacceptable clinical status (mRS 0–4); third, if possible, to improve functional outcome and reduce severe dependency (mRS 0–3). DHC: randomized controlled trials Meanwhile, seven randomized controlled trials were successfully performed between 2000 and 2013 comparing DHC to standard intensive care [Hemicraniectomy And Durotomy upon Deterioration From Infarction Related Swelling Trial (HeADDFIRST); DEcompressive surgery for the treatment of Malignant Infarction of the middle cerebral artery: a randomized, controlled trial in a TURkish population (DEMITUR TRIAL); DECIMAL; HAMLET; DESTINY; DESTINY-II and Decompressive hemicraniectomy in malignant middle cerebral artery infarct: a randomized controlled Vol 9, June 2014, 460–467
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Review trial enrolling patients up to 80 years old], five of which have officially been published (9–11,21,42). The Chinese study by Zhao et al. was not prospectively registered and end-points, sample size calculation, outcome assessment, sub-groups, and statistical analysis are not prespecified. Sub-group analyses were not powered to show statistical significant differences in outcome, and the study is critical from an ethical point of view, because it was started almost exactly copying the protocol of HAMLET and DESTINY when these trials were already published and the treatment effect was known (42). The HeADDFIRST trial and the DEMITUR TRIAL were completed but not officially published so far.* Data are available from conferences or via Internet. The Hemicraniectomy for Malignant Middle cerebral artery Infarction (HEMMI) trial is still ongoing (see Table 1). DHC in patients 18–60 years of age DECIMAL and DESTINY were stopped prematurely because of a marked difference in mortality and the possibility to perform a prospectively planned pooled analysis including data from the ongoing HAMLET trial (9–11). This prospective pooled analysis provides class one evidence for DHC in patients up to 60 years (17): The number needed to treat (NNT) to avoid death (mRS score 6) is 2, to avoid death, or most severe, dependency (mRS score 5 or 6) is 2, and to avoid death most severe and moderately severe disability (mRS 4–6) is 4. The results of the randomized controlled trials are consistent with comparative data from nonrandomized studies and could be reproduced in a medical center without previous experience with DHC in all day clinical practice (19,34,43,44). After the final publication of HAMLET, two metaanalyses including different sets of patients from HAMLET were published. Both meta-analyses were post hoc and not stratified by time since stroke onset. Furthermore, mortality rates in patients treated before and after 48 h of stroke onset in HAMLET differed significantly (11,18). In contrast, pooled data from DESTINY and DECIMAL show the same significant reduction of mortality (mRS 0–5: NNT 2), most severe disability (mRS 0–4: NNT 2), and severe disability at 12 months (mRS 0–3: NNT 4) as the prospective pooled analysis (9,10,17). DHC in patients older than 60 years In the past several nonrandomized case series, retrospective studies and systematic reviews suggested that higher age is an important predictor of unfavorable outcome in MMI with proposed upper age limits between 50 and 60 years (4,19). In the pooled analysis of DECIMAL, HAMLET, and DESTINY, no significantly reduced effectiveness of DHC was observed in patients between 50 and 60 years of age. However, the studies were underpowered to detect such a difference (9–11,17). The study by Zhao et al. showed significantly reduced mortality and most severe disability also in patients older than 60 years. However, these data come from an underpowered sub-group analysis of patients, which was not predefined, comparing 16 patients treated with *HeADDFIRST was finally published in the March 2014 issue of Stroke (Frank JI1, Schumm LP, Wroblewski K, et al. Hemicraniectomy and durotomy upon deterioration from infarction-related swelling trial: randomized pilot clinical trial. Stroke 2014;45:781–7).
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H. Neugebauer and E. Jüttler DHC vs. 13 patients treated conservatively, of whom two-thirds were 61–70 years old (42). To adequately assess the possible benefits of DHC in patients older than 60 years, the DESTINY-II trial, a randomized controlled trial with independent end-point assessment and a sequential interim analysis design, was conducted (21). The inclusion criteria paralleled those of the DESTINY trial. In accordance with the pooled analysis of DECIMAL, HAMLET, and DESTINY, the primary end-point was functional outcome on the mRS dichotomized into 0–4 vs. 5–6 after six-months. Secondary outcome measures were mRS 0–3 vs. 4–6 at 12 months, mortality, time of survival, health outcome, quality of life, retrospective consent, and rate of depression. The trial was stopped after assessment of the primary end-point of the 82nd patient on the basis of the six-months outcomes. Meanwhile, another 30 patients had been included, and data from 112 patients were evaluated in the final analysis. DESTINY-II met its primary endpoint: early DHC within 48 h of stroke onset in patients older than 60 years with MMI is associated with a significant increase in survival without most severe disability (mRS 38% vs. 18%, NNT 5) particularly because of a significant reduction in mortality. The high number of patients with most severe disability (mRS 5) at 6 months was reduced to 19% at 12 months mainly because some of these patients deceased. Nevertheless, one-third of the survivors suffered from this state of complete dependency. About one-half of the survivors suffered from moderately severe disability (mRS score of 4). Only 6% of the survivors were moderately disabled (mRS score of 3), and no patient achieved independency. There were no differences between the treatment groups with regard to the secondary outcome measures in a survivor-based analysis. Retrospective consent to treatment was high in both treatment groups (63% vs. 53%). However, 60% of survivors could not adequately answer this question. The results of DESTINY-II show that DHC is a life-saving procedure also in patients older than 60 years and increases the chance to survive without complete dependency. However, whereas case fatality among older patients is comparable with younger patients under intensive care treatment, outcome after DHC is clearly worse.
Controversies and future directions in DHC for malignant MCA infarction Functional outcome Immediately after the publication of the pooled analysis of DECIMAL, HAMLET, and DESTINY, the scientific community initiated a debate as to whether an mRS of 4 – unable to walk and unable to attend to own bodily needs without assistance – may be called ‘favorable’ (45). With the results from the DESTINY-II trial, this discussion will revive. In the light of a devastating disease such as MMI, where the choice is between permanent moderate to severe disability and death, the definition of favorable outcome on the basis of the mRS, done by healthy academics, may probably not sufficiently address the issue. The mRS has a strong focus on motor abilities and has a neglect for neuropsychological functions and quality of life (46). It is also well known that disabled people indicate a higher quality of life compared with healthy subjects who are asked to imagine comparable situations and that the © 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
02/2004–10/2005
12/2000–11/2005
09/2002–10/2007
DESTINY9
DECIMAL10
HAMLET11
09/2002–10/2007
09/2002-recruiting
HeMMI
– HAMLET
01/2003–12/2007
DEMITUR TRIAL
09/2002–10/2007
05/2000–03/2003
HeADDFIRST
– HAMLET
Duration
Trial/Analysis
18–80 NIHSS > 16/18# 2/3 MCA+ 18–65 MCA stroke and GCS < 6–14/5–9# or NIHSS Item 1a > 0 18–60 y NIHSS > 18/20# & Item 1a > 0 >2/3 MCA+ 18–55 y NIHSS > 15 & Item 1a > 0 >1/2 MCA & DWI > 145 ml 18–60 y NIHSS > 15/20# GCS < 14/10# >2/3 MCA 18–60 y NIHSS > 15/20# >2/3 MCA 18–60 y NIHSS > 15/20# >2/3 MCA
18–75 y NIHSS > 17 Item 1a < 2 > 1/2 MCA w/i 5 h or 3/3 MCA w/i 48 h
Eligibility Criteria
25
39
12 h–2/3 MCA & edema formation >60 y NIHSS > 15/20# >2/3 MCA+
48 h
DESTINY n = 32 DECIMAL n = 38 HAMLET n = 23 DESTINY n = 32 DECIMAL n = 38 HAMLET n = 39 DESTINY n = 32 DECIMAL n = 38 HAMLET n = 64 DESTINY n = 32 DECIMAL n = 28
48 h
48 h
43 h
99 h
48 h
Tx w/i
Eligibility Criteria
112
47
70
134
109
93
(n)
mRS 0–4 vs. 5–6 at 6 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–4 vs. 5–6 at 12 months
mRS 0–4 vs. 5–6 at 6 months mRS 0–3 vs. 4–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
mRS 0–3 vs. 4–6 at 12 months mRS 0–4 vs. 5–6 at 12 months
Primary/ Secondary Endpoint
38 38
75
67 25
51 76
38 68
40 75
43 75
DHC
18 16
13
17 9
23 27
25 34
24 33
21 24
Conservative
Functional Outcome (%)
20* 22*
62*
49* 16
29* 48*
13 34*
16 42*
23* 51*
ARR (%)
43
17
23
22
21
22
DHC
76
70
63
63
71
71
Conservative
Mortality at 12 mo (%)
33*
53*
40*
41*
50*
50*
ARR (%)
Randomized controlled trials and pooled/meta-analyses are listed by content. Data from the HAMLET trial are additionally subdivides into data from patients treated before/after 48 hours. Number of patients from the HAMLET trial included in the different analyses and primary study endpoints are printed in bold letters. Data in brackets have not officially been published in peer-reviewed journals: Results of the HeADDFIRST trial were presented at the 55th Annual AAN Meeting in 2003 [HeADDFIRST was finally published in the March 2014 issue of Stroke (Frank et al. Stroke 2014;45:781–7)], results of the DEMITUR TRIAL are reported on www.strokecenter.org/trial/clinicalstudies. Abbreviations: HeADDFIRST = Hemicraniectomy And Durotomy upon Deterioration From Infarction Related Swelling Trial, DEMITUR TRIAL = DEcompressive surgery for the treatment of Malignant Infarction of the middle cerebral artery in a TURkish population, HeMMI = Hemicraniectomy for Malignant Middle cerebral artery Infarction, DECIMAL = the French DEcompresssive Craniectomy In MALignant middle cerebral artery infarcts, DESTINY = the German DEcompressive Surgery for the Treatment of malignant INfarction of the middle cerebral artery trial, HAMLET = the Dutch Hemicraniectomy After Middle cerebral Artery infarction with Life-threatening Edema Trial, NIHSS = National Institute for Health Stroke Scale, MCA = middle cerebral artery, DWI = diffusion weighted imaging, Tx w/i = Treatment within, mo = months, mRS = modified Rankin Scale, DHC = decompressive hemicraniectomy, ARR = absolute risk reduction; #non-dominant/dominant hemisphere, +at least partial involvement of the basal ganglia, *statistical significant.
DESTINY-II
2009
Meta-Analysis HAMLET11 (retrospective) Meta-Analysis Mitchel P et al.18 (retrospective) Pooled Analysis (DESTINY and DECIMAL) Zhao et al. 201242
21
2007
Pooled Analysis17 (prospective)
2009
Duration
Trial/Analysis
Table 1 Continued
Review H. Neugebauer and E. Jüttler
© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
Review
H. Neugebauer and E. Jüttler
involved in the treatment of MMI and of important relevance in treatment decision.
capacity to cope with a life-changing experience is generally underestimated (47,48). The more adequate question instead of defining favorable vs. unfavorable outcome may therefore be: what degree of disability is ‘still acceptable’ for the individual survivor of MMI. A systemic review on quality of life and outcome satisfaction of survivors after DHC reported that the majority of survivors and caregivers (76·6%) expressed satisfaction with life despite moderate severe disability (mRS = 4) or most severe disability (mRS = 5) in more than 50% of those patients (49). These results are congruent with what is seen in the DESTINY-II trial. Given the high rate of retrospective consent, at least some patients who survived with a mRS of 5 must retrospectively have agreed to their treatment. In younger patients, DHC is associated with more qualityadjusted life-years than medical treatment (50). The reason for the obvious discrepancy of functional disability and satisfaction with treatment is most likely because psychosocial functions such as the premorbid personality, cultural background and lifestyle of the patient, the presence of a strong social and/or family support, and the absence of poststroke depression are important factors in perceiving life worth living (46,51,52). Psychosocial functions are less impaired after malignant MCA infarction than physical functions and successful coping and external support seem to correlate with quality of life and treatment satisfaction (46,49,51–54). In this connection special attention should be made to poststroke depression. It is common in survivors of malignant MCA infarction (56·1%, range 20–81·8%), correlated with impaired healthrelated quality of life and functional outcome, associated with lower rates of retrospective consent, and unfortunately still not treated sufficiently in many survivors of MMI (49,52,55). It has to be noted that most data on quality of life after MMI were derived from heterogeneous, retrospective, and uncontrolled case series. The ongoing DESTINY-R study – an international, multicenter, prospective ‘Registry’ – aims to collect data on functional outcome, retrospective consent, quality of life, and risk factors for predicting outcome, but first results are not to be expected until 2015 (56). Until then, data on quality of life and treatment satisfaction should be presented in addition to rates of disability and mortality in an unbiased way to patients and/or their surrogates, who should outweigh risks and benefits of DHC and make their own decision accordingly.
Summary
Side of infarction The side of the infarction is a common surrogate for the presence of aphasia (dominant hemisphere), and it is of intuitive sense to consider the loss of communication skills in treatment decisions after MMI. Data from the randomized controlled trials including DESTINY-II, systematic reviews, and case series do not find differences in functional outcome, retrospective consent, or quality of life between patients with dominant and nondominant hemispheric infarction (4,9–11,17,19,42). Aphasia frequently improves over time and rarely remains complete after MMI (53,57). In contrast, neuropsychological deficits and depression are common also in nondominant hemispheric infarction and impact negatively on recovery and rehabilitation (52,53,58). Nevertheless, the presence of aphasia is still of special concern among physicians
Decompressive hemicraniectomy is increasingly utilized in the treatment of MMI even though absolute numbers of procedures remain low. Latest neuroradiological studies suggest a reliable early prediction of MMI by infarct size in MRI, severity of perfusion deficit, and intracranial reserve volume. The effectiveness of DHC in the treatment of younger patients with MMI could be reproduced in older patients by the DESTINY-II trial, although the treatment effect is much smaller. With older patients suffering a worse outcome after DHC, the debate as to which degree of functional outcome is still acceptable in survivors is brought back to the fore. It is hoped that ongoing and future trials will answer further questions such as long-term quality of life, the importance of aphasia, the best timing of DHC, and the further reduction of early mortality.
© 2014 The Authors. International Journal of Stroke © 2014 World Stroke Organization
Early mortality Although DCH is considered a live-saving procedure, still more than 20% of younger and more than 40% of older patients die despite surgery (17). This clearly calls for improved intensive care treatment of these patients. TH is an antiedematous and neuroprotective therapy with proven efficacy in global hypoxia. Data from observational studies suggest that TH may also be effective in MMI, reducing early mortality to about 40% (59). The obvious consequence may be the combination of DHC and TH, which has been tested in smaller studies showing promising results (60). To further test this approach, the DEcompressive surgery Plus hypoTHermia for Space-Occupying Stroke (DEPTH-SOS), a multicenter randomized controlled phase II trial, is currently recruiting patients (61). Results are expected for 2015. Timing of surgery There is some evidence from nonrandomized prospective studies that early DHC within 24 h (vs. 48 h) and/or ultra-early DHC within six-hours from symptom onset may further reduce mortality in MMI (62,63). Other case series find no difference in early vs. delayed DHC (4,19). The randomized controlled trials on DHC and the pooled analyses only provide evidence for early treatment of patients with MMI, i.e. within 48 h from symptom onset (9–11). In the HAMLET trial, patients could be treated up to 96 h of symptom onset (11). In these patients, no benefit of DHC was observed, which is often misinterpreted as the ineffectiveness of delayed DHC. However, the lack of an effect in the late time window in HAMLET is rather due to the low mortality rates in the control group of 36% as compared with 78% in patients randomized within 48 h. This points to a bias in the selection of patients in the later time window in HAMLET and does not justify dismissing delayed DHC as ineffective. As long as there are no randomized comparative data, the effect of delayed DHC remains uncertain. Because early DHC is effective, there is currently no indication for a wait-and-see strategy (i.e. waiting for midline shift or further clinical deterioration) once the diagnosis of MMI has been made.
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