Efficacy of Surgical Revascularizations in Young and Middle-aged Patients with Symptomatic Middle Cerebral Arterial Occlusion

Background: Treatments on middle cerebral arterial occlusions (MCAO) remain controversial. This study (aged 18-65 y) with symptomatic MCAO, and making comparisons between surgical procedures. Methods: From a seven-year prospective consecutive registry, 115 cases were enrolled in this study. Patient individually received medical therapy alone (medical group, n=64) and medical therapy plus direct or indirect revascularization (surgical group, n=51). The secondary ischemic events (SIE) was defined as the primary outcome. SIE incidences and SIE-free survival rates were compared between groups. Risk factors were analyzed using the Cox regression analysis. Results: During a follow-up of 42.7 months on average, SIE occurred in 11cases of medical group and 10 cases of surgical group. SIE incidences were indifferent between groups (surgical:medical = 19.6%:17%, P=0.810, 95%CI 0.455-3.034). SIE incidences were 29.4% and 0% in direct revascularization subgroup and indirect revascularization subgroup, respectively. Indirect revascularization induced a higher SIE-free survival rate than direct revascularization (Log-rank P=0.015) and medical therapy (Log-rank P=0.044). An age>43y, with concomitant intracerebral arterial stenosis, and hyperlipidaemia history were correlated to the occurrence of SIE, while presences of compensatory arteries and taking antihypertensive drugs reduced risks of SIE. Conclusions: Indirect revascularization plus medical therapy was more effective on SIE prevention than both medical treatments alone and direct revascularization plus medical therapy in young and middle aged patients with symptomatic MCAO. Direct revascularization was not recommended, for its similar efficacy to medical therapy alone.

.6%:17%, P=0.810, 95%CI 0.455-3.034). SIE incidences were 29.4% and 0% in direct revascularization subgroup and indirect revascularization subgroup, respectively. Indirect revascularization induced a higher SIE-free survival rate than direct revascularization (Log-rank P=0.015) and medical therapy (Log-rank P=0.044). An age>43y, with concomitant intracerebral arterial stenosis, and hyperlipidaemia history were correlated to the occurrence of SIE, while presences of compensatory arteries and taking antihypertensive drugs reduced risks of SIE.
Conclusions: Indirect revascularization plus medical therapy was more effective on SIE prevention than both medical treatments alone and direct revascularization plus medical therapy in young and middle aged patients with symptomatic MCAO. Direct revascularization was not recommended, for its similar efficacy to medical therapy alone.

Background
Middle cerebral arterial occlusion (MCAO) induces ischemic stroke with an annual risk up to 12.5%. (1,2) For preventing the secondary ischemic events (SIEs), conventional medical treatments and surgical revascularizations have been applied with controversies on their efficacies. Surgical revascularizations have been proven to be beneficial, by several studies, on reducing subsequent strokes and fatalities are reported in several studies. (3)(4)(5)(6) However, the benefits diminished in the studies with large scales of participant covering all ages. (7)(8)(9)(10)(11) Aging-related factors are suspected to be responsible for the indifferent clinical outcome of surgical revascularizations, which would be less effects on MCAO patients younger than 65y. The purpose of this study is to investigate the efficacy of surgical revascularizations on preventing SIE in young and middle-aged (aged 18-65y) symptomatic MCAO patients, and making comparisons between surgical procedures.

Study design
A single center prospective consecutive registry was reviewed. The registry included all patients diagnosed with symptomatic MCAO from January 2012 to December 2018 in Beijing Tiantan Hospital.
Patients aged 18-65y were enrolled. Medical records, neuro-image, and results of the long-term follow-up were extracted for intergroup analyses. The study was approved by IRB of Beijing Tiantan Hospital. Written informed consents were obtained from all participants or their next-of-kin.

Patient And Public Involvement
Patients or members of the public did not participant in the design, or conduct, or reporting, or dissemination plans of the research.

Study Participants
Patients enrolled in the registry cohort between Jan 2012 and Dec 2017 were further screened with inclusion and exclusion criteria. The inclusion criteria included: 1) aged 18-65y, 2) with MCAO diagnosed by computed tomographic angiography (CTA) or digital subtraction angiography (DSA), 3) with initial ischemic symptoms or neural functional deficits related to MCAO, and 4) received either surgical revascularization plus medical therapy or medical treatment alone. The exclusion criteria included: 1) received endovascular treatment, 2) moyamoya disease or moyamoya syndrome was not excluded, or 3) with any history of arteritis, immune system diseases, or leptospira infection. Patients with any of the following indications were recommended to receive surgical revascularizations plus medical therapy: 1) symptomatic MCAO, 2) with abnormal cerebral perfusion result, or 3) with aggravating symptoms which was uncontrollable with medical treatments alone. Preferences of patients were considered when making therapeutic decisions. According to treatments performed, patients were divided into medical group and surgical group. In medical group, patients received medical therapy alone, including clopidogrel 75 mg, aspirin 100 mg and atorvastatin 20 mg every day. In surgical group, patients took aspirin 100 mg + atorvastatin 20 mg every day (except the operation day), and received either STA-MCA anastomosis (direct revascularization) or modified encephalo-duro-arterio-synangiosis (mEDAS, indirect revascularization). Conditions of STA and MCA, such as caliber and wall structure, determined the type of procedure. Indirect revascularization was performed when any of following conditions exists: 1) with insufficient caliber for anastomosis, 2) with abnormal vascular wall structure, 3) with compensatory collateral formation in operating field. To ensure the quality of direct revascularization, participating neurosurgeons must have performed ≥ 50 anastomotic procedures in the latest 12 months.

Follow-up
Follow-up were conducted via two methods: 1) telephone follow-up: patients were contacted in every six months by full-time health visitors for self-assessments of mRS, and 2) outpatient follow-up: patients visited outpatient department for neurological and neuroimaging examinations, and neurological functional assessments via mRS in every six months. The outcomes were recorded in detail.

Outcome Evaluation
The occurrence of SIE was the primary outcome event, defined as an aggravating recurrence or a new onset of both transient ischemic attack (TIA) and ischemic stroke, as well as a fatal final stroke. The SIE-free survival time was observed and defined as the duration from receiving treatment to the occurrence of SIE or the end of follow-up.

Statistical Methods
According to published studies, SIE incidence was reported to be 18.6%-45% in medical group and 8.3%-30.9% in surgical group. (1,5,6,8,9,12) With a test power of 80% and a type I error probability of 0.05, the minimum sample size was 44 cases in each group.
All statistical analyses were performed using IBM® SPSS® Statistics (Version 22, IBM, NY, United States). The baselines of the two groups were compared using Student's t-tests and rank-sum tests.
Pearson chi-square tests (or Fisher exact tests) were performed to compare the clinical outcomes between groups and subgroups. Kaplan-Meier estimates were performed to investigate differences in survival time. Receiver operating characteristic (ROC) analyses were used to obtain cutoff ages of different treatments. Cox regressions were performed to investigate correlated factors of SIE-free survival.
Results 124 patients were identified aged 18-65 y. Nine patients were excluded for being treated with endovascular treatment, and 9 patients (7.8%) were lost to follow-up in our study. Among 106 patients remained, nine patients were diagnosed with bilateral MCAOs. A total of 115 MCAOs (represented as Cases below) were involved (Fig. 1).
Sixty-four cases (male: female = 41:23) were involved in medical group, with a mean age of 50.31 ± 9.77 y. Fifty-one cases (male: female = 35:16) were involved in surgical group, with a mean age of 43.86 ± 8.96 y ( Table 1). In the surgical group, 34 cases received direct revascularizations, and 17 cases received indirect revascularizations.   (1,5,6,8,9,12). In this study, the upper age boundary of inclusion criteria was lowered to 65y to investigate the efficacy of surgical revascularization in younger patients. It resulted in a younger mean age of participants than those in published studies. However, it failed to validate the superiority of surgical revascularizations in treating symptomatic MCAO patients aged 18-65 y. Underlying causes were analyzed via further interpretations of our data and inspections of published studies.
Although overall efficacies on SIE prevention were indifferent between groups in our study, a significant superiority was observed in indirect revascularization subgroup. The performing of indirect revascularization plus medical therapy resulted in a remarkably lower SIE incidence than both of direct revascularization subgroup and medical group. Indirect revascularizations is being complained about its incapability of improving distal hemodynamics immediately, (7,13) so that it is commonly performed on the patients with poor intracranial and extracranial arterial condition who are unsuitable for STA-MCA anastomosis. In our experience, significant improvements of territorial perfusion have been observed in a lot of patients after mEDAS (a case example is presented in Fig. 3). On one hand, indirect revascularizations gradually improves the territorial perfusion via the angiogenesis of pial arteries, instead of changing hemodynamics critically via anastomosis. (14,15) On the other hand, the already formed compensatory arteries could be preserved in procedure, that improves the functional prognosis (16)(17)(18). The efficacy of indirect revascularization on treating MCAO needs investigating.
Direct revascularization has been proved to be effective on recovering the hemodynamics and preventing ischemic stroke. (19) However, only Japanese EC/IC Trial (JET) and JET-2 declare that direct revascularization results in more benefits than medical treatments on SIE prevention. (5,6) Hemodynamic factors were emphasized in those studies, such as the threshold of cerebral vasodilatory reserve, cerebrovascular reactivity, cerebral blood flow, and oxygen extraction fraction. (4,6,12,20) With strict hemodynamic criteria, direct revascularization could help preventing SIE. (21) In contrast, SIE occurred in 29.4% of patients receiving direct revascularization in our study. It is a higher incidence than that from Low et al. and JET-2, which is 13% and 8.3%, respectively. (6,12) Lacking of preoperative hemodynamic evaluation might be a main cause of the worse outcome.
Hemodynamic indications of direct revascularization need to be explored. Age-related effects should be considered when making the therapeutic decision of MCAO. The difference of medical and surgical treatment in their cutoff ages were revealed in our study, which developed into a 5-year interval (surgical vs medical = 48y vs 43y). The efficacy on SIE prevention decreased earlier in medical group than surgical group. It was confirmed by the higher SIE-free survival rate of patients aged 43-48y in surgical group. In the comparisons between DR subgroup and medical group, differences in SIE incidence and Kaplan-Meier estimate were observed. Although they were insignificant due to the small sample size of each group, it suggested additional benefits of direct revascularization might exist in a certain age interval. In the Cox regression, an age older than 43y was identified to be a risk factor for patients's SIE-free survival. It could be regarded as another evidence for the age-related effect on treating MCAO. Adaptable age phases of different treatments need to be further explored with larger sample size.

Conclusions
Indirect revascularization plus medical therapy was more effective on SIE prevention than both medical treatments alone and direct revascularization plus medical therapy in young and middle aged patients with symptomatic MCAO. Direct revascularization was not recommended, for its similar efficacy to medical therapy alone.

Ethical approval and consent to participate
The study was approved by IRB of Beijing Tiantan Hospital. Written informed consents were obtained from all participants or their next-of-kin.

Consent for publication
Not applicable.

Data availability statement
The data that support the findings of this study are available from the administrative department of Beijing Tiantan Hospital but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the authors upon reasonable request and with permission of the administrative department of Beijing Tiantan Hospital.

Competing interests
The work was not carried out in the presence of any personal, professional or financial relationships that could potentially be construed as a conflict of interest.

Author's Contribution
MW participated in the study design, data acquisition and interpretation, and manuscript drafting. XL