Edited by: Maurizio Acampa, Azienda Ospedaliera Universitaria Senese, Italy
Reviewed by: Rebecca Ichord, Children's Hospital of Philadelphia, United States; Mario Teo, North Bristol University Hospital, United Kingdom; Yi Yang, First Affiliated Hospital of Jilin University, China
This article was submitted to Stroke, a section of the journal Frontiers in Neurology
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Moyamoya disease (MMD) is characterized by progressive stenosis and occlusion of the terminal internal carotid artery (ICA) and its branches, leading to severely compromised cerebral blood flow and subsequent ischemic or hemorrhagic strokes (
Revascularization for pediatric MMD is not exactly the same as for adult MMD, as most of the pediatric patients manifest ischemic symptoms, while hemorrhagic events are commonly seen during disease process in adult patients (
Pediatric patients (under or equal to 18 years old) who were diagnosed as MMD and given surgical treatments at our center between 2009 and 2015 were retrospectively reviewed from a prospective database. The diagnosis of MMD was made according to the 2012 Guideline set by the Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis. Patients with moyamoya syndrome second to identified etiologies were ruled out. Adult MMD patients, pediatric hemorrhagic-type MMD patients, and patients who did not undergo digital subtraction angiography (DSA) were also excluded (
Flow diagram showing the selection of patients in the study.
Two kinds of surgeries were included in this study, including DB and IB. DB was performed as end-to side anastomosis of STA branch to the cortical branch of MCA (M4 segment), by one single experienced surgeon at our center. IB included multiple bur hole surgery and encephaloduroarteriosynangiosis (EDAS), which were performed as attaching STA branch onto the cortical surface.
After surgery, all patients were given fluid therapy and blood pressure was monitored. Postoperative blood pressure (BP) was controlled with reference to preoperative basic BP and surgical modalities: for direct bypass surgery, postoperative BP was maintained slightly lower than or equal to basic BP; for indirect bypass surgery, it was maintained a bit higher than basic BP for fear of hypoperfusion. No antiplatelet agents were administered. Computed tomography (CT) and magnetic resonance imaging (MRI) were performed when patients had newly-developed symptoms during the postoperative period (within 7 days after the surgery in both DB and IB groups). Postoperative complications including intracerebral hemorrhage, intracerebral infarction, transient neurological deficits (which recovered fully before discharge with no sequela left and demonstrated no newly-developed lesion of infarction or hemorrhage on radiology), and seizures were recorded.
Patients were followed at the clinic or by telephone 3–6 months after surgery and annually thereafter by doctors who were blinded to the baseline information. Recurrent symptoms were recorded, including recurrent intracerebral hemorrhage, intracerebral infarction, transient ischemic attacks (TIAs), and seizures. Neurological status was evaluated by the modified Rankin scale (mRS).
Statistical analyses were performed using R statistical program (R studio; version 3.3.3). Propensity score matching was adopted in this study to overcome the imbalance and heterogeneity between different surgical modalities caused by the retrospective inclusion of patients. Based on logistic model, 1:1 propensity score matching using the “nearest” matching algorithm was performed with respect to age, sex, mRS at admission, Suzuki stage of the operated side, history of cerebral infarction, unilateral/bilateral involvement, and PCA involvement. Postoperative complications and long-term outcomes were then compared between the matched couples.
Categorical variables are presented as counts (with percentages) and continuous variables are presented as the means ± standard deviations. Grouped data were compared using
Statistical power was calculated using G*power software (version 3.1). Sensitivity analysis showed that, for current sample size [given α error probability = 0.05, power (1-β error probability) = 0.8], the study was powered to detect a difference in proportions from 34.7 to 10.0% (estimated rate of postoperative complications and recurrent symptoms) between surgical groups. The effect size for the rank-sum test in this study was 0.62.
A total of 223 pediatric (≤18 years) MMD patients who underwent surgical revascularization at our center between 2009 and 2015 were retrospectively reviewed. Ten Patients with hemorrhagic-type MMD, 31 without preoperative DSA, 20 patients who underwent combined bypass (STA-MCA anastomosis and EDAS), and 24 patients who were lost to follow-up were excluded. Finally, 138 pediatric ischemic-type MMD patients, including 34 who underwent DB and 104 who underwent IB, were retrospectively included in this study (
Clinical characteristics before and after propensity score matching were shown in
Patient characteristics and group comparisons before and after propensity score matching.
After propensity score |
||||||
---|---|---|---|---|---|---|
No. of patients | 34 | 104 | 34 | 34 | ||
Age | 11.21 ± 4.10 | 9.56 ± 3.46 | 0.023 |
11.21 ± 4.10 | 11.26 ± 3.61 | 0.950 |
Male/female ratio | 18:16 | 53:51 | 0.998 | 18:16 | 16:18 | 0.808 |
mRS score on admission | ||||||
0 | 2 (5.9) | 3 (2.9) | 2 (5.9) | 2 (5.9) | ||
1 | 26 (76.5) | 71 (68.3) | 0.395 | 26 (76.5) | 28 (82.4) | 0.789 |
2 | 6 (17.6) | 25 (24.0) | 6 (17.6) | 4 (11.8) | ||
3 | 0 (0.0) | 5 (4.8) | 0 (0.0) | 0 (0.0) | ||
Cerebral infarction | 9 (26.5) | 28 (26.9) | 1.000 | 9 (26.5) | 9 (26.5) | 1.000 |
Suzuki stage | ||||||
I | 1 (2.9) | 3 (2.9) | 1 (2.9) | 1 (2.9) | ||
II | 2 (5.9) | 4 (3.8) | 2 (5.9) | 3 (8.8) | ||
III | 12 (35.3) | 41 (39.4) | 0.836 | 12 (35.3) | 11 (32.4) | 0.914 |
IV | 14 (41.2) | 33 (31.7) | 14 (41.2) | 12 (35.3) | ||
V | 5 (14.7) | 21 (20.2) | 5 (14.7) | 6 (17.6) | ||
VI | 0 (0.0) | 2 (1.9) | 0 (0.0) | 1 (2.9) | ||
Unilateral MMD | 3 (8.8) | 6 (5.7%) | 0.821 | 3 (8.8) | 1 (2.9) | 0.606 |
PCA involvement | 5 (14.7) | 37 (35.6) | 0.037 |
5 (14.7) | 7 (20.6) | 0.750 |
The mean duration of surgery was shorter in IB than DB (138.2 ± 40.6 vs. 203.0 ± 50.9 min,
Surgical complications of matched couples.
Surgical duration, min | 203.0 ± 50.9 | 138.2 ± 40.6 | <0.001 |
Complications | 6 (17.6%) | 3 (8.8%) | 0.476a1 |
Cerebral infarction | 1 (2.9%) | 1 (2.9%) | >0.999 |
Transient neurological deficits | 3 (8.8%) | 2 (5.9%) | >0.999 |
Seizures | 2 (5.9%) | 0 (0.0%) | 0.493 |
Cerebral hemorrhage | 0 (0.0%) | 0 (0.0%) | NA |
mRS at discharge | |||
0 | 5 (14.7%) | 12 (35.3%) | 0.244a2 |
1 | 29 (85.3%) | 19 (55.9%) | |
2 | 0 (0.0%) | 3 (8.8%) |
After propensity score matching, the DB group were followed for a mean of 71.9 ± 22.2 months, and the IB group were followed for a mean of 60.2 ± 24.3 months (
Kaplan-Meier analysis showing a longer stroke-free survival in patients underwent DB than patients who underwent IB (
Long-term follow-up of matched couples.
Follow up, months |
71.9 ± 22.2 | 60.2 ± 24.3 |
mRS at last follow-up | ||
0 | 25 (73.5%) | 26 (76.5%) |
1 | 7 (20.6%) | 8 (23.5%) |
2 | 2 (5.9%) | 0 (0.0%) |
Comparison of patients' mRS score at time of admission and at last follow-up. a. Comparison of mRS in all patients at time of admission and at last follow-up (1.09 ± 0.45 vs. 0.28 ± 0.51,
Both DB and IB have been applied in the revascularization for pediatric MMD patients and received positive effects (
After propensity score matching, 68 pediatric ischemic-type MMD patients (34 matched pairs) were included in this study, with one DB and one IB procedure in each group. Our results showed although the procedure of DB requires a longer time than IB (203.0 ± 50.9 vs. 138.2 ± 40.6 min,
In this series, recurrent stroke events during follow-up were observed in 10 of 68 patients, with a pooled incidence of 14.7%, including 2 (2.9%) cerebral infarctions and 8 (11.7%) TIAs. The incidence of recurrent ischemic strokes was higher in the IB group (23.5%) than DB (5.9%) group, and Kaplan-Meier analysis showed a significant longer stroke-free time in the patients who underwent DB than those underwent IB (
Having said that, our results also showed both DB and IB were effective in improving neurological status of pediatric MMD patients. MRS scores were significantly improved in the long-term follow-up after revascularization surgery, regardless of specific surgical modality (
In this study, we used propensity score matching to reduce the heterogeneity between patients who underwent different surgical revascularizations. The variables that we unified were mainly conditions and characteristics of patients when they had surgery, however, one factor that cannot be matched, but should not be ignored was the surgeon's experience, which might significantly affect patients' outcomes, especially in DB procedure. The DB bypasses we included in the current study were performed by one experienced surgeon, therefore reducing the potential bias that it may cause on the long-term outcome.
This study had some limitations. First, the study was retrospectively designed. Although propensity score matching was used to reduce the heterogeneity that resulted from non-randomization, potential selection bias and confounders could not be totally excluded. Second, the sample size of this study was rather small, especially after propensity score matching, therefore the statistical power might be compromised. Third, the follow-up was conducted mainly by telephone interviews, which is the most available method but could be less reliable. Pediatric patients might forget episodes of TIAs, and sides and extremities involved at the time of ischemic episodes. The lack of long-term follow-up radiological imaging (MRI or CT) made it unable to detest silent strokes. However, with previously limited knowledge of risks and benefits, we were not able to proceed a randomized trial directly, therefore, a study with matched couples might currently be the most suitable method for this investigation. Future studies are still needed to confirm the effect of DB and IB for pediatric MMD patients.
Both direct bypass and indirect bypass are effective in improving the neurological status of pediatric ischemic-type MMD patients, and direct bypass might be more superior in preventing recurrent ischemic strokes.
YahZ and XD: conception and design. YahZ, SY, JLu, and JLi: acquisition of data. YahZ: analysis and interpretation of data and drafting the article. YanZ, DZ, RW, HW, and YuaZ: technical supports and surgery. YuaZ: study supervision and approved the final version of the manuscript on behalf of all authors. All authors: critically revising the article and reviewed submitted version of manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.