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Cerebral Hyperperfusion Syndrome After Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Meta-Analysis
Journal Pre-proof Cerebral Hyperperfusion Syndrome after Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Meta-analysis Jin Yu, MD, Jibo Zhang, MD, Jieli Li, B.S, Jianjian Zhang, Ph.D, Jincao Chen, Ph.D., Prof. PII:
S1878-8750(19)32903-1
DOI:
https://doi.org/10.1016/j.wneu.2019.11.065
Reference:
WNEU 13734
To appear in:
World Neurosurgery
Received Date: 6 July 2019 Accepted Date: 12 November 2019
Please cite this article as: Yu J, Zhang J, Li J, Zhang J, Chen J, Cerebral Hyperperfusion Syndrome after Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Metaanalysis, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.11.065. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Manuscript title Cerebral Hyperperfusion Syndrome after Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Meta-analysis
Authors Jin Yu, MD1）,* ; Jibo Zhang, MD1), *; Jieli Li, B.S1); Jianjian Zhang, Ph.D 1); Jincao Chen, Ph.D., Prof.1)
1) Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China * These authors contributed equally to this work
Corresponding authors: Jincao Chen Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan 430071, China Tel: +86 027 67813118 Fax: +86 027 67813118 Email: [email protected]
Keywords: Cerebral hyperperfusion syndrome; Moyamoya disease; Incidence; Bypass surgery Running head: Cerebral hyperperfusion syndrome in moyamoya disease Sources of financial support: None
Number of words:3,210 words Figures: 4 Tables: 2
1
Authors' contributions Jin Yu contributed to conceptualization, methodology, software, formal analysis, investigation, writing – original draft preparation of the study. Jibo Zhang contributed to methodology, software of the study. Jianjian Zhang and Jincao Chen contributed to supervision and project administration of the study. Jieli Li contributed to data curation and writing – review and editing of the data. All authors read and approved the final manuscript. Acknowledgments The authors thank all participants in the study. Disclosure The author reports no conflicts of interest in this work.
2
1
Manuscript title:
2
Cerebral Hyperperfusion Syndrome after Revascularization Surgery in Patients with
3
Moyamoya Disease: Systematic Review and Meta-analysis
4 5
Short title: Cerebral Hyperperfusion Syndrome in Moyamoya Disease
6 7
Abstract:
8
BACKGROUND: Cerebral hyperperfusion syndrome (CHS) following bypass surgery is
9
known as a complication of moyamoya disease (MMD). However, the incidence of CHS
10
has not been accurately reported, and there is no consensus on related risk factors.
11
OBJECTIVE: To evaluate the incidence and characteristics of CHS in patients with
12
MMD after revascularization surgery via meta-analysis.
13
METHODS: Relevant cohort studies were retrieved through a literature search in
14
PubMed, Embase and Ovid until December 1, 2018. Eligible studies were identified per
15
search criteria. A systematic review and meta-analysis were used to assess the CHS total
16
incidence, incidence in pediatric MMD patients and adult MMD patients, incidence for
17
direct and combined bypass surgery, progress rate, proportion of each symptom (included
18
transient neurological deficits (TNDs), haemorrhage and seizure).
19
RESULTS: A total of 27 cohort studies with 2,225 patients were included in this
20
meta-analysis. The weighted proportions per random-effects model were 16.5% (11.3%
21
to 22.3%) for the CHS total incidence, 3.8% (0.3% to 9.6%) for pediatric MMD patients,
22
and 19.9% (11.7% to 29.4%) for adult MMD patients, 15.4% (5.4% to 28.8%) for direct
23
bypass surgery and 15.2% (8.4% to 23.2%) for combined bypass surgery. Progress rate
24
was 39.5% (28.7% to 50.8%). The most common CHS-related symptoms were TNDs
25
70.2% (56.3% to 82.7%), followed by haemorrhage 15.0% (5.5% to 26.9%) and seizure
26
5.3% (0.6% to 12.9%).
27
CONCLUSION: CHS is a common complication after revascularization surgery in
28
MMD. It is more frequently seen in adult patients. The most common CHS-related
29
symptoms were TNDs, followed by haemorrhage and seizure.
30
KEYWORDS: Cerebral hyperperfusion syndrome, Moyamoya disease, Incidence,
31
bypass surgery 1
32
Introduction
33
Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive
34
stenosis or occlusion of the internal carotid artery and/or its terminal branches, which
35
results in an abnormal development of compensatory vascular networks with tiny blood
36
vessels ("moyamoya vessels") at the base of the brain1. MMD has been found all over the
37
world, especially in Japan, Korea and China2. According to epidemiological data, the
38
morbidity and incidence of MMD in East Asian countries or the United States are
39
increasing year by year. MMD is the most common pediatric cerebrovascular disease in
40
East Asia, which leading to high morbidity, disability and even death3. The main clinical
41
manifestations of MMD include cerebral ischemia caused by stenosis or occlusion of
42
cerebral artery and intracranial haemorrhage caused by the rupture of fragile vessels in
43
compensatory network4. Ischemic symptoms, such as transient ischemic attack or
44
cerebral infarction5, 6, are predominant in paediatric MMD, while intracranial
45
haemorrhage in adult cases7, 8. Surgical revascularization, such as superficial temporal
46
artery-middle cerebral artery (STA-MCA) direct bypass surgery, is effective in
47
improving damages associated with intra-cerebral haemorrhage. The use of indirect
48
bypass of vascularized donor tissues such as encephalo-duro-arterio-myo-synangiosis
49
(EDMS) is also considered a valid treatment for MMD9.
50
Cerebral hyperperfusion syndrome (CHS), characterized by a series of neurological
51
deficits induced by postoperative high cerebral blood flow (CBF) perfusion, is one of the
52
most serious complications of revascularization surgery for MMD, especially in adult
53
patients10, 11. It occurs in up to 50% of MMD patients after direct bypass surgery12, and its
54
clinical symptoms may vary from minor discomforts such as headache, aphasia,
55
hemiparesis, paresis, facial palsy, and limb weakness, to major signs such as dysarthria
56
and intra-cerebral haemorrhage13. Most of these symptoms may completely resolve in 2
57
weeks without permanent brain injury14,15. CBF can well reflect the state of cerebral
58
perfusion. It is often used to diagnose or predict the occurrence of CHS by detecting the
59
changes of CBF in clinic10. Numerous imaging diagnostic methods such as 123I
60
N-isopropyl-p-iodoamphetamine
61
(SPECT), magnetic resonance imaging (MRI) and magnetic resonance angiography
62
(MRA) have been used to measure the change of CBF pre- and postoperative16,17,18,19.
single-photon
2
emission
computed
tomography
63
Though various studies have reported this complication, the molecular mechanism of
64
CHS remains unclear.
65
Although multiple previous studies on CHS in MMD patients treated with bypass
66
surgery have been published, most of them were of limited sample size and reported
67
inconsistent findings. We have therefore performed a systematic review and
68
meta-analysis to examine the incidence and characteristics of CHS.
69
Methods
70
The present meta-analysis was reported in accordance with the Preferred Reporting Items
71
for Systematic reviews and Meta-Analysis (PRISMA) guidelines.
72
Search strategy and study identification
73
A comprehensive literature search in PubMed, Embase and Ovid was performed. Search
74
terms included all possible combinations of ‘moyamoya disease’, ‘perfusion’,
75
‘hyperperfusion’, ‘complication’, ‘operation’, and ‘revascularization’ (both as a Medical
76
Subject Heading [MeSH] and free text term). Only human studies published in English or
77
Chinese up to December 1, 2018, were considered. References in identified articles were
78
also manually screened.
79
Selection criteria
80
Inclusion criteria: ① Patients with MMD diagnosis confirmed by radiological and
81
clinical criteria. ② treated by surgical bypass procedures. ③ confirmed diagnosis of
82
CHS after revascularization surgery . ⑤ clinical randomized controlled trial or
83
observational study.
84
Exclusion criteria: ① incomplete data（lack of information on the number of
85
operations, number of CHS, or specific bypass methods）; ② sample size < 10; ③
86
study population already included in another study; ④ study presented by languages
87
other than English or Chinese; and ⑤review articles or technical notes.
88
Two reviewers independently examined the titles, abstracts and full texts of all
89
study reports identified by the literature search, to select eligible studies that met the
3
90
inclusion and exclusion criteria. Discrepancies between the two reviewers were resolved
91
by discussion.
92
Data extraction
93
Two reviewers independently extracted the following data from the included studies: ①
94
study characteristics (year of publication, country and cohort size), ② patient
95
characteristics (age, gender, population, method and criteria for MMD diagnosis, and
96
type of surgical treatment performed) and ③ outcome measures (number of operated
97
hemispheres, number of patients with postoperative hyper-perfusion, number of CHS
98
cases, and profile of CHS-related symptoms). A third investigator double-checked the
99
extracted data, resolved discrepancies and corrected errors.
100
Statistical analysis
101
The following rates were transformed with the Freeman-Tukey variant of arcsine square
102
prior to statistical pooling (the CHS incidence in all subjects, CHS incidence in pediatric
103
MMD patients, incidence in adult MMD patients, incidence for direct bypass surgery,
104
incidence for combined bypass surgery, progress rate, proportion of each symptom
105
(included transient neurological deficits (TNDs), haemorrhage and seizure) in CHS). For
106
any given outcome of interest, all studies with available data were included for
107
meta-analysis. Transformed proportions were then combined by random-effects model（
108
Considering significant heterogeneity is common in pooled analysis of event rates,
109
meta-analyses by random-effects model were performed）. The I2 statistic and Cochran’s
110
Q test were used to evaluate between-study heterogeneity and the funnel plots with
111
Egger’s test were used to assess publication bias.
112
version 3.5.1(The R Foundation for Statistical Computing) and the package ‘meta’. All
113
statistical tests were two sided. Results were considered statistically significant when p <
114
0.05.
115
4
All analyses were performed using R
116
Results
117
Literature search and included studies
118
1,120 publications were initially identified as potentially relevant studies (Figure 1). 134
119
records were excluded as duplicates and 937 studies were excluded after title and abstract
120
review. Full texts were retrieved for 49 studies. 22 studies were excluded per exclusion
121
criteria. A total of 27 studies were included in the final meta-analysis (Table 1) 16, 18, 20, 21,
122
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44.
123
All studies were published between 2007 and 2018. The majority of studies (92.6%)
124
were conducted either in the Japan (n = 21) or China (n = 4). The median number of
125
operated hemispheres was 55 (range 12 – 500).
126
Meta-analysis
127
According to random-effects meta-analyses of rates, the pooled rate was 16.5% (n = 27,
128
95% confidence interval (CI) = [11.3%, 22.3%]) for CHS total incidence (Figure 2A,B);
129
3.8% (n = 10, 95% CI = [0.3%, 9.6%]) in pediatric and 19.9% (n = 19, 95% CI [11.7% to
130
29.4%]) in adults (Figure 3A, B), 15.4% (n = 9, 95% CI [5.4% to 28.8%] for direct
131
bypass surgery and 15.2% (n = 13, 95% CI [8.4% to 23.2%] for combined bypass surgery
132
(Figure 3C,D). Progress rate was 39.5% (n = 8, 95% CI [28.7% to 50.8%]) (Figure 4A).
133
The most common CHS-related symptoms were TNDs 70.2% (n = 21, 95% CI [56.3% to
134
82.7%]) (Figure 4B), followed by haemorrhage 15.0% (n=21, 95% CI [5.5% to 26.9%])
135
and seizure 5.3% (n = 8, 95% CI [0.6% to 12.9%]), respectively (Figure 4C, D).
136
Heterogeneity evaluation by I2 statistic and Cochran’s Q test could be found in
137
Table 2. The funnel plot for each outcome parameter (see online supplementary Figure
138
S1-8).
139
Discussion
140
CHS was first described by Uchino et al in 1998.45 In recent years, the understanding of
141
CHS has evolved from the concept of “reactive hyperaemia and luxury perfusion” to a
142
syndrome including a spectrum of symptoms induced by abnormal elevation of CBF after
143
operation.46 As the artificial anastomosis of extracranial-intracranial (EI-IC) vascular
144
system, the un-regulation to a sudden hemodynamic converting led to abnormally 5
145
increases of CBF, and caused a series of transient or permanent neurological impairment.
146
As a common complication after revascularization of MMD, more attention should be
147
paid to CHS in case of serious consequences.
148
Incidence of CHS:
149
In recent years, many clinical researches have reported CHS after MMD surgery. The
150
incidence of CHS was generally around 17%.47 Our meta-analysis showed a pooled total
151
incidence for CHS with 16.5% (11.3% to 22.3%), which was consistent with previous
152
reports. The CHS was more frequent compared to other postoperative complications,
153
such
154
postoperative hypoperfusion, poor scalp healing and infection51, 52, 53 and some other rare
155
complications.9 Accordingly, in order to improve the clinical therapeutic effect of MMD,
156
it was important to pay more attention to CHS and establish a systematic program for the
157
prevention and management of this syndrome.
as postoperative infarction/stroke,48,
49
postoperative bypass
occlusion,50
158
Studies also reported the frequency of CHS among patients treated with different
159
surgical procedures, in different age groups, and with different preoperative onset types.
160
There was a consensus that CHS was more prevalent in adult patients with MMD.
161
Indeed, our systematic analysis showed that the incidence of CHS was much higher in
162
adult patients (19.9% (11.7% to 29.4%)) than in pediatric patients (3.8% (0.3% to 9.6%)).
163
We speculated that this phenomenon may be related to the difference in cerebrovascular
164
quality between adults and children. As the formation and development of collateral
165
compensatory vessels in adults was generally less notable than those in children,54 when
166
blood flow from the extra-cranial circulation system has been suddenly introduced into
167
the affected area, a large number of incoming flow could be more hard to effectively
168
shunt in the surgical hemisphere in adults than in pediatric patients, and thus induced the
169
increase of local perfusion, which could cause serious consequences more easily for
170
adults.
171
Our study showed that the choice of direct (15.4% (5.4% to 28.8%)) or combined
172
(15.2% (8.4% to 23.2%)) surgery has no effect on the incidence of CHS. We believed
173
that this was due to the similar interference of hemodynamics in both surgical procedures.
174
Other studies suggested that CHS also occurred when MMD was treated indirectly
6
175
alone.11 However, we have note that indirect surgical treatment of MMD alone was very
176
rare in the literature. This might be due to the fact that in clinical practice it is routinely
177
involved the direct revascularization to completely eliminate the causes of ischemia and
178
haemorrhage, which makes it very difficult to obtain data on the incidence of CHS after
179
indirect surgery.
180
Although CHS was not specific in MMD after revascularization, studies have
181
compared the revascularization of a variety of cerebrovascular diseases (including carotid
182
endarterectomy (CEA) or carotid artery stenting (CAS) for carotid artery stenosis, bypass
183
surgery for atherosclerotic cerebrovascular disease and bypass surgery for MMD),28 and
184
the incidence of postoperative CHS was found to be significantly higher in patients with
185
MMD, which has been confirmed previously.27
186
Diagnosis of CHS:
187
With the rapid development of imaging technology, more and more methods become
188
available for the detection of CBF and assessment of the regional or global cerebral
189
perfusion status after surgery. Conventional methods of CBF measurement, including
190
SPECT, MRI, MRA, P-CT and Xe-CT, could effectively evaluate the CBF pre- and
191
post-operation.17, 55 SPECT is the most typical one, and has been regarded as the gold
192
standard for examining CBF perfusion and diagnosing CHS. Indeed, more than 70% of
193
the studies we collected used SPECT as the diagnostic tool. The diagnostic criteria for
194
CHS included all the following: (1) The presence of a significant focal increase in CBF,
195
which was confined to the vascular territory of one major branch of the middle cerebral
196
artery (MCA), at the site of the anastomosis, which is responsible for apparent focal
197
neurological signs. (2) Apparent visualization of STA-MCA bypass by MRA and the
198
absence of any ischemic changes by diffusion-weighted imaging (DWI). (3) The absence
199
of other pathologies such as compression of the brain surface by the temporal muscle
200
inserted for indirect pial synangiosis, ischemic attack, venous infarction, or CBF increase
201
secondary to seizure. In addition to these items, the blood pressure-dependent
202
aggravation of symptoms and/or amelioration of symptoms by clinically lowering blood
203
pressure indicated a diagnosis of CHS.
204
caused by CHS were usually significant from the second to the seventh day after
20, 23, 32
7
Because the neurological symptoms
205
operation, many studies suggested that SPECT should be performed within 48 hours after
206
operation to evaluate cerebral perfusion, and then on the second and seventh days,
207
respectively.56 In addition, in order to confirmed the efficiency of anastomotic
208
connection, it was recommended that SPECT should be performed immediately after
209
operation.29
210
Interestingly, in recent years, more methods such as indocyanine green videography
211
(ICG-VG), fluid attenuated inversion recovery (FLAIR) images, positron emission
212
tomography (PET), multi-inversion time arterial spin labelling (mTI-ASL), and
213
technetium-99m-hexamethylpropyleneamine
214
reported to be used in clinical examination of CBF after MMD.57, 58, 59, 60, 61, 62 Moreover,
215
some studies have proposed other indicators trying to replace CBF to indicate the
216
cerebral perfusion status after surgery, such as cerebrovascular reactivity (CVR) value
217
and mean transit time (MTT).63, 64, 65 However, the effectiveness of these methods and
218
indicators still needed more investigation.
219
Progress of CHS:
220
At present review, we evaluated the progress rate of CHS, which means the proportion of
221
patients developed from hyperperfusion to symptomatic hyperperfusion syndrome. We
222
compared the sample size of hyperperfusion and symptomatic hyperperfusion, and found
223
a progress rate of 39.5% (28.7% to 50.8%). Interestingly, the proportions of MMD
224
patients with elevated CBF after revascularization was relatively high,23, 26, 33 while the
225
proportions of CHS was significantly lower. We speculated that there were two possible
226
reasons: 1. The self-regulation of cerebrovascular allowed patients gradually adapt to
227
hyperperfusion, and developed into asymptomatic hyperperfusion; 2. Clinical
228
prophylactic lower blood pressure and drug treatment have alleviated the progress of
229
hyperperfusion.29, 33, 37
230
Symptoms of CHS:
231
CHS usually caused transient neurological impairment which usually completely relieved
232
in 7-14 days after operation without permanent cerebral damage. However, it should be
233
noted that intracranial haemorrhage and subarachnoid haemorrhage secondary to CHS
234
may lead to serious consequences.39 Our statistics showed that TNDs (70.2% (56.3% to 8
oxime
(99mTc-HMPAO)
have
been
235
82.7%)) was the most common CHS-related symptoms, followed by haemorrhage
236
(15.0% (5.5% to 26.9%)) and seizure (5.3% (0.6% to 12.9%)).
237
The detailed classification of TNDs included aphasia, hemiparesis, headache, facial
238
palsy, etc.42 TNDs was mainly due to the transient dysfunction of the related neurological
239
areas caused by high local perfusion, high pressure or local edema. The specific
240
mechanism of TNDs was still unclear, and it was believed that the reversible decrease of
241
cerebral metabolism and the repression of cortical neurotransmitter receptor function
242
caused by post-operation hyperperfusion may partially explained the occurrence of
243
TNDs.66 Other theories included the increase of free radicals after vascular surgery, were
244
trying to explain this phenomenon.44 In fact, the appearance of TNDs was not only
245
related to hyperperfusion, but also to hypoperfusion after operation. It might be due to the
246
blood flow competition caused by the damage of brain self-regulation and the fluctuation
247
of cerebral microcirculation.67
248
Cerebral haemorrhage caused by CHS was not uncommon,46,
68
but its exact
249
mechanism was still unclear. It might be that excessive hemodynamic stress on fragile
250
vessels triggered increased vascular permeability and subsequent bleeding. At the same
251
time, because reactive oxygen species (ROS) was related to cerebral ischemia/reperfusion
252
injury, the overproduction of ROS during vascular remodeling might affect vascular
253
permeability and the maintenance of vascular structure.69 In addition, some studies have
254
found that the serum level of matrix metalloproteinases (MMP) in patients with MMD
255
was significantly higher than that in normal controls. Increased expression of MMP-9
256
might lead to pathological angiogenesis and/or instability of vascular structure, decreased
257
the quality of cerebrovascular and regulating ability to cope with the stress of
258
hemodynamic changes, which might lead to haemorrhage in MMD.70
259
Several studies have reported seizure after bypass methods of MMD patients, and
260
the incidence were not low.71,72 However, whether this symptom was caused by CHS or
261
some other pathogeny was hard to distinguish. According to the literatures we collected,
262
seizure caused by CHS was not that common than previous reports. We speculated this
263
was due to no clear distinction between the causes of postoperative seizure. As the
264
postoperative seizure usually were classified into 3 types based on the time interval after
265
surgery: immediate seizures, early seizure and late seizure,70 and the corresponding 9
266
treatment methods were different, it was significant to clarify the accurate cause when
267
seizure occurred.
268
Risk factors for CHS:
269
Many risk factors, such as patient characteristics, onset types, surgical methods and
270
surgical hemisphere, have been extensively studied,14,
271
unified conclusion. At present, adult-onset is the most recognized risk factor for CHS
272
after MMD surgery. Our conclusion also confirmed that adult-onset MMD is more likely
273
to have postoperative CHS and the reason has been discussed previously. Some studies
274
have mentioned that patients with hemorrhagic MMD were susceptible to CHS.26
275
However, other studies have suggested that ischemia or hemorrhagic onset has no
276
significant difference on the morbidity of post-operative CHS.73 The seeking for
277
predictive indicators of post-operative CHS, including new biomarkers,74 remains to be
278
explored.
279
Management of CHS:
280
The prophylactic management of CHS was essential because the clinical conditions of
281
patients could become more complex once they became symptomatic.32 Therefore, we
282
instituted
283
complications: (1) General anesthesia is continued after bypass surgeries; (2) When
284
hyperperfusion is observed by our methods, strict blood pressure control under sedation
285
is continued until the CBF falls to normal; and (3) The free radical scavenger edaravone,
286
which reduces the incidence of hyperperfusion-related TNDs, is administered.33, 38
the
following
counter
measures
to
20, 26, 28
prevent
but there was still no
hyperperfusion-related
287
Fujimura et al have managed postoperative CHS by intravenous administration of
288
minocycline hydrochloride (200 mg/day) under strict blood pressure control, and did not
289
suffer any neurological deterioration during the perioperative period. Postoperative
290
magnetic resonance imaging showed no evidence of vasogenic edema and therefore
291
considered minocycline has potential role for preventing cerebral hyperperfusion to be
292
symptomatic, by blocking MMP-9 in the acute stage after EC-IC bypass.75
293
Although blood pressure lowering is generally accepted as the standard
294
management of CHS, the risk of ischemic complications in the acute stage is high with
295
blood pressure lowering under an anesthetic state according to Kawamata et al.22 To 10
296
resolve this problem, Fujimura et al prefered prophylactic blood pressure control between
297
110 and 130 mmHg in the acute stage on patients in a conscious state, which effectively
298
lowered the risk of CHS following EC–IC bypass for MMD below that of the patients
299
treated under normotensive conditions.32
300
Strengths and limitations
301
This is, to our knowledge, the first meta-analysis to report the CHS after
302
revascularization surgery in patients with MMD. We assessed CHS total incidence,
303
incidence in pediatric MMD patients, incidence in adult MMD patients, incidence for
304
direct bypass surgery, incidence for combined bypass surgery, progress rate, proportion
305
of each symptom included TNDs, haemorrhage and seizure in CHS. All of this makes our
306
results more reliable.
307
We would like to acknowledge several limitations in our study. Firstly, studies span
308
a wide period of time, from 2007 to the present. Potential heterogeneity can present in
309
study indications (selection bias), patient baseline characteristics (institutional referral
310
bias), medical standards, surgeons’ skill and laboratory testing. Secondly, we did not
311
study the incidence of CHS for indirect surgery, because the data of many studies did not
312
explicitly segment it. Lastly, we have limited data on addressing the above potential bias
313
in our study that may also influence our results. Outcome analysis was performed only in
314
papers with available data. Some studies included feasible data, but we cannot get the
315
data for being restricted by language, were excluded accordingly, leading to reduced
316
sample size and potential selection bias.
317
Conclusion
318
CHS is a common complication after revascularization surgery in MMD patients. It is
319
more frequently seen in adult patients. The most common CHS-related symptoms were
320
TNDs, followed by haemorrhage and seizure.
321
Conflict of interest statement
322
None.
11
323
Funding
324
None.
325 326
References
327
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567
20
568
Figure Legends
569 570
Figure 1 Flow chart for search strategy and study selection.
571 572
Figure 2
573
(A) Forest plots of total incidence of CHS assessed in the present meta-analysis. Squares
574
and horizontal bars indicate point estimate and 95% CI of proportions in each
575
individual study, respectively. Diamonds indicate summary estimates that are
576
calculated per random-effects model. Column ‘Total’ represents the total number of
577
patients in each study.
578 579
(B) Funnel plot for total incidence of CHS was grossly symmetrical with the most data points within the funnel area.
580 581
Figure 3
582
(A) Forest plots of incidence of CHS for pediatric,
583
(B) Forest plots of incidence of CHS for adult ,
584
(C) Forest plots of incidence of CHS for direct bypass surgery
585
(D) Forest plots of incidence of CHS for combined bypass surgery
586
Squares and horizontal bars indicate point estimate and 95% CI of proportions in each
587
individual study, respectively.
588 589
Figure 4
590
(A) Forest plots of progress rate
591
(B) Forest plots of proportion of TNDs in CHS
592
(C) Forest plots of proportion of haemorrhage in CHS
593
(D) Forest plots of proportion of seizure in CHS
594
Squares and horizontal bars indicate point estimate and 95% CI of proportions in each
595
individual study, respectively.
596 597 598
21
599
Supplemental figure Legends
600 601
Supplementary figure 1. Funnel plot for Incidence of CHS in pediatric MMD patients
602
demonstrates approximately symmetrical.
603 604
Supplementary figure 2. Funnel plot for Incidence of CHS in adult MMD patients
605
demonstrates mild asymmetry.
606 607
Supplementary figure 3. Funnel plot for Incidence of CHS for direct bypass surgery
608
demonstrates mild asymmetry.
609 610
Supplementary figure 4. Funnel plot for Incidence of CHS for combined bypass surgery
611
demonstrates mild asymmetry.
612 613
Supplementary figure 5. Funnel plot for Progress rate demonstrates approximately
614
symmetrical.
615 616
Supplementary figure 6. Funnel plot for Proportion of TNDs in CHS demonstrates
617
approximately symmetrical.
618 619
Supplementary figure 7. Funnel plot for Proportion of haemorrhage in CHS
620
demonstrates approximately symmetrical.
621
22
622
Supplementary figure 8. Funnel plot for Proportion of seizure in CHS demonstrates
623
approximately symmetrical.
23
Table 1. The main characteristics of included studies (1) No. of Authors & Year
Country
Patient Population
Operations
Diagnostic Tools
Surgery
Methods
Fujimura M et al., 2007 16
JPN
Adult
34
SPECT
Direct/Combined
STA-MCA + EDMS
Fujimura M et al., 2008 20
JPN
Pediatric
17
SPECT
Direct/Combined
STA-MCA + EDMS
Nakagawa A et al., 2009 21
JPN
Both
26
SPECT
Combined
STA-MCA + EDMS
MikiFujimura et al., 2009 22
JPN
Both
80
SPECT
Direct/Combined
STA-MCA + EDMS
Zhao H et al., 2009 23
CHN
Both
18
SPECT
Direct/Indirect
STA-MCA / EDMS
Kawamata T et al., 2011 24
JPN
Both
27
Xe-CT
Direct
STA-MCA
Miki Fujimura et al., 2011 25
JPN
Both
121
SPECT
Direct/Combined
STA-MCA + EDMS
JPN
Both
150
SPECT
Combined
STA-MCA + EDMS
JPN
Both
40
SPECT
Combined
STA-MCA + EDMS
Uchino H et al., 2012 28
JPN
Both
58
SPECT
Combined
STA-MCA + EDMS
Kaku Y et al., 2012 29
JPN
Adult
42
SPECT
Direct
STA-MCA
Sugino T et al., 2013 18
JPN
Both
15
SPECT
Direct/Combined
STA-MCA + EDMS
Kr
Adult
99
SPECT
Direct
STA-MCA
JPN
Both
12
SPECT
Direct/Combined
STA-MCA + EDMS
Fujimura M et al., 2012 Hayashi K et al., 2012
26
27
J.W.Hwang et al., 2013 30 Uchino H et al., 2014 31
1
Horie N et al., 2014 32
JPN
Both
55
SPECT
Combined
STA-MCA + EMS
Wang D et al., 2015 33
CHN
Adult
14
PWI
Combined
STA-MCA + EDMS
Fujimura M et al., 2015 34
JPN
Adult
23
SPECT
Combined
STA-MCA + EDMS
JPN
Adult
92
SPECT
Direct/Combined
STA-MCA + EDMS
Sato K et al., 2016 36
JPN
Both
25
SPECT
Combined
STA +EMS/EGS
Kashiwazaki D et al., 2017 37
JPN
Adult
176
SPECT
Combined
STA-MC+EDMS
Kraemer M et al., 2018 38
GER
Adult
64
MRI
Direct/Combined
STA-MCA+EDMS
Nomura S et al., 2018 39
JPN
Adult
72
Xe-CT
Direct
STA-MCA
Ishiguro T et al., 2018 40
JPN
Adult
52
Xe-CT
Direct
STA-MCA
Ishikawa T et al., 2018 41
JPN
Both
251
Xe-CT
Direct
STA-MCA
Zhao M et al., 2018 42
CHN
Both
500
MRI/CT
Direct/Combined
STA-MCA+EMS
Yang T et al., 2018 43
JPN
Both
105
SPECT
Direct/Combined
STA-MCA+EMS
CHN
Both
57
P-CT
Combined
STA-MCA+EMS
Uchino H et al., 2016
Xu S et al., 2018
35
44
Notes: JPN: Japan, CHN: China, Kr: Korea, GER: Germany; NA: not applicable, SPECT： ：123I N-isopropyl-p-iodoamphetamine single-photon emission computed tomography, Xe-CT: xenon-computed tomography; PWI: Perfusion-weighted imaging, MRI: magnetic resonance imaging, P-CT: perfusion computed tomography, STA-MCA: superficial temporal artery-middle cerebral artery, EDMS: encephalo-duro-arterio-myo-synangiosis; EMS: encephalo-myo-synangiosis, EGS: encephalo-galeo-synangiosis.
2
Tab. 2 The heterogeneity and Egger test for included outcome measures (2)
Outcome measures
I2
No. of studies
Cochran Q test (P)
Egger test (P)
CHS total incidence
27
90.20%
< 0.0001
0.01357
CHS incidence for in pediatric MMD patients
10
30.50%
0.165
0.9159
CHS incidence for in adult MMD patients
19
89.80%
< 0.0001
0.1402
CHS incidence for direct bypass surgery
9
94.80%
< 0.0001
NA
CHS incidence for combined bypass surgery
13
84.40%
< 0.0001
0.04617
Progress rate
8
53.80%
0.034
NA
CHS-related TNDs
21
72.70%
< 0.0001
0.2903
CHS-related haemorrhage
21
71.70%
< 0.0001
0.7074
CHS-related seizure
21
58.10%
0.0005
0.106
Notes: NA: not applicable.
1
Funnel plot for Incidence of CHS in pediatric MMD patients
Supplementary figures Supplementary figure 1. Funnel plot for Incidence of CHS in pediatric MMD patients demonstrates approximately symmetrical.
Funnel plot for Incidence of CHS in adult MMD patients
Supplementary figure 2. Funnel plot for Incidence of CHS in adult MMD patients demonstrates mild asymmetry
Funnel plot for Incidence of CHS for direct bypass surgery
Supplementary figure 3. Funnel plot for Incidence of CHS for direct bypass surgery demonstrates mild asymmetry
Funnel plot for Incidence of CHS for combined bypass surgery
Supplementary figure 4. Funnel plot for Incidence of CHS for combined bypass surgery demonstrates mild asymmetry
Funnel plot for Progress rate
Supplementary figure 5. Funnel plot for Progress rate demonstrates approximately symmetrical.
Funnel plot for Proportion of TNDs in CHS
Supplementary figure 6. Funnel plot for Proportion of TNDs in CHS demonstrates approximately symmetrical.
Funnel plot for Proportion of haemorrhage in CHS
Supplementary figure 7. Funnel plot for Proportion of haemorrhage in CHS demonstrates approximately symmetrical.
Funnel plot for Proportion of seizure in CHS
Supplementary figure 8. Funnel plot for Proportion of seizure in CHS demonstrates approximately symmetrical.
Disclosure-Conflict of Interest The authors report no conflicts of interest in this work. Authors: Jin Yu, Miao Hu, Jieli Li, Jianjian Zhang, Jincao Chen.
Abbreviations list MMD
Moyamoya disease
CHS
Cerebral Hyperperfusion Syndrome
CBF
Cerebral blood flow
TNDs
Transient neurological deficits
NA
Not applicable
SPECT
123
I N-isopropyl-p-iodoamphetamine single-photon emission computed tomography,
Xe-CT
Xenon-computed tomography
PWI
Perfusion-weighted imaging
MRI
Magnetic resonance imaging
P-CT
Perfusion computed tomography
STA-MCA
Superficial temporal artery-middle cerebral artery
EDMS
Encephalo-duro-arterio-myo-synangiosis
EMS
Encephalo-myo-synangiosis
EC-IC
Extracranial-intracranial
CEA
Carotid endarterectomy
CAS
Carotid artery stenting
MCA
Middle cerebral artery
DWI
Diffusion-weighted imaging
mTI-ASL
Multi-inversion time arterial spin labeling
ROS
Reactive oxygen species
PET
positron emission tomography
S1878-8750(19)32903-1
DOI:
https://doi.org/10.1016/j.wneu.2019.11.065
Reference:
WNEU 13734
To appear in:
World Neurosurgery
Received Date: 6 July 2019 Accepted Date: 12 November 2019
Please cite this article as: Yu J, Zhang J, Li J, Zhang J, Chen J, Cerebral Hyperperfusion Syndrome after Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Metaanalysis, World Neurosurgery (2019), doi: https://doi.org/10.1016/j.wneu.2019.11.065. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Elsevier Inc. All rights reserved.
Manuscript title Cerebral Hyperperfusion Syndrome after Revascularization Surgery in Patients with Moyamoya Disease: Systematic Review and Meta-analysis
Authors Jin Yu, MD1）,* ; Jibo Zhang, MD1), *; Jieli Li, B.S1); Jianjian Zhang, Ph.D 1); Jincao Chen, Ph.D., Prof.1)
1) Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Wuhan 430071, China * These authors contributed equally to this work
Corresponding authors: Jincao Chen Department of Neurosurgery, Zhongnan Hospital of Wuhan University, Donghu Road 169, Wuhan 430071, China Tel: +86 027 67813118 Fax: +86 027 67813118 Email: [email protected]
Keywords: Cerebral hyperperfusion syndrome; Moyamoya disease; Incidence; Bypass surgery Running head: Cerebral hyperperfusion syndrome in moyamoya disease Sources of financial support: None
Number of words:3,210 words Figures: 4 Tables: 2
1
Authors' contributions Jin Yu contributed to conceptualization, methodology, software, formal analysis, investigation, writing – original draft preparation of the study. Jibo Zhang contributed to methodology, software of the study. Jianjian Zhang and Jincao Chen contributed to supervision and project administration of the study. Jieli Li contributed to data curation and writing – review and editing of the data. All authors read and approved the final manuscript. Acknowledgments The authors thank all participants in the study. Disclosure The author reports no conflicts of interest in this work.
2
1
Manuscript title:
2
Cerebral Hyperperfusion Syndrome after Revascularization Surgery in Patients with
3
Moyamoya Disease: Systematic Review and Meta-analysis
4 5
Short title: Cerebral Hyperperfusion Syndrome in Moyamoya Disease
6 7
Abstract:
8
BACKGROUND: Cerebral hyperperfusion syndrome (CHS) following bypass surgery is
9
known as a complication of moyamoya disease (MMD). However, the incidence of CHS
10
has not been accurately reported, and there is no consensus on related risk factors.
11
OBJECTIVE: To evaluate the incidence and characteristics of CHS in patients with
12
MMD after revascularization surgery via meta-analysis.
13
METHODS: Relevant cohort studies were retrieved through a literature search in
14
PubMed, Embase and Ovid until December 1, 2018. Eligible studies were identified per
15
search criteria. A systematic review and meta-analysis were used to assess the CHS total
16
incidence, incidence in pediatric MMD patients and adult MMD patients, incidence for
17
direct and combined bypass surgery, progress rate, proportion of each symptom (included
18
transient neurological deficits (TNDs), haemorrhage and seizure).
19
RESULTS: A total of 27 cohort studies with 2,225 patients were included in this
20
meta-analysis. The weighted proportions per random-effects model were 16.5% (11.3%
21
to 22.3%) for the CHS total incidence, 3.8% (0.3% to 9.6%) for pediatric MMD patients,
22
and 19.9% (11.7% to 29.4%) for adult MMD patients, 15.4% (5.4% to 28.8%) for direct
23
bypass surgery and 15.2% (8.4% to 23.2%) for combined bypass surgery. Progress rate
24
was 39.5% (28.7% to 50.8%). The most common CHS-related symptoms were TNDs
25
70.2% (56.3% to 82.7%), followed by haemorrhage 15.0% (5.5% to 26.9%) and seizure
26
5.3% (0.6% to 12.9%).
27
CONCLUSION: CHS is a common complication after revascularization surgery in
28
MMD. It is more frequently seen in adult patients. The most common CHS-related
29
symptoms were TNDs, followed by haemorrhage and seizure.
30
KEYWORDS: Cerebral hyperperfusion syndrome, Moyamoya disease, Incidence,
31
bypass surgery 1
32
Introduction
33
Moyamoya disease (MMD) is a cerebrovascular disease characterized by progressive
34
stenosis or occlusion of the internal carotid artery and/or its terminal branches, which
35
results in an abnormal development of compensatory vascular networks with tiny blood
36
vessels ("moyamoya vessels") at the base of the brain1. MMD has been found all over the
37
world, especially in Japan, Korea and China2. According to epidemiological data, the
38
morbidity and incidence of MMD in East Asian countries or the United States are
39
increasing year by year. MMD is the most common pediatric cerebrovascular disease in
40
East Asia, which leading to high morbidity, disability and even death3. The main clinical
41
manifestations of MMD include cerebral ischemia caused by stenosis or occlusion of
42
cerebral artery and intracranial haemorrhage caused by the rupture of fragile vessels in
43
compensatory network4. Ischemic symptoms, such as transient ischemic attack or
44
cerebral infarction5, 6, are predominant in paediatric MMD, while intracranial
45
haemorrhage in adult cases7, 8. Surgical revascularization, such as superficial temporal
46
artery-middle cerebral artery (STA-MCA) direct bypass surgery, is effective in
47
improving damages associated with intra-cerebral haemorrhage. The use of indirect
48
bypass of vascularized donor tissues such as encephalo-duro-arterio-myo-synangiosis
49
(EDMS) is also considered a valid treatment for MMD9.
50
Cerebral hyperperfusion syndrome (CHS), characterized by a series of neurological
51
deficits induced by postoperative high cerebral blood flow (CBF) perfusion, is one of the
52
most serious complications of revascularization surgery for MMD, especially in adult
53
patients10, 11. It occurs in up to 50% of MMD patients after direct bypass surgery12, and its
54
clinical symptoms may vary from minor discomforts such as headache, aphasia,
55
hemiparesis, paresis, facial palsy, and limb weakness, to major signs such as dysarthria
56
and intra-cerebral haemorrhage13. Most of these symptoms may completely resolve in 2
57
weeks without permanent brain injury14,15. CBF can well reflect the state of cerebral
58
perfusion. It is often used to diagnose or predict the occurrence of CHS by detecting the
59
changes of CBF in clinic10. Numerous imaging diagnostic methods such as 123I
60
N-isopropyl-p-iodoamphetamine
61
(SPECT), magnetic resonance imaging (MRI) and magnetic resonance angiography
62
(MRA) have been used to measure the change of CBF pre- and postoperative16,17,18,19.
single-photon
2
emission
computed
tomography
63
Though various studies have reported this complication, the molecular mechanism of
64
CHS remains unclear.
65
Although multiple previous studies on CHS in MMD patients treated with bypass
66
surgery have been published, most of them were of limited sample size and reported
67
inconsistent findings. We have therefore performed a systematic review and
68
meta-analysis to examine the incidence and characteristics of CHS.
69
Methods
70
The present meta-analysis was reported in accordance with the Preferred Reporting Items
71
for Systematic reviews and Meta-Analysis (PRISMA) guidelines.
72
Search strategy and study identification
73
A comprehensive literature search in PubMed, Embase and Ovid was performed. Search
74
terms included all possible combinations of ‘moyamoya disease’, ‘perfusion’,
75
‘hyperperfusion’, ‘complication’, ‘operation’, and ‘revascularization’ (both as a Medical
76
Subject Heading [MeSH] and free text term). Only human studies published in English or
77
Chinese up to December 1, 2018, were considered. References in identified articles were
78
also manually screened.
79
Selection criteria
80
Inclusion criteria: ① Patients with MMD diagnosis confirmed by radiological and
81
clinical criteria. ② treated by surgical bypass procedures. ③ confirmed diagnosis of
82
CHS after revascularization surgery . ⑤ clinical randomized controlled trial or
83
observational study.
84
Exclusion criteria: ① incomplete data（lack of information on the number of
85
operations, number of CHS, or specific bypass methods）; ② sample size < 10; ③
86
study population already included in another study; ④ study presented by languages
87
other than English or Chinese; and ⑤review articles or technical notes.
88
Two reviewers independently examined the titles, abstracts and full texts of all
89
study reports identified by the literature search, to select eligible studies that met the
3
90
inclusion and exclusion criteria. Discrepancies between the two reviewers were resolved
91
by discussion.
92
Data extraction
93
Two reviewers independently extracted the following data from the included studies: ①
94
study characteristics (year of publication, country and cohort size), ② patient
95
characteristics (age, gender, population, method and criteria for MMD diagnosis, and
96
type of surgical treatment performed) and ③ outcome measures (number of operated
97
hemispheres, number of patients with postoperative hyper-perfusion, number of CHS
98
cases, and profile of CHS-related symptoms). A third investigator double-checked the
99
extracted data, resolved discrepancies and corrected errors.
100
Statistical analysis
101
The following rates were transformed with the Freeman-Tukey variant of arcsine square
102
prior to statistical pooling (the CHS incidence in all subjects, CHS incidence in pediatric
103
MMD patients, incidence in adult MMD patients, incidence for direct bypass surgery,
104
incidence for combined bypass surgery, progress rate, proportion of each symptom
105
(included transient neurological deficits (TNDs), haemorrhage and seizure) in CHS). For
106
any given outcome of interest, all studies with available data were included for
107
meta-analysis. Transformed proportions were then combined by random-effects model（
108
Considering significant heterogeneity is common in pooled analysis of event rates,
109
meta-analyses by random-effects model were performed）. The I2 statistic and Cochran’s
110
Q test were used to evaluate between-study heterogeneity and the funnel plots with
111
Egger’s test were used to assess publication bias.
112
version 3.5.1(The R Foundation for Statistical Computing) and the package ‘meta’. All
113
statistical tests were two sided. Results were considered statistically significant when p <
114
0.05.
115
4
All analyses were performed using R
116
Results
117
Literature search and included studies
118
1,120 publications were initially identified as potentially relevant studies (Figure 1). 134
119
records were excluded as duplicates and 937 studies were excluded after title and abstract
120
review. Full texts were retrieved for 49 studies. 22 studies were excluded per exclusion
121
criteria. A total of 27 studies were included in the final meta-analysis (Table 1) 16, 18, 20, 21,
122
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44.
123
All studies were published between 2007 and 2018. The majority of studies (92.6%)
124
were conducted either in the Japan (n = 21) or China (n = 4). The median number of
125
operated hemispheres was 55 (range 12 – 500).
126
Meta-analysis
127
According to random-effects meta-analyses of rates, the pooled rate was 16.5% (n = 27,
128
95% confidence interval (CI) = [11.3%, 22.3%]) for CHS total incidence (Figure 2A,B);
129
3.8% (n = 10, 95% CI = [0.3%, 9.6%]) in pediatric and 19.9% (n = 19, 95% CI [11.7% to
130
29.4%]) in adults (Figure 3A, B), 15.4% (n = 9, 95% CI [5.4% to 28.8%] for direct
131
bypass surgery and 15.2% (n = 13, 95% CI [8.4% to 23.2%] for combined bypass surgery
132
(Figure 3C,D). Progress rate was 39.5% (n = 8, 95% CI [28.7% to 50.8%]) (Figure 4A).
133
The most common CHS-related symptoms were TNDs 70.2% (n = 21, 95% CI [56.3% to
134
82.7%]) (Figure 4B), followed by haemorrhage 15.0% (n=21, 95% CI [5.5% to 26.9%])
135
and seizure 5.3% (n = 8, 95% CI [0.6% to 12.9%]), respectively (Figure 4C, D).
136
Heterogeneity evaluation by I2 statistic and Cochran’s Q test could be found in
137
Table 2. The funnel plot for each outcome parameter (see online supplementary Figure
138
S1-8).
139
Discussion
140
CHS was first described by Uchino et al in 1998.45 In recent years, the understanding of
141
CHS has evolved from the concept of “reactive hyperaemia and luxury perfusion” to a
142
syndrome including a spectrum of symptoms induced by abnormal elevation of CBF after
143
operation.46 As the artificial anastomosis of extracranial-intracranial (EI-IC) vascular
144
system, the un-regulation to a sudden hemodynamic converting led to abnormally 5
145
increases of CBF, and caused a series of transient or permanent neurological impairment.
146
As a common complication after revascularization of MMD, more attention should be
147
paid to CHS in case of serious consequences.
148
Incidence of CHS:
149
In recent years, many clinical researches have reported CHS after MMD surgery. The
150
incidence of CHS was generally around 17%.47 Our meta-analysis showed a pooled total
151
incidence for CHS with 16.5% (11.3% to 22.3%), which was consistent with previous
152
reports. The CHS was more frequent compared to other postoperative complications,
153
such
154
postoperative hypoperfusion, poor scalp healing and infection51, 52, 53 and some other rare
155
complications.9 Accordingly, in order to improve the clinical therapeutic effect of MMD,
156
it was important to pay more attention to CHS and establish a systematic program for the
157
prevention and management of this syndrome.
as postoperative infarction/stroke,48,
49
postoperative bypass
occlusion,50
158
Studies also reported the frequency of CHS among patients treated with different
159
surgical procedures, in different age groups, and with different preoperative onset types.
160
There was a consensus that CHS was more prevalent in adult patients with MMD.
161
Indeed, our systematic analysis showed that the incidence of CHS was much higher in
162
adult patients (19.9% (11.7% to 29.4%)) than in pediatric patients (3.8% (0.3% to 9.6%)).
163
We speculated that this phenomenon may be related to the difference in cerebrovascular
164
quality between adults and children. As the formation and development of collateral
165
compensatory vessels in adults was generally less notable than those in children,54 when
166
blood flow from the extra-cranial circulation system has been suddenly introduced into
167
the affected area, a large number of incoming flow could be more hard to effectively
168
shunt in the surgical hemisphere in adults than in pediatric patients, and thus induced the
169
increase of local perfusion, which could cause serious consequences more easily for
170
adults.
171
Our study showed that the choice of direct (15.4% (5.4% to 28.8%)) or combined
172
(15.2% (8.4% to 23.2%)) surgery has no effect on the incidence of CHS. We believed
173
that this was due to the similar interference of hemodynamics in both surgical procedures.
174
Other studies suggested that CHS also occurred when MMD was treated indirectly
6
175
alone.11 However, we have note that indirect surgical treatment of MMD alone was very
176
rare in the literature. This might be due to the fact that in clinical practice it is routinely
177
involved the direct revascularization to completely eliminate the causes of ischemia and
178
haemorrhage, which makes it very difficult to obtain data on the incidence of CHS after
179
indirect surgery.
180
Although CHS was not specific in MMD after revascularization, studies have
181
compared the revascularization of a variety of cerebrovascular diseases (including carotid
182
endarterectomy (CEA) or carotid artery stenting (CAS) for carotid artery stenosis, bypass
183
surgery for atherosclerotic cerebrovascular disease and bypass surgery for MMD),28 and
184
the incidence of postoperative CHS was found to be significantly higher in patients with
185
MMD, which has been confirmed previously.27
186
Diagnosis of CHS:
187
With the rapid development of imaging technology, more and more methods become
188
available for the detection of CBF and assessment of the regional or global cerebral
189
perfusion status after surgery. Conventional methods of CBF measurement, including
190
SPECT, MRI, MRA, P-CT and Xe-CT, could effectively evaluate the CBF pre- and
191
post-operation.17, 55 SPECT is the most typical one, and has been regarded as the gold
192
standard for examining CBF perfusion and diagnosing CHS. Indeed, more than 70% of
193
the studies we collected used SPECT as the diagnostic tool. The diagnostic criteria for
194
CHS included all the following: (1) The presence of a significant focal increase in CBF,
195
which was confined to the vascular territory of one major branch of the middle cerebral
196
artery (MCA), at the site of the anastomosis, which is responsible for apparent focal
197
neurological signs. (2) Apparent visualization of STA-MCA bypass by MRA and the
198
absence of any ischemic changes by diffusion-weighted imaging (DWI). (3) The absence
199
of other pathologies such as compression of the brain surface by the temporal muscle
200
inserted for indirect pial synangiosis, ischemic attack, venous infarction, or CBF increase
201
secondary to seizure. In addition to these items, the blood pressure-dependent
202
aggravation of symptoms and/or amelioration of symptoms by clinically lowering blood
203
pressure indicated a diagnosis of CHS.
204
caused by CHS were usually significant from the second to the seventh day after
20, 23, 32
7
Because the neurological symptoms
205
operation, many studies suggested that SPECT should be performed within 48 hours after
206
operation to evaluate cerebral perfusion, and then on the second and seventh days,
207
respectively.56 In addition, in order to confirmed the efficiency of anastomotic
208
connection, it was recommended that SPECT should be performed immediately after
209
operation.29
210
Interestingly, in recent years, more methods such as indocyanine green videography
211
(ICG-VG), fluid attenuated inversion recovery (FLAIR) images, positron emission
212
tomography (PET), multi-inversion time arterial spin labelling (mTI-ASL), and
213
technetium-99m-hexamethylpropyleneamine
214
reported to be used in clinical examination of CBF after MMD.57, 58, 59, 60, 61, 62 Moreover,
215
some studies have proposed other indicators trying to replace CBF to indicate the
216
cerebral perfusion status after surgery, such as cerebrovascular reactivity (CVR) value
217
and mean transit time (MTT).63, 64, 65 However, the effectiveness of these methods and
218
indicators still needed more investigation.
219
Progress of CHS:
220
At present review, we evaluated the progress rate of CHS, which means the proportion of
221
patients developed from hyperperfusion to symptomatic hyperperfusion syndrome. We
222
compared the sample size of hyperperfusion and symptomatic hyperperfusion, and found
223
a progress rate of 39.5% (28.7% to 50.8%). Interestingly, the proportions of MMD
224
patients with elevated CBF after revascularization was relatively high,23, 26, 33 while the
225
proportions of CHS was significantly lower. We speculated that there were two possible
226
reasons: 1. The self-regulation of cerebrovascular allowed patients gradually adapt to
227
hyperperfusion, and developed into asymptomatic hyperperfusion; 2. Clinical
228
prophylactic lower blood pressure and drug treatment have alleviated the progress of
229
hyperperfusion.29, 33, 37
230
Symptoms of CHS:
231
CHS usually caused transient neurological impairment which usually completely relieved
232
in 7-14 days after operation without permanent cerebral damage. However, it should be
233
noted that intracranial haemorrhage and subarachnoid haemorrhage secondary to CHS
234
may lead to serious consequences.39 Our statistics showed that TNDs (70.2% (56.3% to 8
oxime
(99mTc-HMPAO)
have
been
235
82.7%)) was the most common CHS-related symptoms, followed by haemorrhage
236
(15.0% (5.5% to 26.9%)) and seizure (5.3% (0.6% to 12.9%)).
237
The detailed classification of TNDs included aphasia, hemiparesis, headache, facial
238
palsy, etc.42 TNDs was mainly due to the transient dysfunction of the related neurological
239
areas caused by high local perfusion, high pressure or local edema. The specific
240
mechanism of TNDs was still unclear, and it was believed that the reversible decrease of
241
cerebral metabolism and the repression of cortical neurotransmitter receptor function
242
caused by post-operation hyperperfusion may partially explained the occurrence of
243
TNDs.66 Other theories included the increase of free radicals after vascular surgery, were
244
trying to explain this phenomenon.44 In fact, the appearance of TNDs was not only
245
related to hyperperfusion, but also to hypoperfusion after operation. It might be due to the
246
blood flow competition caused by the damage of brain self-regulation and the fluctuation
247
of cerebral microcirculation.67
248
Cerebral haemorrhage caused by CHS was not uncommon,46,
68
but its exact
249
mechanism was still unclear. It might be that excessive hemodynamic stress on fragile
250
vessels triggered increased vascular permeability and subsequent bleeding. At the same
251
time, because reactive oxygen species (ROS) was related to cerebral ischemia/reperfusion
252
injury, the overproduction of ROS during vascular remodeling might affect vascular
253
permeability and the maintenance of vascular structure.69 In addition, some studies have
254
found that the serum level of matrix metalloproteinases (MMP) in patients with MMD
255
was significantly higher than that in normal controls. Increased expression of MMP-9
256
might lead to pathological angiogenesis and/or instability of vascular structure, decreased
257
the quality of cerebrovascular and regulating ability to cope with the stress of
258
hemodynamic changes, which might lead to haemorrhage in MMD.70
259
Several studies have reported seizure after bypass methods of MMD patients, and
260
the incidence were not low.71,72 However, whether this symptom was caused by CHS or
261
some other pathogeny was hard to distinguish. According to the literatures we collected,
262
seizure caused by CHS was not that common than previous reports. We speculated this
263
was due to no clear distinction between the causes of postoperative seizure. As the
264
postoperative seizure usually were classified into 3 types based on the time interval after
265
surgery: immediate seizures, early seizure and late seizure,70 and the corresponding 9
266
treatment methods were different, it was significant to clarify the accurate cause when
267
seizure occurred.
268
Risk factors for CHS:
269
Many risk factors, such as patient characteristics, onset types, surgical methods and
270
surgical hemisphere, have been extensively studied,14,
271
unified conclusion. At present, adult-onset is the most recognized risk factor for CHS
272
after MMD surgery. Our conclusion also confirmed that adult-onset MMD is more likely
273
to have postoperative CHS and the reason has been discussed previously. Some studies
274
have mentioned that patients with hemorrhagic MMD were susceptible to CHS.26
275
However, other studies have suggested that ischemia or hemorrhagic onset has no
276
significant difference on the morbidity of post-operative CHS.73 The seeking for
277
predictive indicators of post-operative CHS, including new biomarkers,74 remains to be
278
explored.
279
Management of CHS:
280
The prophylactic management of CHS was essential because the clinical conditions of
281
patients could become more complex once they became symptomatic.32 Therefore, we
282
instituted
283
complications: (1) General anesthesia is continued after bypass surgeries; (2) When
284
hyperperfusion is observed by our methods, strict blood pressure control under sedation
285
is continued until the CBF falls to normal; and (3) The free radical scavenger edaravone,
286
which reduces the incidence of hyperperfusion-related TNDs, is administered.33, 38
the
following
counter
measures
to
20, 26, 28
prevent
but there was still no
hyperperfusion-related
287
Fujimura et al have managed postoperative CHS by intravenous administration of
288
minocycline hydrochloride (200 mg/day) under strict blood pressure control, and did not
289
suffer any neurological deterioration during the perioperative period. Postoperative
290
magnetic resonance imaging showed no evidence of vasogenic edema and therefore
291
considered minocycline has potential role for preventing cerebral hyperperfusion to be
292
symptomatic, by blocking MMP-9 in the acute stage after EC-IC bypass.75
293
Although blood pressure lowering is generally accepted as the standard
294
management of CHS, the risk of ischemic complications in the acute stage is high with
295
blood pressure lowering under an anesthetic state according to Kawamata et al.22 To 10
296
resolve this problem, Fujimura et al prefered prophylactic blood pressure control between
297
110 and 130 mmHg in the acute stage on patients in a conscious state, which effectively
298
lowered the risk of CHS following EC–IC bypass for MMD below that of the patients
299
treated under normotensive conditions.32
300
Strengths and limitations
301
This is, to our knowledge, the first meta-analysis to report the CHS after
302
revascularization surgery in patients with MMD. We assessed CHS total incidence,
303
incidence in pediatric MMD patients, incidence in adult MMD patients, incidence for
304
direct bypass surgery, incidence for combined bypass surgery, progress rate, proportion
305
of each symptom included TNDs, haemorrhage and seizure in CHS. All of this makes our
306
results more reliable.
307
We would like to acknowledge several limitations in our study. Firstly, studies span
308
a wide period of time, from 2007 to the present. Potential heterogeneity can present in
309
study indications (selection bias), patient baseline characteristics (institutional referral
310
bias), medical standards, surgeons’ skill and laboratory testing. Secondly, we did not
311
study the incidence of CHS for indirect surgery, because the data of many studies did not
312
explicitly segment it. Lastly, we have limited data on addressing the above potential bias
313
in our study that may also influence our results. Outcome analysis was performed only in
314
papers with available data. Some studies included feasible data, but we cannot get the
315
data for being restricted by language, were excluded accordingly, leading to reduced
316
sample size and potential selection bias.
317
Conclusion
318
CHS is a common complication after revascularization surgery in MMD patients. It is
319
more frequently seen in adult patients. The most common CHS-related symptoms were
320
TNDs, followed by haemorrhage and seizure.
321
Conflict of interest statement
322
None.
11
323
Funding
324
None.
325 326
References
327
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12
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567
20
568
Figure Legends
569 570
Figure 1 Flow chart for search strategy and study selection.
571 572
Figure 2
573
(A) Forest plots of total incidence of CHS assessed in the present meta-analysis. Squares
574
and horizontal bars indicate point estimate and 95% CI of proportions in each
575
individual study, respectively. Diamonds indicate summary estimates that are
576
calculated per random-effects model. Column ‘Total’ represents the total number of
577
patients in each study.
578 579
(B) Funnel plot for total incidence of CHS was grossly symmetrical with the most data points within the funnel area.
580 581
Figure 3
582
(A) Forest plots of incidence of CHS for pediatric,
583
(B) Forest plots of incidence of CHS for adult ,
584
(C) Forest plots of incidence of CHS for direct bypass surgery
585
(D) Forest plots of incidence of CHS for combined bypass surgery
586
Squares and horizontal bars indicate point estimate and 95% CI of proportions in each
587
individual study, respectively.
588 589
Figure 4
590
(A) Forest plots of progress rate
591
(B) Forest plots of proportion of TNDs in CHS
592
(C) Forest plots of proportion of haemorrhage in CHS
593
(D) Forest plots of proportion of seizure in CHS
594
Squares and horizontal bars indicate point estimate and 95% CI of proportions in each
595
individual study, respectively.
596 597 598
21
599
Supplemental figure Legends
600 601
Supplementary figure 1. Funnel plot for Incidence of CHS in pediatric MMD patients
602
demonstrates approximately symmetrical.
603 604
Supplementary figure 2. Funnel plot for Incidence of CHS in adult MMD patients
605
demonstrates mild asymmetry.
606 607
Supplementary figure 3. Funnel plot for Incidence of CHS for direct bypass surgery
608
demonstrates mild asymmetry.
609 610
Supplementary figure 4. Funnel plot for Incidence of CHS for combined bypass surgery
611
demonstrates mild asymmetry.
612 613
Supplementary figure 5. Funnel plot for Progress rate demonstrates approximately
614
symmetrical.
615 616
Supplementary figure 6. Funnel plot for Proportion of TNDs in CHS demonstrates
617
approximately symmetrical.
618 619
Supplementary figure 7. Funnel plot for Proportion of haemorrhage in CHS
620
demonstrates approximately symmetrical.
621
22
622
Supplementary figure 8. Funnel plot for Proportion of seizure in CHS demonstrates
623
approximately symmetrical.
23
Table 1. The main characteristics of included studies (1) No. of Authors & Year
Country
Patient Population
Operations
Diagnostic Tools
Surgery
Methods
Fujimura M et al., 2007 16
JPN
Adult
34
SPECT
Direct/Combined
STA-MCA + EDMS
Fujimura M et al., 2008 20
JPN
Pediatric
17
SPECT
Direct/Combined
STA-MCA + EDMS
Nakagawa A et al., 2009 21
JPN
Both
26
SPECT
Combined
STA-MCA + EDMS
MikiFujimura et al., 2009 22
JPN
Both
80
SPECT
Direct/Combined
STA-MCA + EDMS
Zhao H et al., 2009 23
CHN
Both
18
SPECT
Direct/Indirect
STA-MCA / EDMS
Kawamata T et al., 2011 24
JPN
Both
27
Xe-CT
Direct
STA-MCA
Miki Fujimura et al., 2011 25
JPN
Both
121
SPECT
Direct/Combined
STA-MCA + EDMS
JPN
Both
150
SPECT
Combined
STA-MCA + EDMS
JPN
Both
40
SPECT
Combined
STA-MCA + EDMS
Uchino H et al., 2012 28
JPN
Both
58
SPECT
Combined
STA-MCA + EDMS
Kaku Y et al., 2012 29
JPN
Adult
42
SPECT
Direct
STA-MCA
Sugino T et al., 2013 18
JPN
Both
15
SPECT
Direct/Combined
STA-MCA + EDMS
Kr
Adult
99
SPECT
Direct
STA-MCA
JPN
Both
12
SPECT
Direct/Combined
STA-MCA + EDMS
Fujimura M et al., 2012 Hayashi K et al., 2012
26
27
J.W.Hwang et al., 2013 30 Uchino H et al., 2014 31
1
Horie N et al., 2014 32
JPN
Both
55
SPECT
Combined
STA-MCA + EMS
Wang D et al., 2015 33
CHN
Adult
14
PWI
Combined
STA-MCA + EDMS
Fujimura M et al., 2015 34
JPN
Adult
23
SPECT
Combined
STA-MCA + EDMS
JPN
Adult
92
SPECT
Direct/Combined
STA-MCA + EDMS
Sato K et al., 2016 36
JPN
Both
25
SPECT
Combined
STA +EMS/EGS
Kashiwazaki D et al., 2017 37
JPN
Adult
176
SPECT
Combined
STA-MC+EDMS
Kraemer M et al., 2018 38
GER
Adult
64
MRI
Direct/Combined
STA-MCA+EDMS
Nomura S et al., 2018 39
JPN
Adult
72
Xe-CT
Direct
STA-MCA
Ishiguro T et al., 2018 40
JPN
Adult
52
Xe-CT
Direct
STA-MCA
Ishikawa T et al., 2018 41
JPN
Both
251
Xe-CT
Direct
STA-MCA
Zhao M et al., 2018 42
CHN
Both
500
MRI/CT
Direct/Combined
STA-MCA+EMS
Yang T et al., 2018 43
JPN
Both
105
SPECT
Direct/Combined
STA-MCA+EMS
CHN
Both
57
P-CT
Combined
STA-MCA+EMS
Uchino H et al., 2016
Xu S et al., 2018
35
44
Notes: JPN: Japan, CHN: China, Kr: Korea, GER: Germany; NA: not applicable, SPECT： ：123I N-isopropyl-p-iodoamphetamine single-photon emission computed tomography, Xe-CT: xenon-computed tomography; PWI: Perfusion-weighted imaging, MRI: magnetic resonance imaging, P-CT: perfusion computed tomography, STA-MCA: superficial temporal artery-middle cerebral artery, EDMS: encephalo-duro-arterio-myo-synangiosis; EMS: encephalo-myo-synangiosis, EGS: encephalo-galeo-synangiosis.
2
Tab. 2 The heterogeneity and Egger test for included outcome measures (2)
Outcome measures
I2
No. of studies
Cochran Q test (P)
Egger test (P)
CHS total incidence
27
90.20%
< 0.0001
0.01357
CHS incidence for in pediatric MMD patients
10
30.50%
0.165
0.9159
CHS incidence for in adult MMD patients
19
89.80%
< 0.0001
0.1402
CHS incidence for direct bypass surgery
9
94.80%
< 0.0001
NA
CHS incidence for combined bypass surgery
13
84.40%
< 0.0001
0.04617
Progress rate
8
53.80%
0.034
NA
CHS-related TNDs
21
72.70%
< 0.0001
0.2903
CHS-related haemorrhage
21
71.70%
< 0.0001
0.7074
CHS-related seizure
21
58.10%
0.0005
0.106
Notes: NA: not applicable.
1
Funnel plot for Incidence of CHS in pediatric MMD patients
Supplementary figures Supplementary figure 1. Funnel plot for Incidence of CHS in pediatric MMD patients demonstrates approximately symmetrical.
Funnel plot for Incidence of CHS in adult MMD patients
Supplementary figure 2. Funnel plot for Incidence of CHS in adult MMD patients demonstrates mild asymmetry
Funnel plot for Incidence of CHS for direct bypass surgery
Supplementary figure 3. Funnel plot for Incidence of CHS for direct bypass surgery demonstrates mild asymmetry
Funnel plot for Incidence of CHS for combined bypass surgery
Supplementary figure 4. Funnel plot for Incidence of CHS for combined bypass surgery demonstrates mild asymmetry
Funnel plot for Progress rate
Supplementary figure 5. Funnel plot for Progress rate demonstrates approximately symmetrical.
Funnel plot for Proportion of TNDs in CHS
Supplementary figure 6. Funnel plot for Proportion of TNDs in CHS demonstrates approximately symmetrical.
Funnel plot for Proportion of haemorrhage in CHS
Supplementary figure 7. Funnel plot for Proportion of haemorrhage in CHS demonstrates approximately symmetrical.
Funnel plot for Proportion of seizure in CHS
Supplementary figure 8. Funnel plot for Proportion of seizure in CHS demonstrates approximately symmetrical.
Disclosure-Conflict of Interest The authors report no conflicts of interest in this work. Authors: Jin Yu, Miao Hu, Jieli Li, Jianjian Zhang, Jincao Chen.
Abbreviations list MMD
Moyamoya disease
CHS
Cerebral Hyperperfusion Syndrome
CBF
Cerebral blood flow
TNDs
Transient neurological deficits
NA
Not applicable
SPECT
123
I N-isopropyl-p-iodoamphetamine single-photon emission computed tomography,
Xe-CT
Xenon-computed tomography
PWI
Perfusion-weighted imaging
MRI
Magnetic resonance imaging
P-CT
Perfusion computed tomography
STA-MCA
Superficial temporal artery-middle cerebral artery
EDMS
Encephalo-duro-arterio-myo-synangiosis
EMS
Encephalo-myo-synangiosis
EC-IC
Extracranial-intracranial
CEA
Carotid endarterectomy
CAS
Carotid artery stenting
MCA
Middle cerebral artery
DWI
Diffusion-weighted imaging
mTI-ASL
Multi-inversion time arterial spin labeling
ROS
Reactive oxygen species
PET
positron emission tomography