Abstract
This study aimed to investigate the impact of controlling serum homocysteine on improving surgical outcomes in patients with moyamoya disease (MMD) and hyperhomocysteinemia. In this prospective observational cohort study, 477 patients with MMD post-encephaloduroarteriosynangiosis are divided into the HHcy-MMD post-control group (n = 193), HHcy-MMD uncontrolled group (n = 91), and MMD group (n = 193), with the HHcy-MMD post-control group further subdivided into good (homocysteine 0–10 μmol/L, n = 121) and general (homocysteine 10–15 μmol/L, n = 72) control groups. The differences in imaging and long-term clinical prognosis among the three groups were compared. No significant differences were noted in the Matsushima grade after encephaloduroarteriosynangiosis between the MMD group and HHcy-MMD post-control group (P > 0.05); however, there was a significant difference between the HHcy-MMD post-control group and HHcy-MMD uncontrolled group (P < 0.001). A significant difference was noted between the good and general control groups in the Matsushima grade (P = 0.025) and long-term follow-up clinical outcomes (P = 0.035). The area under the curve of homocysteine levels for predicting adverse clinical outcomes was 85.48% (95% confidence interval: 80.31–90.65%). Effective control of serum Hcy level after EDAS surgery in Moyamoya disease patients with HHcy may lead to better prognosis.
Clinical Trial Registration: This study was registered at ClinicalTrials.gov (NCT03613701).
Keywords: Moyamoya disease, hyperhomocysteinemia, encephaloduroarteriosynangiosis, treatment, clinical outcome
Introduction
Moyamoya disease (MMD) is characterized by slow and progressive thickening of the intima at the end of the internal carotid artery, the beginning of the anterior cerebral artery and middle cerebral artery (MCA), gradual narrowing and even occlusion of the arterial lumen, and compensatory dilation of the basal cerebral artery. 1 Extracranial -intracranial vascular revascularization is still the only effective method for treating MMD. 2 Encephaloduroarteriosynangiosis (EDAS) is an effective indirect vascular reconstructive surgery for improving cerebral blood flow and reducing the risk of secondary stroke in children and adults with MMD.3 –8 However, in some adult patients, the effect of vascular reconstruction is poor due to various factors affecting the curative effect of surgery. A previous study demonstrated that hyperhomocysteinemia (HHcy) is an essential factor impacting the effect of Indirect reconstruction. 9
Homocysteine (Hcy), a sulfur-containing amino acid, is produced as an intermediary of methionine metabolism. Hcy concentrations are impacted by dietary folic acid and B vitamins, lifestyle factors such as smoking, and genetic factors.10 –12 Increased plasma Hcy (HHcy) is an independent risk factor for developing cardiovascular and cerebrovascular diseases and cerebral small-vessel diseases.13 –15 HHcy is a risk factor for poor collateral circulation formation and poor clinical prognosis after EDAS in adults with MMD. 9 However, whether serum Hcy levels should be controlled in patients with MMD after indirect vascular reconstruction has not been elucidated.
This study aimed to explore the optimal level of Hcy control after EDAS in patients with MMD combined with HHcy.
Material and methods
Patient selection
A consecutive surgical series of patients with MMD who underwent EDAS between January 2010 and December 2017 at the Department of Neurosurgery, Fifth Medical Center of the Chinese People’s Liberation Army, were prospectively included. Patients aged 18 years or older were selected as study participants to avoid age-related bias. All patients were diagnosed with MMD based on cerebral digital subtraction angiography findings. Inclusion and exclusion criteria were set based on MMD diagnosis and treatment criteria. 16 We divided patients with MMD into three groups: the MMD group (patients with normal Hcy levels before and after surgery), HHcy-MMD post-control group (patients with high preoperative Hcy levels and well-controlled postoperative Hcy levels), and HHcy-MMD uncontrolled group (patients with high preoperative Hcy levels and poor postoperative control). All patients with HHcy had received a definite diagnosis of HHcy according to the World Health Organization’s definition—an increase in serum Hcy exceeding 15 μmol/L is deemed HHcy. 17 A total of 315 patients with high preoperative Hcy levels were included, and 31 patients were excluded due to incomplete imaging data or missing follow-up. The patients in the MMD group were randomly selected according to the number of patients in the HHcy-MMD post-control group. The cerebral hemisphere statistical algorithm was used to analyze the imaging differences of patients in different groups to eliminate statistical errors.
Clinical data of patients
Clinical records, including hospital charts, clinic notes, and radiological studies, were reviewed. All data was collected through October 2022. This study was approved by the Research Ethics Committee of the First Medical Center of the Chinese People’s Liberation Army General Hospital (ky-2018-3-14), and all participants provided written informed consent. All procedures involving human participants were performed in accordance with the Declaration of Helsinki (1964). This study has been registered at ClinicalTrials.gov (ChiCTR2200064160).
Angiographic evaluation
Cerebral angiography was routinely performed within 1 week preoperatively. The angiographic staging was performed according to Suzuki’s classification. 1 Angiographic collateral grading was performed according to the system described in a previous study. 18 The score range was 1–12 points. During the venous delay period, the anatomic range of pia collateral blood included the posterior cerebral artery supplying area to the anterior cerebral artery and the MCA supplying area. The basal brain perforator and smoke vessel were determined according to Suzuki staging. The condition of the collateral circulation of patients with MMD was divided into three stages: scores of 1–4 were defined as poor collateral circulation (stage I), scores of 5–8 as good collateral circulation (stage II), and scores of 9–12 as excellent collateral circulation (stage III).
All patients were followed up by angiography 6 months after EDAS. The development of collateral circulation of the MCA via bypass was graded according to the system described by Matsushima, et al. 19 as follows: Grade A, blood supply area of the surgical bypass covered more than two-thirds of the MCA distribution; Grade B, blood supply covered one- to two-thirds of the MCA distribution; and Grade C, only one-third of the MCA distribution or no collateral circulation was observed.
All angiographic images were reviewed by two experienced viewers blinded to the angiographic results and clinical details. Any differences in the observation indicators were resolved through discussion.
Magnetic resonance imaging
One week preoperatively and 6 months postoperatively, the cerebral hemodynamic status was assessed by dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) using a MAGNETOM Skyra 3-T MRI scanner (Siemens, Erlangen, Germany) following previously described methods. 20 The acquired DSC-MRI images were processed using a post-processing workstation (Syngo Via 20, Siemens) and analyzed with MR Neuro-Perfusion software. We used time to peak (TTP, the time at which contrast level reaches its maximum), mean transit time (average time required for the contrast agent to travel from the arterial side of the skull to the venous side), mean relative cerebral blood flow, and mean relative cerebral blood volume, a hemodynamic parameter calculated by MR perfusion, to evaluate the hemodynamic status of patients.
Homocysteine assay
Blood was drawn from fasting patients and collected in tubes containing ethylenediaminetetraacetic acid. Plasma Hcy specimens were placed on ice and transported to the laboratory within 30 min of collection, and blood was centrifuged for 1–2 h after venipuncture. Plasma was frozen at −20°C until analysis. Hcy concentration was determined using a competitive immunoassay.21,22 Patients with HHcy on admission were routinely treated with a complex nutrient regimen comprising 1000 mg natural betaine, 0.8 mg folic acid, 2.8 mg vitamin B2, 2.8 mg vitamin B6, and 4.8 μg vitamin B12. 23 Hcy levels that did not decrease to <15 μmol/L were considered uncontrolled. A reduction in Hcy levels to 10–15 μmol/L was considered general control, whereas a reduction to 0–10 μmol/L was considered well-controlled.
Surgical procedure
All patients underwent EDAS performed by the same neurosurgeon. Specific surgical methods are described in previous studies.24,25
Clinical follow-up
The long-term outcome was ascertained via clinical visits and telephone. Clinical outcomes were divided into four grades: 1) excellent (preoperative symptoms had disappeared with no fixed neurological deficits); 2) good (symptoms had markedly decreased, but neurological deficits remained); 3) fair (symptoms persisted though less frequently); and 4) poor (preoperative status remained either unchanged or worsened or new symptoms appeared).26,27 The modified Rankin scale (mRS) was used to determine pre- and postoperative neurological functional outcomes. 28 Perioperative stroke was defined as either infarction or hemorrhage present on MRI or computed tomography performed intraoperatively or within one month postoperatively. Late postoperative stroke was defined as a stroke event occurring during the follow-up period.
Statistical analysis
The baseline characteristic data of all patients were presented as mean ± standard deviation (continuous variable) and n (%) (categorical variable). The χ2 test was used to compare categorical variables, and the independent sample t-test or analysis of variance was used to compare continuous variables. The optimal cut-off value was determined using a receiver operating characteristic curve analysis by maximizing the Youden index. The cut-off value accuracy was evaluated using measures such as sensitivity, specificity, predictive values, and likelihood ratios. All statistical analyses were carried out using SPSS software for Windows (version 20.0; IBM, Armonk, NY). Statistical significance was established at P < 0.005.
Results
Patient characteristics
A total of 477 patients were included: 193 patients in the MMD group, 193 patients in the HHcy-MMD post-control group, and 91 patients in the HHcy-MMD uncontrolled group. Table 1 shows a comparison of baseline characteristics among the three patient groups. There were no significant between-group differences in baseline characteristics (P > 0.05).
Table 1.
Clinical comparison of the three patient groups. a
| Patient characteristic | Total(n = 477) | MMD group(n = 193) | HHcy-MMD post-control group(n = 193) | HHcy-MMD uncontrolled group(n = 91) | P-value |
|---|---|---|---|---|---|
| Mean age, years | 35.7 ± 13.9 | 35.5 ± 14.0 | 34.7 ± 13.8 | 38.3 ± 13.8 | 0.125 |
| Female | 171 (35.8%) | 66 (34.2%) | 74 (38.3%) | 31 (34.1%) | 0.645 |
| Initial symptoms | |||||
| Asymptomatic | 6 (1.3%) | 3 (1.6%) | 2 (0.5%) | 1 (2.2%) | |
| TIA | 177 (37.1%) | 70 (36.3%) | 73 (37.8%) | 34 (37.4%) | |
| Infarction | 105 (22.0%) | 41 (21.2%) | 44 (22.8%) | 20 (22.0%) | 0.996 |
| Hemorrhage | 122 (25.6%) | 52 (26.9%) | 45 (23.3%) | 25 (27.5%) | |
| Others (headache, epilepsy) | 67 (14.0%) | 27 (14.0%) | 29 (15.0%) | 11 (12.1%) | |
| Stroke risk factors | |||||
| Hypertension | 150 (31.4%) | 63 (32.6%) | 54 (28.0%) | 33 (36.3%) | 2.184 |
| Diabetes mellitus | 61 (12.8%) | 27 (14.0%) | 23 (11.9%) | 11 (12.1%) | 0.421 |
| Hyperlipidemia | 184 (38.6%) | 77 (39.9%) | 69 (35.8%) | 38 (41.8%) | 1.181 |
| Smoking or alcohol consumption | 226 (47.4%) | 97 (50.3%) | 89 (46.1%) | 40 (44.0%) | 1.194 |
| PCI | 115 (24.1%) | 45 (23.3%) | 54 (28.0%) | 16 (17.6%) | 0.152 |
| mRS score at admission | |||||
| 0 | 6 (1.3%) | 3 (1.6%) | 1 (0.5%) | 2 (2.2%) | |
| 1 | 186 (39.0%) | 71 (36.8%) | 84 (43.5%) | 31 (34.1%) | |
| 2 | 171 (35.8%) | 72 (37.3%) | 63 (32.6%) | 36 (39.6%) | |
| 3 | 81 (17.0%) | 33 (17.1%) | 35 (18.1%) | 13 (14.3%) | 0.463 |
| 4 | 32 (6.7%) | 14 (7.3%) | 9 (4.7%) | 9 (9.9%) | |
| 5 | 1 (0.2%) | 0 | 1 (0.5%) | 0 |
MMD: moyamoya disease; HHcy: hyperhomocysteinemia; SD: standard deviation; TIA: transient ischemic attack; PCI: posterior circulation involvement; mRS: modified Rankin scale; HHcy-MMD post-control group: high preoperative Hcy levels and well-controlled Hcy levels after the operation. HHcy-MMD uncontrolled group: high preoperative Hcy levels and poor postoperative control.
aValues are presented as the number of patients (%) unless otherwise noted.
Angiography and MRI outcomes
In the MMD group of 193 patients, 79 underwent bilateral EDAS, and 114 underwent unilateral EDAS, with a total of 272 cerebral hemispheres. In the HHcy-MMD post-control group of 193 patients, 77 underwent bilateral EDAS, and 116 underwent unilateral EDAS, with a total of 270 cerebral hemispheres. Of the 91 patients in the HHcy-MMD uncontrolled group, 51 underwent bilateral EDAS, and 40 underwent unilateral EDAS, with 142 cerebral hemispheres. The MMD and HHcy-MMD post-control groups, as well as the HHcy-MMD post-control and HHcy-MMD uncontrolled groups, were compared and analyzed. No significant differences were noted in preoperative collateral circulation grading, preoperative Suzuki staging, or preoperative MRI perfusion between the two comparison groups (P > 0.05), indicating that the three patient groups were well matched. No significant difference was noted in postoperative collateral circulation grading or postoperative Suzuki stage between the two control groups (P > 0.05), and TTP on postoperative DSC-MRI was significantly improved in the HHcy-MMD post-control group compared with the HHcy-MMD uncontrolled group (P = 0.007). No significant difference was noted in the Matsushima grade between the MMD and HHcy-MMD post-control groups (P > 0.05). However, a significant difference was observed between the HHcy-MMD post-control group and the HHcy-MMD uncontrolled group (P < 0.001), indicating that the HHcy-MMD uncontrolled group had more difficulty in postoperative collateral neovascularization (Table 2).
Table 2.
Comparison of preoperative and postoperative imaging features of the operative hemisphere among the three patient groups. a
| Variable | MMD group | HHcy-MMD post-control group | P-value | HHcy-MMD post-control group | HHcy-MMD uncontrolled group | P-value |
|---|---|---|---|---|---|---|
| Preoperative collateral grade | ||||||
| Poor (stage I) | 135 (49.6%) | 139 (51.5%) | 0.799 | 139 (51.5%) | 66 (46.5%) | 0.595 |
| Fair (stage II) | 133 (48.9%) | 126 (46.7%) | 126 (46.7%) | 74 (52.1%) | ||
| Good (stage III) | 4 (1.5%) | 5 (1.8%) | 5 (1.8%) | 2 (1.4%) | ||
| Postoperative collateral grade | ||||||
| Poor (stage I) | 75 (27.6%) | 90 (33.3%) | 0.343 | 90 (33.3%) | 35 (24.6%) | 0.112 |
| Fair (stage II) | 181 (66.5%) | 166 (61.5%) | 166 (61.5%) | 101 (71.1%) | ||
| Good (stage III) | 16 (5.9%) | 14 (5.2%) | 14 (5.2%) | 6 (4.3%) | ||
| Preoperative Suzuki stage | ||||||
| 1 | 19 (7.0%) | 25 (9.3%) | 0.500 | 25 (9.3%) | 7 (4.9%) | 0.080 |
| 2 | 46 (16.9%) | 39 (14.4%) | 39 (14.4%) | 34 (23.9%) | ||
| 3 | 57 (21.0%) | 57 (21.1%) | 57 (21.1%) | 30 (21.1%) | ||
| 4 | 72 (26.5%) | 59 (21.9%) | 59 (21.9%) | 40 (28.2%) | ||
| 5 | 41 (15.1%) | 41 (15.2%) | 41 (15.2%) | 17 (12.0%) | ||
| 6 | 37 (13.5%) | 49 (18.1%) | 49 (18.1%) | 14 (9.9%) | ||
| Postoperative Suzuki stage | ||||||
| 1 | 11 (4.0%) | 10 (3.7%) | 0.887 | 10 (3.7%) | 6 (4.2%) | 0.222 |
| 2 | 27 (9.9%) | 27 (10.0%) | 27 (10.0%) | 17 (12.0%) | ||
| 3 | 33 (12.1%) | 34 (12.6%) | 34 (12.6%) | 15 (10.6%) | ||
| 4 | 44 (16.2%) | 40 (14.8%) | 40 (14.8%) | 32 (22.5%) | ||
| 5 | 106 (39.0%) | 97 (35.9%) | 97 (35.9%) | 51 (35.9%) | ||
| 6 | 51 (18.8%) | 62 (23.0%) | 62 (23.0%) | 21 (14.8%) | ||
| DSC-MRI on preoperative | ||||||
| TTP (s) | 3.6 ± 8.1 | 3.0 ± 2.6 | 0.310 | 3.0 ± 2.6 | 3.8 ± 10.8 | 0.256 |
| MTT (s) | 42.0 ± 28.6 | 42.5 ± 28.9 | 0.833 | 42.5 ± 28.9 | 39.6 ± 28.3 | 0.333 |
| rCBV (mL/100 g) | 2.0 ± 1.0 | 2.1 ± 1.2 | 0.347 | 2.1 ± 1.2 | 1.7 ± 0.7 | 0.252 |
| rCBF (mL/100 g.min) | 1.3 ± 0.4 | 1.3 ± 0.4 | 0.532 | 1.3 ± 0.4 | 1.2 ± 0.3 | 0.422 |
| DSC-MRI on postoperative | ||||||
| TTP (s) | 2.3 ± 1.9 | 2.0 ± 1.8 | 0.776 | 2.0 ± 1.8 | 2.3 ± 1.8 | 0.007 |
| MTT (s) | 35.6 ± 25.0 | 36.1 ± 26.1 | 0.838 | 36.1 ± 26.1 | 34.9 ± 23.1 | 0.635 |
| rCBV (mL/100 g) | 1.8 ± 0.6 | 1.8 ± 0.7 | 0.915 | 1.8 ± 0.7 | 1.8 ± 0.7 | 0.973 |
| rCBF (mL/100 g.min) | 1.3 ± 0.5 | 1.3 ± 0.5 | 0.694 | 1.3 ± 0.5 | 1.3 ± 0.4 | 0.757 |
| Matsushima grade | ||||||
| Grade A + B | 203 (74.6%) | 205 (75.9%) | 0.727 | 205 (75.9%) | 73 (51.4%) | <0.001 |
| Grade C | 69 (25.4%) | 65 (24.1%) | 65 (24.1%) | 69 (48.6%) | ||
| Total | 272 | 270 | 270 | 142 |
DSC-MRI: dynamic susceptibility contrast MRI; TTP: time to peak; MTT: mean transit time; rCBV: relative cerebral blood volume; rCBF: relative cerebral blood flow; MMD: moyamoya disease; HHcy: hyperhomocysteinemia. The HHcy-MMD post-control group included patients with high preoperative Hcy levels and well-controlled Hcy levels after the operation. The HHcy-MMD uncontrolled group included patients with high preoperative Hcy levels and poor postoperative control.
Values are presented as the number of hemispheres (%); both were evaluated for all patients.
The HHcy-MMD post-control group was further divided into a general control group of 72 patients (Hcy, 10–15 μmol/L) and a good control group of 121 patients (Hcy, 0–10 μmol/L) according to postoperative Hcy level. In the general control group (n = 72), 21 patients underwent bilateral EDAS, and 51 underwent unilateral EDAS, totaling 93 cerebral hemispheres. In the good control group (n = 121), 56 patients underwent bilateral EDAS, and 65 underwent unilateral EDAS, totaling 177 cerebral hemispheres. No significant difference was noted between the two groups in terms of preoperative collateral circulation grading, preoperative Suzuki stage, preoperative DSC-MRI findings, postoperative collateral circulation grading, postoperative Suzuki stage, or postoperative DSC-MRI findings. However, the Matsushima grade differed between the two groups (P = 0.025; Table 3).
Table 3.
Collateral grade, Suzuki stage, Matsushima grade, and DSC-MRI findings on the operative hemisphere between the two control groups. a
| Variable | Good control group(Hcy, 0–10 μmol/L) | General control group(Hcy, 10–15 μmol/L) | P-Value |
|---|---|---|---|
| Preoperative collateral grade | |||
| Poor (stage I) | 85 (48.0%) | 54 (58.0%) | 0.166 |
| Fair (stage II) | 88 (49.7%) | 38 (40.9%) | |
| Good (stage III) | 4 (2.3%) | 1 (1.1%) | |
| Postoperative collateral grade | |||
| Poor (stage I) | 57 (32.2%) | 33 (35.5%) | 0.390 |
| Fair (stage II) | 110 (62.1%) | 56 (60.2%) | |
| Good (stage III) | 10 (5.7%) | 4 (4.3%) | |
| Preoperative Suzuki stage | |||
| 1 | 19 (10.7%) | 6 (6.5%) | 0.274 |
| 2 | 20 (11.3%) | 19 (20.4%) | |
| 3 | 36 (20.3%) | 21 (22.6%) | |
| 4 | 41 (23.2%) | 18 (19.6%) | |
| 5 | 34 (19.2%) | 7 (7.4%) | |
| 6 | 27 (15.3%) | 22 (23.5%) | |
| Postoperative Suzuki stage | |||
| 1 | 8 (4.5%) | 2 (2.1%) | 0.351 |
| 2 | 17 (9.6%) | 10 (10.8%) | |
| 3 | 20 (11.3%) | 14 (15.1%) | |
| 4 | 26 (14.7%) | 14 (15.1%) | |
| 5 | 69 (39.0%) | 28 (30.0%) | |
| 6 | 37 (20.9%) | 25 (26.9%) | |
| DSC-MRI on preoperative | |||
| TTP (s) | 3.0 ± 2.7 | 3.0 ± 2.5 | 0.408 |
| MTT (s) | 41.0 ± 30.1 | 43.7 ± 26.4 | 0.177 |
| rCBV (mL/100 g) | 2.1 ± 1.4 | 1.9 ± 0.7 | 0.330 |
| rCBF (mL/100 g.min) | 1.3 ± 0.5 | 1.2 ± 0.4 | 0.319 |
| DSC-MRI on postoperative | |||
| TTP (seconds) | 2.4 ± 2.0 | 1.9 ± 1.4 | 0.084 |
| MTT (s) | 38.7 ± 27.9 | 31.6 ± 22.8 | 0.085 |
| rCBV (mL/100 g) | 1.8 ± 0.6 | 1.8 ± 0.8 | 0.147 |
| rCBF (mL/100 g.min) | 1.2 ± 0.4 | 1.3 ± 0.5 | 0.129 |
| Matsushima grade | |||
| Grade A + B | 138 (77.9%) | 67 (72.1%) | 0.025 |
| Grade C | 39 (22.1%) | 26 (27.9%) | |
| Total | 177 | 93 |
DSC-MRI: dynamic susceptibility contrast MRI; TTP: time to peak; MTT: mean transit time; rCBV: relative cerebral blood volume; rCBF: relative cerebral blood flow; MMD: moyamoya disease; Hcy: homocysteine.
Values are expressed as the number of operative hemispheres (%).
Clinical follow-up results
All 477 patients underwent EDAS and were followed up in August 2024. The average follow-up time was 105.28 ± 57.45 (range, 65–121) months in the general control group and 108.37 ± 61.58 (range, 61–125) months in the good control group, indicating no significant difference (P > 0.05). However, a significant difference was noted in long-term clinical outcomes (P = 0.035) and follow-up mRS scores (P = 0.038) between these groups (Table 4).
Table 4.
Distribution of clinical outcomes between the two control groups. a
| Variables | Good control group (Hcy, 0–10 μmol/L) | General control group (Hcy, 10–15 μmol/L) | P-Value |
|---|---|---|---|
| Clinical outcome | |||
| Poor | 32 (26.5%) | 21 (29.1%) | 0.035 |
| Fair | 33 (27.3%) | 27 (37.5%) | |
| Good | 28 (23.1%) | 12 (16.7%) | |
| Excellent | 28 (23.1%) | 12 (16.7%) | |
| Follow-up mRS score | |||
| 0 | 41 (33.9%) | 16 (22.2%) | 0.038 |
| 1 | 52 (42.9%) | 34 (47.2%) | |
| 2 | 19 (15.7%) | 14 (19.4%) | |
| 3 | 7 (5.9%) | 6 (8.4%) | |
| 4 | 2 (1.6%) | 2 (2.8%) | |
| 5 | 0 | 0 | |
| 6 | 0 | 0 | |
| Total | 121 | 72 | |
mRS: modified Rankin scale; Hcy: homocysteine.
Values are presented as number of patients (%).
Receiver operating characteristic curve analysis was performed to determine the efficacy of serum Hcy levels in predicting the clinical treatment outcome of MMD (Figure 1). We defined excellent and good clinical outcomes as good and fair and poor clinical outcomes as poor. The area under the curve for poor clinical outcomes was 85.48% (95% confidence interval [CI]: 80.31–90.65%), sensitivity was 73.81%, specificity was 80.73%, and accuracy was 77.72%. The cut-off value was 9.55, indicating that Hcy levels >9.55 μmol/L have significant predictive power for adverse clinical outcomes.
Figure 1.
Model of Hcy level of patients with MMD and analysis of patients' working characteristic curve with the probability of adverse postoperative clinical outcomes. Hcy: homocysteine; MMD: moyamoya disease; AUC: area under the curve.
Patients in this study were divided into two groups based on the Hcy cut-off of >9.55 or ≤9.55 μmol/L. The Kaplan–Meier method was used to analyze the difference in the risk of postoperative stroke between the two groups, and the results showed a significant difference (log-rank test, P = 0.0099; Figure 2). In the HHcy-MMD post-control group, among 265 patients (out of 477) with Hcy ≤9.55 μmol/L after surgery, 12 patients had a recurrent stroke (recurrence rate: 4.52%). Among 212 patients with Hcy >15 μmol/L, 22 had recurrent stroke (recurrence rate: 10.37%). The recurrent stroke risk decreased 2.29-fold in the group with postoperative Hcy ≤9.55 μmol/L.
Figure 2.
Kaplan–Meier analyses for the predictive factors of postoperative stroke events in the two groups. Hcy: homocysteine.
Discussion
Surgical intervention is still the first choice for treating MMD, including direct, indirect, and combined surgical methods. Indirect revascularization is the main surgical method for MMD due to its simple procedure, low complications, and good prognosis; EDAS is the most widely used surgical method in indirect revascularization.3,5,8 However, the application of EDAS in adult MMD is still controversial because of individual differences in the effect of indirect vascular reconstruction surgery. With the accumulation of evidence on the efficacy of MMD treatment, progressively more factors affecting the impact of EDAS have been discovered. A previous study found that patients with MMD complicated with HHcy had poor collateral vessel formation after EDAS, faster disease progression, and worse clinical outcomes. 9 Accordingly, we continued exploring the ideal Hcy control range in patients with MMD complicated with HHcy after EDAS. In this retrospective study with a large sample size and long follow-up, we found that effective control of Hcy levels after EDAS in patients with MMD combined with HHcy can achieve the same therapeutic effect as patients without MMD combined with Hcy. Hcy controlled at <9.55 μmol/L is more likely to have a good therapeutic effect in patients with MMD. To our knowledge, this study is the first to report on how to control Hcy levels in patients with MMD complicated with HHcy, providing an essential theoretical basis for the clinical treatment and medication guidance of MMD.
Previous studies have shown that Hcy concentration is affected by the dietary intake of folic acid and B vitamins, smoking and alcohol consumption, sex, and genetic factors.21,29,30 Chen et al. 31 and Bao et al. 32 believe that HHcy is an independent risk factor for developing cardiovascular and cerebrovascular diseases. Simultaneously, HHcy has been shown to be a risk factor for hypertension, dementia, chronic kidney disease, liver disease, and other diseases.33 –36 Therefore, effective control of Hcy level is essential for many diseases, including MMD. Den Heijer et al. found that compound nutritional supplements can reduce Hcy by a further 20–30% compared with folic acid supplementation alone. 23 Therefore, we used complex nutritional supplements in this study (1000 mg natural betaine, 0.8 mg folic acid, 2.8 mg vitamin B2, 2.8 mg vitamin B6, and 4.8 μg vitamin B12) to control MMD in patients with HHcy. In 284 patients with MMD combined with HHcy, 193 had Hcy <15 μmol/L, and 91 did not at 6 months after EDAS. HHcy was not effectively controlled because of the high level of basic Hcy, the short duration of medication, and the patients’ compliance with medication.
HHcy is an independent risk factor for postoperative poor collateral circulation and adverse clinical outcomes in patients with MMD. Whether people with MMD and HHcy should be operated on has long perplexed clinicians and patients.37,38 We found no significant difference in the Matsushima grade after EDAS between the MMD group and the HHcy-MMD post-control group. However, a significant difference was noted between the HHcy-MMD post-control group and HHcy-MMD uncontrolled group in Matsushima grade evaluation after EDAS, indicating that HHcy is an influential factor for poor collateral circulation formation after EDAS. However, the effective control of Hcy after EDAS does not affect the formation of collateral neovascularization after EDAS. In addition, we explored what level of Hcy is most effective for treatment in patients with MMD and HHcy. At present, intensive lipid-lowering therapy can significantly reduce the risk of stroke in cerebrovascular patients. Considering this, does the same principle hold for Hcy, and are lower Hcy levels better? HHcy refers to serum Hcy level ≥15 μmol/L. 39 Recently, serum Hcy ≥10 μmol/L has been shown to significantly increase the risk of cardiovascular and cerebrovascular diseases, Parkinson’s disease, and other diseases. 40 Therefore, patients in our HHcy-MMD post-control group were divided into two groups according to the serum Hcy level for postoperative review: 0–10 and 10–15 μmol/L. The imaging and long-term clinical follow-up results of both these groups showed that patients with Hcy controlled at 0–10 μmol/L had better therapeutic effects at 6 months postoperatively. Concurrently, patients with Hcy controlled at <9.55 μmol/L showed better clinical treatment effects. Patients with controlled Hcy ≤9.55 μmol/L after surgery had a 2.24-fold lower risk of recurrent stroke than those with controlled Hcy of 9.55–15 μmol/L. This finding gives hope to patients with MMD and guides clinicians in decision-making. We suggest that patients with MMD complicated with HHcy should strictly take compound nutritional preparations to control their Hcy after EDAS and that their Hcy control effect be reviewed after taking medication for 3 months; their medication should be modified if necessary. Hcy <9.55 μmol/L is optimal for patients with MMD.
This study has some limitations. First, this was a single-center study wherein patients in the MMD group were matched by age and sex, and other potential confounding factors could not be controlled. Second, the biases of selection bias, ascertainment bias, and recall bias may cause errors in the results. Third, we only studied the correlation between HHcy and the Matsushima grade and clinical outcomes after EDAS in patients with MMD. The lack of an MMD animal model may be the greatest obstacle to exploring the etiology, pathology, and pathophysiological mechanism of collateral circulation in patients with MMD. Therefore, we cannot conduct a fundamental study to explain our findings.
In conclusion, effective control of serum Hcy level after EDAS surgery in Moyamoya disease patients with HHcy may lead to better prognosis.
Acknowledgements
We thank the Department of Neurosurgery, Chinese PLA General Hospital, for their support during this study.
Funding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the The National Key Research and Development Program of China (grant numbers: 2022YFC2703304 and 2022YFA1105501).
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Authors’ contributions: Drs. GG, RMY, LD and JNZ conceived the study; Drs. GG and XPW supervised and coordinated all aspects of the work; Drs. GG, MJW, FBH, and CH designed the experiments; Drs. GG and QNW wrote the paper; Drs. SML, XPW, QBG and JJL performed the experiments, analyzed the data, and prepared the figures and tables; Drs. MJW and JJL contributed with analytical tools.
ORCID iDs: Qing-Bao Guo https://orcid.org/0000-0001-6538-375X
Jian-ning Zhang https://orcid.org/0009-0003-2796-5451
Ethical considerations
This study was approved by the Research Ethics Committee of the First Medical Center of the Chinese People’s Liberation Army General Hospital (ky-2018-3-14).
Consent to participate
All participants provided written informed consent.
Consent for publication
All the authors approved the publication of the study.
Data availability
The data that support the findings of this study are available upon request from the corresponding author (Jianning Zhang).
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are available upon request from the corresponding author (Jianning Zhang).