Accepted Manuscript

Neurological Functional Outcomes of Decompressive Hemicraniectomy versus

Conventional Treatment for Malignant Middle Cerebral Artery Infarction: a Systematic
Review and Mata-Analysis

Yu-ping Li, MD., Meng-zhuo Hou, MD., Guang-yu Lu, PhD., Natalia Ciccone, MSC.,
Xing-dong Wang, MSC, Lun Dong, PhD., Chen Cheng, MD., Heng-zhu Zhang, MD.
PII: S1878-8750(16)31384-5
DOI: 10.1016/j.wneu.2016.12.069
Reference: WNEU 5030

To appear in: World Neurosurgery

Received Date: 11 November 2016

Revised Date: 12 December 2016
Accepted Date: 15 December 2016

Please cite this article as: Li Y-p, Hou M-z, Lu G-y, Ciccone N, Wang X-d, Dong L, Cheng C, Zhang
H-z, Neurological Functional Outcomes of Decompressive Hemicraniectomy versus Conventional
Treatment for Malignant Middle Cerebral Artery Infarction: a Systematic Review and Mata-Analysis,
World Neurosurgery (2017), doi: 10.1016/j.wneu.2016.12.069.

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Title Page

Neurological Functional Outcomes of Decompressive Hemicraniectomy versus Conventional Treatment

for Malignant Middle Cerebral Artery Infarction: a Systematic Review and Mata-Analysis
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Running title: DHC for MMI

Yu-ping Li1,2, MD., Meng-zhuo Hou2 MD., Guang-yu Lu3,4 PhD., Natalia Ciccone2 MSC., Xing-dong Wang1 MSC,

Lun Dong1 PhD., Chen Cheng5 MD., Heng-zhu Zhang1* MD.

1. Department of Neurosurgery, The Clinical Medical College of Yangzhou University, 225001, Yangzhou, China

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2. Neurosurgical Research, Department of Neurosurgery, Ludwig-Maximilians University of Munich, 81377, Munich, Germany

3. Department of Preventive Medicine, Medical College of Yangzhou University, Yangzhou University, 225001 Yangzhou, China

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4. Disease Control in Disadvantaged Population Group, Institute of Public Health, Medical School, Ruprecht-Karls-University,

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Heidelberg, Germany

5. Department of Neurology, Tianjin Medical University General Hospital, 300050, Tianjin, China
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Yuping Li, Mengzhuo Hou, and Guangyu Lu have contribution equally
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*To whom correspondence should be addressed to Hengzhu Zhang, MD, PhD,

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Department of Neurosurgery, Clinical medical College of Yang Zhou University, Yangzhou, 225001 China

E-mail: [email protected].
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Trial registration: This research was registered at PROSPERO. (Registration Number: CRD42016033302)
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Abstract:

Background: This study aims to evaluate the effect of decompressive hemicraniectomy (DHC) versus conventional treatments (CT)

for patients with malignant middle cerebral artery infarction (MMI), and to investigate the impact of age and surgical timing on
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neurological function and mortality.

Methods: We searched English and Chinese databases for randomized controlled trials (RCTs) or observational studies (OSs)

published before August 2016. The outcomes included good functional outcome (GFO), mortality, National Institutes of Health Stroke

Scale (NIHSS) score, and Barthel Index (BI) score.

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Results: Twenty-five studies were included in this meta-analysis (1727 patients). There were statistically significant differences

between the DHC and CT groups in terms of GFO (P<0.0001), mortality (P<0.00001), NIHSS and BI score (P<0.0001) at different

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follow-ups. Between these two groups, significant differences were observed in survival with moderately severe disability

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(P<0.00001); while no differences were observed in survival with severe disability. In the subgroup analysis, within the DHC group,

GFO were less in patients >60 (9.65%) versus ≤60 years (38.94%); while more patients >60 had moderately severe or severe
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disability (55.27%) compared to patients ≤60 years (44.21%).
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Conclusions: The study provides evidence that DHC could significantly improve the GFO and reduces the mortality of patients of all
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ages with MMI as compared with CT, without increasing patients surviving with severe disability. However, patients in DHC group

suffered more frequently with moderately severe disability. Moreover, patients aged >60 years with MMI had higher risk of surviving
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with moderately severe or severe disability and less GFO.

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Key words: hemicraniectomy; decompressive surgery; stroke; infraction; functional outcomes; meta-analysis
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Introduction

Cerebral ischemic stroke is the second most common cause of death worldwide, and the leading cause of disability.1 Malignant

middle cerebral artery (MCA) infarction (MMI) is defined as acute infarction in the entire MCA territory. Infarction in this large
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cerebral region usually causes rapid brain edema within 2 to 5 days, which can persist up to 14 days after the onset of symptoms.

MMI, which accounts for 10% of all supratentorial infarctions, may cause massive brain swelling, increased intracranial pressure

(ICP), subsequent herniation, and early death.2,3 Traditional treatment, such as ICP control treatment, does not improve the prognosis,

and mortality remains at 80%.4 When severe swelling occurs, surgical treatment should be considered to decrease the ICP, relieve the

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mass effect, and prevent the brain herniation caused by brain edema or hematoma. In 2012, a study reported that the mortality of 382

patients with MMI after decompressive hemicraniotomy (DHC) was 24%, of which 157 patients (41%) had favorable outcomes.5

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Therefore, DHC has been suggested as a therapeutic alternative for MMI to decrease severe brain edema and prevent subsequent

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herniation.

Several case series studies have indicated that DHC can prolong the survival of patients with MMI at an early stage.6-8 A
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pooled study of several non-randomized trials indicated that surgery on patients with MMI could be a life-saving procedure.9
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However, data on the long-term functional outcome were insufficient. In 2006, 3 randomized control trials (RCTs) investigated the
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efficacy of DHC for patients with MMI, namely the HAMLET trail (Netherlands), DECIMAL trail (France), and DESTINY trials

(Germany).10-12 A previous meta-analysis based on these 3 RCTs indicated that surgical decompression significantly reduces the risk of
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death or disability among patients as compared to conventional therapy (CT) alone.13 However, the study only included patients who
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underwent surgical treatment within 48 h after the onset of symptoms and who were ≤60 years old.13 Additionally, the sample size of
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the meta-analysis was rather limited, involving a total of 93 patients. In recent years, newly conducted RCTs, assessing the efficacy of

DHC in patients of all ages with MMI, have been published.14,15 Some of these RCTs enrolled a much larger sample (up to 219
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patients). Moreover, newly published RCTs on this topic (in Chinese) have enrolled patients aged up to 80 years and have reported
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complete procedures and outcomes.16-18

Therefore, in this analysis, we searched all relevant RCTs and observational studies (OSs) published in English and Chinese to

assess the long-term functional outcomes of DHC as compared with CT alone in patients of all ages with MMI. Moreover, we

investigated the impact of age and surgical timing on the neurological functional outcomes and mortality of MMI.

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Materials and Methods

This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

guidelines.19 The protocol of our research was registered at the Centre for Reviews and Dissemination PROSPERO (Registration
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Number: CRD42016033302). There is no necessary for ethic approval in this study, because the research is a meta-analysis mainly

based on the published studies.

Literature Search

A systematic literature research including several English (PubMed, EMBASE, the Cochrane Central Register of Controlled

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Trials, and ISI Web of Science) and Chinese electronic databases (CBM, VIP, CNKI, and WanFang database), was carried out to

identify relevant studies published between January 1966 and August 2016. The search strategy included the following MeSH terms

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and keywords: “hemicraniectomy”, “decompressive surgery”, “severe infraction”, “stroke”, “cerebral artery infarction”, “middle

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cerebral artery infarction”, “MCA”, and “DHC”. We also searched unfinished clinical trials, which are registered in the Cochrane

central registry of controlled trials and ClinicalTrials.gov, to identify relevant journal and reference lists.
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Two independent reviewers (YP LI and MZ HOU) assessed the literature based on the titles and abstracts to identify potentially
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relevant studies. Disagreements were discussed until a consensus had been reached. Full versions of all relevant articles were obtained
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and inspected. The literature selection is presented in the PRISMA flow chart according to the PRISMA guidelines.19

Study selection
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The inclusion criteria were the following: (1) RCTs or prospective or retrospective OSs; (2) DHC was performed on patients with
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MMI and compared with CT; (3) Studies reported data on the outcome measures applied in this meta-analysis (primary or secondary
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outcomes); (4) a minimum follow-up of 30 days.

Outcome Measures
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The primary outcome was the neurological functional outcome, including the good functional outcome (GFO) 20, which is
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defined as a patient being able to care for themself, corresponding to a modified Rankin Scale (mRS) of 0, 1, 2, or 3, or a Glasgow

Outcome Scale (GOS) of 4 or 5, surviving with moderated severe disability (mRS = 4), and surviving with severe disability (mRS =

5); Secondary outcomes were: (1) mortality at different follow-ups (30 d, 3 m, 6 m, and 12 m); (2) National Institutes of Health Stroke

Scale (NIHSS) score and Barthel Index (BI) score; (3) The age (≤60y versus >60y) and surgical timing (≤48h versus >48h) on

neurological functional outcomes and mortality comparing the DHC with CT.

Data Extraction and Quality Access

Two researchers independently (GY LU and YP LI) read through full texts of all included articles and extracted the data. The

methodological quality of RCTs and ORs was assessed according to the Cochrane Reviewer's Handbook 5.0.0 21, and the Newcastle-
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Ottawa Scale (NOS).22

Statistical Analysis

The statistical software RevMan 5.3.0 (The Cochrane Collaboration) was used. The odds ratio (OR) with a 95% confidence
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interval (CI) was used as the effective indicator for the dichotomous variables. The assumption of heterogeneity was analyzed with the

χ2-based Q test. When P>0.05 for the Q test, indicating a lack of heterogeneity among the studies, the OR estimate was calculated

using the fixed-effects model (the Mantel-Haenszel method). Otherwise, the random-effects model (the Der-Simonian and Laird

method) was applied. Sensitivity analysis was conducted to check the stability of the results of each study, and the impact of different

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interventions was evaluated. The potential small-study effects (e.g. publication bias), were explored using the sensitivity analysis and

funnel plots with Egger's test of asymmetry.

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Results

Study Characteristics

The initial search yielded 2315 potentially relevant articles (Figure 1). Of these, 2278 studies were excluded after reading title
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and abstracts. Three independent reviewers assessed full texts of the remaining 38 articles (YP LI, MZ HOU, and GY LU). Thirteen

studies were further excluded because of insufficient clinical data, lack of a control group, or an inadequate follow-up duration (<30

days). Finally, twenty-five studies with a total of 1727 patients with MMI were included in this research.10-12,14-18,23-39 Table 1 showed

the characteristics of included studies. Of these twenty-five studies published between 2001 and 2015, nineteen were in English 10-12,14-

18,29-39
, and 6 were in Chinese 23-28. Fourteen studies were described as RCTs 10-12,14-18,23-28, and other 11 articles were described as OSs,

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29-31
including 3 prospective OSs , and 8 retrospective Oss 32-39. The sample size of included trials ranged from 24 to 219.

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- Figure 1 about here -

- Table 1 about here -

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Primary Outcomes
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The GFO (mRS≤3, GOS≥4) in patients of all ages with MMI

Twenty-three studies presented the data of GFO in patients of all ages with MMI between DHC and CT.10-12,14-18,23,24,26-33,35-39
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There were 8 studies showing GFO at 3 month 15,26,27,29,30,32,35,38, 13 studies reporting data at 6 months 11,12,14,15-17,28,30-33,36,37, 9 studies at
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12 months 10-12,14,17,23,24,30,39, and one paper at 36 months follow-up 18. No statistically significant heterogeneity was observed between
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studies (I2=10% at 3 m, 28% at 6 m, 0% at 12 m, and 31% at 36 m); so the fixed effect model was applied. The pooled OR of GFO

was 8.04 (95%CI, 4.44-14.57; P<0.00001) at 3 months, 3.80 (95%CI, 2.52-5.72; P<0.00001) at 6 months, 2.39 (95%CI, 1.56-3.64;
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P<0.0001) at 12 months, and 1.17 (95%CI, 0.39-3.57; P=0.78) at 36months. (Figure 2) The proportion of patients with the GFO was
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19.38% in DHC group versus 10.76% in CT group at 6 months, and 25.24% versus 12.91% at 12 months, as shown in Figure 3.

- Figure 2 about here -

- Figure 3 about here -

Survival With Moderately Severe Disability (mRS=4) in patients of all ages with MMI

Eight studies presented the data of patients in the DHC group survived with moderately severe disability at 6 months follow-up
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11,12,14,15,17,28,36,37 10-12,14,17,24,39
, and seven studies presented the data at 12 months as compared with CT group . No statistically

significant heterogeneity was observed between studies, I2=0% at 6 months, 8% at 12 months; so the fixed effect model was applied.

The results showed 38.76% patients who underwent DHC had moderately severe disability compared with 19.72% patient who
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receive CT at 6 months, and 37.38% versus 13.97 at 12 months, respectively. (Figure 3) The pooled OR of surviving with moderately

severe disability was 3.06 (95%CI, 1.94-4.82; P<0.00001) at 6 months, and 3.53 (95%CI, 2.24-5.58; P<0.00001) at 12 months.

(Figure 4)

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- Figure 4 about here -

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Survival With Severe disability (mRS=5) in patients of all ages with MMI

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Eight included studies reported the data of patients in the DHC group survival with severe disability at 6 months 11,12,14,15,17,28,36,37,

seven trials presented data at 12 months as compared with CT 10-12,14,17,24,39. The fixed effect model was applied in 6 months follow-up
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because the test of heterogeneity didn´t shows significant differences (I2＝13%), while the random effect model used in 12 months
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follow-up due to the I2 was 60%. The results showed there was no significant difference in the risk of survival with severe disability at
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6 months (OR, 1.25; 95% CI, 0.74-2.12; P=0.41), and 12 months (OR, 0.86; 95% CI, 0.29-2.61; P=0.80) (Figure 5).
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- Figure 5 about here -

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Secondary Outcomes

The mortality in patients of all ages with MMI

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All included studies reported the data of mortality. The fixed effect model was applied because the test of heterogeneity didn´t
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shows significant differences in each study (I2=18). There were 11 studies reporting the mortality at 30 days after DHC resulting in the

pooled OR was 0.23 (95% CI, 0.16-0.31; P<0.00001).12,15,25-27,30,32,33,35, 37,38,39 Three studies presented mortality at a 3 months follow-

up.15,29,34 Here the DHC group showed a mortality of 58.06% compared to the 77.78% of the CT group defining a pooled OR was 0.39

11,12,14,15,17,28,30,31,33, 35-37
(95% CI, 0.16-0.95; P=0.04). For 12 included studies depicting mortality at a 6 follow-up , the pooled OR was

0.25 (95% CI, 0.18-0.34; P<0.00001). While the pooled OR was 0.21 (95% CI, 0.14-0.30; P<0.00001) for ten studies presented the

mortality at a 12 months follow-up.10-12,14,16,17,23,24,30,39 Only one study recorded mortality at a 36 months follow-up showing a 25% and

62.5% mortality for the DHC and the CT group respectively.18 (Figure 6) The results showed 25.57% patients in DHC group had died

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compared with 56.51% patient in CT group at 6 months, and 26.22% versus 61.29％ at 12 months, respectively. (Figure 3)

- Figure 6 about here -

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The NIHSS and BI in patients of all ages with MMI

Five studies presented the NIHSS score 25,26,28,34,38, one study presenting the early-stage outcome (1m) 38, and 4 studies reporting

25,26,28,34
long-term follow up (>3m) . The overall pooled OR was -1.60 (95%CI, -5.34-1.29; P=0,21) and -3.32 (95%CI, -4.70-3.00;

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P=0.001) at early- and long-term follow-ups respectively (as shown in Figure 7).

There are 3 studies reporting the BI scores of MMI patients.28,35,38 Two studies reported the BI score was after either 3 38
or 6 28

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months follow-up, while one study recorded the BI score at both follow-ups . There is a statistically significant heterogeneity

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between studies (I2=91% at 3 months, 0% at 6 months), hence the random effect model was applied. The pooled OR was 11.97

(95%CI, -37.32-61.26; P=0.63) at 3 months and 12.91 (95%CI, 9.61-16.21; P<0.00001) at 6 months. (Figure 8)
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- Figure 8 about here -

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Subgroup Analyses:
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We conducted subgroup analysis to investigate the impact of age, surgical timing, and study design on the neurological
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functional outcomes and mortality of MMI.

The influence of age on patients with MMI

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Eight studies reported the data of GFO, mortality, and surviving with moderately severe or severe disability (mRS=4, and 5) in
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different age groups at 12 months between the DHC and CT groups.10-12,14,17,31,33,38 The pooled OR of GFO was 2.96 (95%CI, 1.11-

7.91; P=0.03) in patients aged >60 years, and 2.28 (95%CI, 1.18-4.40; P=0.01) in patients aged ≤60 years. (Figure 9) The GFO was

significant improved both in patients aged >60 years (3.44% to 9.65%) and aged ≤60 years (21.95% to 38.94%) comparing DHC with

CT. (Figure 10) With respect to surviving with moderately severe or severe disability, the OR was 4.26 (95%CI, 2.51-7.22;

P<0.00001) in patients aged >60 years, and 3.67 (95%CI, 1.16-7.65; P=0.0005) in patients aged ≤60 years. (Figure 11) The proportion

of patients with the mRS = 4 and 5 was significant increased from 22.28% to 55.27% in patients aged >60 years comparing DHC with

CT, and 15.86% to 44.21% in patients aged ≤60 years. We also find in the DHC group, patients with MMI aged >60 years had less

GFO (9.65% vs. 38.94%) and high risk for moderately severe or severe disability (55.27% vs. 44.21%) than those aged ≤60 years.
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(Figure 10) The pooled results showed a significant difference in mortality in patients aged >60 years compared DHC with CT

(OR=0.19; 95%CI, 0.12-0.33; P<0.00001), as well as in patients aged ≤60 years (OR=0.14; 95%CI, 0.07-0.27; P<0.00001) (Figure

12). The mortality reduced from 74.28% to 35.08% in patients aged >60 years compared DHC with CT, and from 62.19% to 16.85%
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in patients aged ≤60 years, as shown in Figure 10.

- Figure 9 about here -

- Figure 10 about here -

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- Figure 11 about here -

- Figure 12 about here -

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The influence of surgical timing on patients with MMI

There are 5 studies presented the data on GFO in different surgical timing groups (≤48h versus >48h) over 3 months follow-
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up.10,15,36-39 The pooled results did not showed any significant difference in GFO between early and late surgery (OR=1.31; 95%CI,
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0.61-2.82; P=0.49) (Figure 13). Six studies presented the data of mortality at different surgical timings at early stage (<1m) and long-
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term outcomes (>3m).10,15,36-39 Since no statistically significant heterogeneity between studies (I2=0% of early outcome, 0% of long-

term outcome), we applied fixed-effect model was applied. The pooled OR of mortality was 0.57 (95%CI, 0.21-1.56; P=0.27) at an
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early stage, 0.62 (95%CI, 0.30-1.31; P=0.21) at long-term outcome, as shown in Figure 14.
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The impact of study design on patients with MMI

A subgroup analysis to investigate the impact of different study designs (RCTs or OS) on pooled results of outcome measures

were performed (Table 2). The results indicated that no significant differences were observed on the majority of outcome measures

between RCTs and OS. There were only differences on GFO at 3 months (P=0.05) and on NIHSS score (P=0.01).

- Table 2 about here –

Quality Assessment and Publication Bias

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 The quality assessment of the included studies is shown in Table 1. Of included twenty-five studies, 14 RCTs was assessed

with the Cochrane Reviewer's Handbook 5.0.0., and 11 OSs were evaluated according to the Newcastle-Ottawa Scale (NOS). Of 14

RCTs, there were 8 studies conforming to the grade A, while the other 6 studies fitted to the grade B. The funnel plot showed that the
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publication bias is rather low regarding the GFO (Figure S1), mortality (Figure S2), moderately severe disability (mRS=4, Figure S3)

and severe disability (mRS=5, Figure S4), subgroup analysis of different age (Figure S5), and surgical timing (Figure S6). The

publication bias is moderate regarding NISHH and BI score (Figure S7 and S8).

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Discussion

We investigated the neurological functional outcomes of DHC for MMI based on 25 published clinical trials (written in English

and Chinese), which is much more comprehensive compared to previous meta-analysis.40-42 The present research made several
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principal findings: 1) DHC significantly increases the GFO and overall survival in patients of all ages with MMI, indicating that it is a

life-saving procedure. Compared with the CT group, an increased number of patients in DHC group survived with moderately severe

disability (mRS=4). However, there was no significant difference in survival between the two groups for patients with severe disability

(mRS=5). 2) The NISHH score in the DHC group was lower than that in the CT group, while the BI score in the DHC was higher; 3)

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Subgroup analysis suggested that patients aged >60 and ≤60 years, who underwent DHC had greater GFO and less mortality than

those in the CT group. However, compared to patients aged ≤60 years, patients aged >60 years had more unfavorable outcomes

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(mRS=4 or 5); 4) No significant differences in GFO and mortality were observed in the subgroup analysis of surgical timing (within

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48 h versus 48 h onwards); 5) No significant differences were observed in subgroup analysis of different study designs on the majority

of outcome measures between RCTs and OS, except on GFO at 3 months (P=0.05) and on NIHSS score (P=0.01). Although DHC is
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relatively safe and effective for patient with MMI as compared to CT, comprehensive consideration should be made to determine the
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proper treatment for patient with MMI, especially those age >60 years. The consideration should be based on clinical evidence, patient
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health status, acceptability of potential unfavorable outcomes, and the affordability of treatment.

Fairburn and Oliver first reported DHC as a treatment for increased ICP in 1956 by.43 With the continued development of
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neurosurgical techniques, a variety of treatment strategies has been developed and applied to control ICP, and relieve tissue edema,
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thereby preventing brain herniation. DHC for patients with MMI has been considered a lifesaving approach since the last decade.
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However, whether DHC decreases mortality, and improves long-term functional outcomes in patients with MMI at all ages, especially

patients aged >60 years, remain questionable. Moreover the effect of age and surgical time on the functional outcomes and mortality
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in MMI remain controversial.

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The definition of a mRS score of 4 is people when a patient is unable to walk and take care of their own bodily needs without

assistance.13 Based on this definition, a previous study evaluated the neurological functional outcome by applying mRS≤4 as the

favorable outcome measures. By contrast the results of the ORACLE stroke study in 2015 revealed that the majority of patients felt

that survival with a mRS = 4 was to an unaccepted outcomes.44 Therefore, we applied mRS≤3 as a standard of GFO, measuring

favorable neurological functional outcome between DHC- and CT- treated patients with MMI. The present study shows that the DHC

significantly improved GFO both in the short- and long-term follow-up. This result is consistent with two previous meta-analyses, in

which mRS≤3 were also applied as a favorable outcomes.40,41

Previous clinical trials have indicated that more surviving patients in the DHC group remained severely disabled.10-12,18,45 The
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trials suggested that mortality might have been decreased at the cost of the patients' prognosis and quality of life. Different results

were reported in two previous studies, which indicated no significant difference in the poor neurological outcomes (mRS=4, 5)

between DHC and CT groups at different follow-ups.40,41 However, by drawing this conclusion the authors of the two studies
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incorrectly calculated the proportion of patients with MMI with mRS = 4 and 5 by using the surviving patients in the DHC and CT

groups as the denominator. In fact, the denominator should have included all patients with MMI (including those who had died), as

there were more surviving patients in the DHC group. In this case, the studies did not accurately reflect the impact of different

treatments (DHC versus CT) on moderately severe or severe disability. Therefore, to compare poor neurological outcomes (mRS = 4,

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5) between DHC and CT more accurately, the proportion of patients surviving with moderately severe disability (mRS = 4) and severe

disability (mRS = 5) accounting for all patients with MMI was adopted. In our study, the proportion of survival with the mRS = 4 was

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significantly increased from 19.72% to 38.76% in the DHC group as compared with the CT group at 6 months, and from 13.97% to

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37.38% at 12 months; that of the surviving patients with the mRS = 5 only increased by 3%, with no significant difference between

the two treatment groups. This result is consistent with previous findings 13, suggesting no significant difference in the risk of patients
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surviving with mRS = 5 in the DHC group, as compared with the CT group. However, differing from the previous meta-analysis, we
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found that the probability of surviving with mRS = 4 increased significantly in DHC group, which indicated that the surviving patients
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were at higher risk of moderately severe disability. From the perspective of degrees of neurological recovery, DHC dramatically

reduces the mortality, while patients have higher risk of survival with moderately severe disability. Considering mRS = 4 as an
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unacceptable outcome and that being alive is worth preserving for many patients, even with severe disability , the decision to
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perform DHC should consider long-term moderately severe disability as a potential outcome. Thus, doctors should, in practice, declare
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the risk of survival with moderately severe disability before performing DHC.

With regard to mortality, we found that there was a significantly decreased mortality in the DHC group as compared with the CT
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group for patients of all ages with MMI. This finding was consistent with the previous meta-analysis although it is based on a limited
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number of RCTs.13 The previous meta-analysis provided evidence at the 12-months follow-ups that surgical decompression improves

survival of patients with MMI. By investigating mortality at different follow-ups between two treatment groups, we assessed mortality

at 30-days, 3-months, 6-months, 12-months and 36-months. Our findings further demonstrate that DHC reduces mortality at the

different time points, especially in the long term, i.e., up to 3 years. However, clinical trials implementing long-term follow-ups of

mortality are limited as they are time-consuming, costly, and hard to follow.

The NIHSS and BI scores have been described as important outcome predictors in patients with stroke.47-49 Our study is the first

meta-analysis to evaluate the NIHSS and BI scores between patients with MMI who underwent DHC or CT. Compared with the CT

group at 6 months, the NIHSS score was significantly decreased; inversely the BI score in the DHC group was significantly increased.
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This finding indicates that DHC significantly improves the prognosis and quality of life of patients with MMI. In addition, our results

suggest that the NIHSS and BI score could be potential indicators of early prediction of ischemia, which would help doctors determine

an optimal treatment strategy (such as hemicraniectomy).

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Age might have affected the GFO and mortality of patients with MMI between the two treatment groups. Previously studies have

suggested that DHC reduces mortality in patients with MMI aged ≤60 years as compared with CT, but the efficacy of DHC for patient

with MMI aged >60 years remains unclear.11,12,17,50-54 In the present study, we also performed subgroup analysis to compared GFO and

mortality in patients aged >60 and ≤60 years between the two treatment groups. Our findings showed increased GFO and survival in

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both groups when DHC was compared with CT. This finding suggests that DHC is an effective treatment for patients with MMI age

>60 and ≤60 years as comparing with CT.

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When we compared the influence of age on patients with MMI after the surgical treatment, patients aged ≤60 years had higher

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GFO than those aged >60 years (38.94% versus 9.65%). Moreover, we found that patients aged >60 years had higher risk of surviving

with moderately severe or severe disability as compared with those aged ≤60 years. In the DHC group, more aged >60 years died as
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compared to those aged ≤60 years (35.8% versus 16.85%). This finding is consistent with findings from a previous retrospective study,
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which suggested higher mortality in patients with MMI aged >60 as compared to those aged ≤60 years after the surgical treatment
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(33.3% versus 7.7%).55 Similar findings were observed in a study that compared the mortality of DHC for MMI in different age

groups through the 60-years cut-age, where the results showed 51.3% mortality in patients aged >60 years and 20.8% mortality in
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patients aged ≤60 years.46 This could be explained by the greater frequency of comorbidities in older age patients. Therefore, care
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should be taken when applying DHC for patients aged >60 years.47
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Surgical timing might affect impact MMI mortality and prognosis. A previous study showed that early DHC could decrease

mortality as compared with CT, while late surgery did not increase the survival between the two groups.41 However, the study did not
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compare the differences between surgical timings (early surgery: ≤48 h versus late surgery: >48 h) in the DHC group, but compared
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that between CT and DHC. In our study, we only included trials that reported the effects of surgical timing in the DHC group, as this

assessed the efficacy of surgical timing on the GFO and mortality in the DHC group more accurately. Our findings suggest no

significant difference between early surgery (≤48h) and late surgery (>48h) on GFO and mortality. This result is consistent with that of

a previous study.9 Moreover, the result of short-term (<1 months) and long-term (>3 months) follow-up was not significantly for GFO

and mortality between early and late surgery. These findings are somewhat similar to that of several clinical trials.56,57 Moreover,

another important question is when there is a difference in outcome of patients with MMI in order to define the optimal surgical

treatment window. Olnhausen et al. recently published a research investigated the time to surgical treatment on patients with MMI

comparing favorable outcomes and poor prognosis.58 The results showed the median time to surgery was 42.9 h in the favorable
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outcome group and 24.4 h in the unfavorable outcome group (p = 0.074). Since the patients with a massive infarction presenting

transtentorial herniation or pupillary dilation are more likely to receive surgery earlier than patients displaying mild neurological

symptoms, the level of infarction might influence the results. The determination of surgical timings lack of definite evidence, therefore
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further studies are needed to define the surgical treatment window for patient with MMI

For clinical practice, the decompressive craniectomy was considered as the major surgical procedure on patients with MMI.

Surgical techniques have improved significantly in the past decades, including addition of zygomatic arch resection，cranioplasty，

cisternostomy, etc..59-61 A recent research conducted by Cherian et al. suggested that cisternostomy as an emerging surgical treatment

61

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for TBI and might replace the DHC , which might provide a potential alternative therapy for MMI. However, regarding the

effectiveness and safety of cisternostomy as a surgical therapy for MMI, more large sample size clinical trials are needed.

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The present study although included 25 clinical trials with 14 RCTs and 11 OSs, has several limitations. First, Some included

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studies based on a relative small sample size, which might generate clinical bias; Second, small-volume observational studies might

have a tendency to report more impressive effects than those with large-volume and randomized studies; Third, our study did not
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evaluate DHC related complications because of insufficient data, considering complications from surgery intervention could have an
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influence the MMI patients’ prognosis. Thus future clinical trials with larger sample size should also consider complications as an
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outcome in study design. Forth, a research conduced by Schaller B et al. showed the DHC might cause some persisting

pathophysiological processes in cat brain.62 In addition, several clinical trials suggested that DHC could rapidly increase the cerebral
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vascular perfusion pressure causing aggravate cerebral edema and secondary brain injury on patients with traumatic brain injury.63,64
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Until now, the mechanism of this phenomenon is unclear. Therefore, further researches on this topic are needed to clarify this
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phenomenon. In clinical practice, this persisting pathophysiological processes caused by DHC should be taken into consideration for

surgical decision-making.
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Conclusions

Our research indicated that DHC could significantly improve the GFO and reduces the mortality of patients of all ages with

MMI as compared with CT. However, the proportion of surviving with moderately severe disability significantly increased (mRS=4)
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in DHC group comparing with CT group. The NIHSS and BI score could be considered as prognostic indicators on the MMI patients’

prognosis. In subgroup analysis of age, although DHC could improve the survival and GFO both in patients aged >60 and ≤60 years as

compared with CT, patients aged >60 years had higher risk of surviving with moderately severe or severe disability as compared with

those aged ≤60 years. The subgroup analysis of different surgical timings did not show any differences on GFO and mortality between

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early and late surgery groups. The decision to apply the DHC for MMI patients, especially for patients aged >60 years, should be

based on a combination of clinical evidence, patients’ health status, acceptability of potential unfavorable outcomes, and the

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affordability of treatment.

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Competing interests

All authors declare that they have no other relationships or activities that could appear to have influenced the submitted work.
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Figure and Table Legend

Figure 1. The PRISMA flow chart of the meta-analysis.

Figure 2. The pooled analysis of GFO comparing DHC with CT in patients of all ages with MMI at different follow-ups (GFO: good
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functional outcome; DHC: Decompressive hemicraniotomy; CT: conventional treatment; MMI: malignant middle cerebral artery

(MCA) infarction)

Figure 3. The neurological functional outcome of DHC versus CT in patients of all ages with MMI at 6 and 12 months follow-ups

(DHC: Decompressive hemicraniotomy; CT: conventional treatment; MMI: malignant middle cerebral artery (MCA) infarction)

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Figure 4. The pooled analysis of survival with moderately severe disability (mRS=4) comparing DHC with CT in patients of all ages

with MMI at 6 months and 12 months followed-up (DHC: Decompressive hemicraniotomy; CT: conventional treatment; MMI:

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malignant middle cerebral artery (MCA) infarction; mRS: modified Rankin Scale)

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Figure 5. The pooled analysis of survival with severe disability (mRS=5) comparing DHC with CT in patients of all ages with MMI at

6 months and 12 months followed-up. (DHC: Decompressive hemicraniotomy; CT: conventional treatment; MMI: malignant middle
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cerebral artery (MCA) infarction; mRS: modified Rankin Scale)
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Figure 6. The pooled analysis of mortality comparing DHC with CT in patients of all ages with MMI at different follow-ups (DHC:
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Decompressive hemicraniotomy; CT: conventional treatment; MMI: malignant middle cerebral artery (MCA) infarction)

Figure 7. The pooled analysis of NISHH score of DHC versus CT in patients of all ages with MMI at early stage (<1 month) and late
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followed-up (>3 months) (NIHSS: National Institutes of Health Stroke Scale; DHC: Decompressive hemicraniotomy; CT:
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conventional treatment; MMI: malignant middle cerebral artery (MCA) infarction)

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Figure 8. The pooled analysis of BI score of DHC versus CT in patients of all ages with MMI at 3 and 6 months follow-ups (BI:

Barthel Index score; DHC: Decompressive hemicraniotomy; CT: conventional treatment; MMI: malignant middle cerebral artery
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(MCA) infarction)
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Figure 9. The subgroup analysis of the influence of age (≤60 versus >60) on GFO comparing DHC with CT (GFO: good functional

outcome; DHC: Decompressive hemicraniotomy; CT: conventional treatment)

Figure 10. The neurological functional outcome of different age groups (≤60 versus >60) comparing DHC with CT at 12 months

follow-ups (DHC: Decompressive hemicraniotomy; CT: conventional treatment)

Figure 11. The subgroup analysis of the influence of age (≤60 versus >60) on the moderately severe or severe disability (mRS = 4 or

5) comparing DHC with CT (DHC: Decompressive hemicraniotomy; CT: conventional treatment; mRS: modified Rankin Scale)

Figure 12. The subgroup analysis of the influence of age (≤60 versus >60) on the mortality comparing DHC with CT (DHC:

Decompressive hemicraniotomy; CT: conventional treatment)

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Figure 13. The subgroup analysis of the GFO in patient underwent DHC treatment between early surgery and late surgery (GFO:

good functional outcome; DHC: Decompressive hemicraniotomy; CT: conventional treatment)

Figure 14. The subgroup analysis of the mortality on patient underwent DHC treatment between early surgery and late surgery (DHC:
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Decompressive hemicraniotomy; CT: conventional treatment)

Table 1. The characteristic of included studies.

Table 2. The subgroup analysis of the impact of different study design (RCT versus OS) on the pooled results

Figure S1. The funnel plot of GFO analysis

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Figure S2. The funnel plot of mortality analysis

Figure S3. The funnel plot of moderately severe disability (mRS=4)

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Figure S4. The funnel plot of severe disability (mRS=5)

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Figure S5. The funnel plot of subgroup analysis of the influence of age on patients with MMI

Figure S6. The funnel plot of subgroup analysis of the influence of surgical timing on patients with MMI
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Figure S7. The funnel plot of the NISHH score
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Figure S8. The funnel plot of the BI score

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 ACCEPTED MANUSCRIPT

Table I. The characteristic of included studies

Age Cases (M) Initial GCS
Study Date Design Follow up (m) Quality of RCTs NOS

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DHC CT DHC CT DHC CT
J Hofmeijer 10 2009 RCT 50 47.7 32(20) 32(18) 10 10 12 B /
K Vahedi 11 2007 RCT 43.5 43.3 20(9) 18(9) NG NG 12 A /
E Jüttler 12 2007 RCT 43.2 46.1 17(8) 15(7) NG NG 12 A /

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E Jüttler 14 2014 RCT 70 70 49(25) 63(31) 12 10 12 A /
J. Frank 15 2014 RCT 57.9 52.3 10(6) 14(9) NG OS 6 A /
J Slezins 16 2012 RCT 57.2 65 11 13 8.8 8.7 NG A /

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JW Zhao 17 2012 RCT 63.5 64 24(18) 23(16) 8.5 8 12 A /
M Geurts 18 2013 RCT NG NG 32 32 NG NG 36 B /
YJ Dai 23 2015 RCT 38.3 38.1 31 31 5.9 5.3 12 B /

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SB Fan 24 2014 RCT 52.67 54.09 35(20) 34(21) 14 15 12 B /
XC Liu 25 2014 RCT 64.8 66.6 55(30) 55(35) NG NG NG B /

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GQ Wu 26 2014 RCT 55.2 55.5 30(18) 30(19) 7.4 7.3 NG B /
JM Fu 27 2012 RCT NG NG 30 30 NG NG NG A /
WX Xu 28 2012 RCT 63.5 63.2 32(21) 32(17) NG NG 6 B /
A Rahmanian 29 2014 P-OS 59.0 62.1 30(11) 30(16) 6,9 6 3 / ★★★/★/★★

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V.K Rai 30 2014 P-OS 44.6 57.12 36(27) 24(16) 10.44 9.95 12 / ★★★/★/★★
CL Tsai 31 2012 P-OS 65.54 75.90 37(18) 42(22) 7.46 6.36 6 / ★★/★/★★

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M. AMR 32 2014 R-OS 53.8 53.8 90 35 6.9 6.0 6 / ★★/★/★★
J.W Yu 33 2012 R-OS 62.10 72.64 58 (35) 73(36) NG NG 6 / ★★/★/★★
A. Fiorot Jr. 34 2008 R-OS 52 68
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18 14 6 9 3 / ★★/★/★★
K. Mori 35 2001 R-OS 63.3 71.8 19 (13) 15 (7) 10.2 10.8 3 / ★★★/★/★★
W. Wang 36 2006 R-OS 61.60 66.73 21 (12) 41(27) 13.00 10.90 6 / ★★/★/★★
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K. Mori 37 2004 R-OS 65 72 50 (36) 21 (8) 11.2 6.7 6 / ★★★/★/★★

XF Yang 38 2005 R-OS 58.7 65.9 10 (5) 14(10) NG NG 3 / ★★/★/★★
ZL Hao 39 2015 R-OS 53.19 63.68 31(14) 188(87) 8 10 12 / ★★/★/★★
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DHC: decompressive hemicraniotomy; CT: conventional treatment; GCS: Glasgow Outcome Scale; RCT: randomised controlled trial; OS: observational study; NG: no given.
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P-OS: prospective observational study; R-OS: retrospective observational study; NOS: Newcastle-Ottawa Scale.
 ACCEPTED MANUSCRIPT

Table 2: Subgroup analysis of the Impact of different study design (RCT versus OS) on the pooled results
Outcome RCT OS p
Measures Studies Participants OR Studies Participants OR

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GFO 3m 3 144 4.25 [1.88, 9.61] 5 303 14.40 [5.75, 36.07] 0.05
6m 6 277 3.15 [1.49, 6.69] 7 592 4.10 [2.51, 6.70] 0.56
12m 7 424 1.95 [1.19, 3.19] 2 279 4.49 [1.96, 10.27] 0.09

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mRS=4 6m 6 317 3.90 [2.23, 6.83] 2 133 1.96 [0.86, 4.44] 0.17
12m 6 359 4.36 [2.55, 7.46] 1 219 1.56 [0.58, 4.19] 0.07
mRS=5 6m 6 317 1.20 [0.66, 2.18] 2 133 1.44 [0.47, 4.42] 0.78

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12m 6 359 1.08 [0.57, 2.04] 1 219 0.73 [0.21, 2.60] 0.59
Mortality 1m 5 286 0.23 [0.12, 0.44] 7 664 0.22 [0.15, 0.33] 0.95
6m 5 253 0.19 [0.11, 0.33] 7 501 0.24 [0.16, 0.36] 0.49

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12m 8 447 0.18 [0.11, 0.28] 2 279 0.28 [0.14, 0.53] 0.27
Age GFO >60y 2 140 1.82 [0.45, 7.37] 3 149 4.94 [1.21, 20.09] 0.32

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<60y 4 152 1.99 [0.99, 4.01] 2 25 6.84 [0.66, 70.90] 0.32
mRS=4, or 5 >60y 2 140 4.19 [1.99, 8.82] 3 149 4.32 [2.04, 9.18] 0.95
<60y 4 152 5.03 [2.18, 11.63] 2 25 0.96 [0.18, 5.28] 0.09
mortality >60y 2 140 0.19 [0.09, 0.40] 3 149 0.20 [0.09, 0.41] 0.95

M
<60y 4 152 0.16 [0.08, 0.32] 2 25 0.07 [0.01, 0.80] 0.55
Surgical Timing GFO 2 46 1.02 [0.26, 3.95] 3 102 1.48 [0.58, 3.76] 0.66
Early Outcome 1 14 0.60 [0.04, 8.73] 3 91 0.57 [0.19, 1.67] 0.97

D
Long-term Outcome 2 46 0.70 [0.18, 2.73] 3 102 0.60 [0.25, 1.45] 0.85
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RCT: randomised controlled trial; OS: observational studie; GFO: good functional outcome; mRS: modified Rankin Scale; NIHSS: National Institutes of Health Stroke Scale;

BI: Barthel Index score; GOS: Glasgow Outcome Scale; OR: odds ratio;
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Highlights
• This comprehensive meta-analysis investigated the long-term neurological functional outcomes

and mortality of DHC for MMI based on 25 published clinical trials.

• Several subgroup analyses were conducted to evaluated the impact of age (>60 versus ≤60) and

surgical timing (early versus later) on neurological function and mortality.

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• Our study is the first meta-analysis applying the NIHSS and BI scores as outcome measures to

evaluate patient’s neurological functional recovery.

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Abbreviations list:

DHC: decompressive hemicraniectomy

CT: conventional treatments

MMI: malignant middle cerebral artery infarction

GFO: good functional outcome

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NIHSS score: National Institutes of Health Stroke Scale score

BI score: Barthel Index score.

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Disclosure-Conflict of Interest
All authors declare that they have no conflict interest and other relationships or activities that could appear to
have influenced the submitted work.

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