Moyamoya disease (MMD) is an uncommon chronic intracerebral vascular disorder of unknown etiology characterized by stenosis or occlusion of the distal internal carotid artery or proximal middle cerebral artery along with a collateral network of vessels at the base of the brain (1, 2). Epidemiological data demonstrate that MMD is more prevalent in East Asian countries than the western countries (3). Even though no medical therapies were able to halt the pathologic process of moyamoya, revascularization surgeries including direct bypass, indirect bypass, and combined procedures have been proven to be effective treatments to stabilize the progression of MMD (4–6). However, postoperative complications related to compromised cerebral hemodynamics, are still a significantly impaired prognosis for patients. Intracranial hemorrhage or ischemic stroke was mostly reported adverse events due to hyper- or hypo-perfusion after revascularization (7). Of these complications, cerebral ischemia, with reported incidence ranging from 1.5 to 11.4% (8, 9) is still a challenging issue for adult patients (10) after revascularization, which impeded clinical outcome as a result of neurological deterioration and long-term neurological deficits (11). For pediatrics, the rate of perioperative cerebra infarction could be as high as 22.2% (12, 13). Therefore patients with MMD who underwent revascularization will greatly benefit from the identification of novel risk factors for cerebral ischemic complications in preoperative management.

Various clinical factors relating to the occurrence of cerebral ischemic complications post revascularization have been sporadically reported, but such data were mostly demographics like neurological status and radiological characteristics (5, 14). There is emerging literature to support the vital role of altered nutritional status in the pathogenesis of cerebral ischemic stroke (15, 16). Variables from laboratory tests and a series of nutritional screening tools are commonly used to evaluate nutritional status, but the results of nutritional screening tools may vary resulting from the complexity of computing indexes as well as expert experience of the examiners (17). Recently omics technologies are promising to identify diverse biomarkers for nutritional assessment (18), whereas they were not as easily accessed as laboratory parameters from blood tests in each medical institution. Studies were lacking in the identification of nutritional-associated risk factors in patients with MMD for the purposes of investigating the relationship with postoperative cerebral ischemic complications. Additionally, fewer data are available to generate a predictive model based on such risk factors. Taken together, we had 2 objectives in this study: (1) to explore independent risk factors for postoperative cerebral ischemic complications in terms of nutritional blood parameters from patients with MMD;(2) to create a predictive model incorporating novel risk factors for the purpose of prevention and effective management within the preoperative phase.

The present study investigated the association between clinical features, preoperative nutritional blood parameters, and the onset of cerebral ischemic complications after revascularization surgeries in patients with MMD. Our findings elicited patients with lower mRS score on initial admission, and surgeries performed on the left hemisphere were likely to encounter postoperative cerebral ischemia. Besides, nutritional blood parameters, lower WBC and higher TC levels, were identified as novel risk factors linked to the occurrence. Combined use of these four variables presented a good predictive ability for the onset of cerebral ischemic complications in MMD. To our knowledge, surgical side, WBC, and TC were newly reported independent indicators in comparison with previous research (12, 14, 20).

Revascularization is deemed as the most successful therapy to reduce the risk of stroke recurrence for patients with MMD by augmenting cerebral blood flow, but clinical outcomes remain to be challenged due to postoperative complications that are associated with impaired hemodynamic status (21). It has been discovered that patients with MMD suffer a relatively higher risk of additional ischemic events during the perioperative period (1). The frequency of TIA as a reversible symptom after revascularization surgeries in our study was similar to a rate of 6.1 % from a previous report (22), and there are still certain cases presented with TIA as the initial symptom and subsequently culminated in severe cerebral infarction or even cerebral hernia, which inevitably led to a worse outcome. Thus, it is reasonable that risk factors should be fully analyzed in preoperative management to prevent ischemic complications.

Numerous factors indicating the risk of complications after revascularization of MMD have been explored, and most are baseline characteristics like age, blood pressure, mRS on admission, or Suzuki stage (23, 24). Recently published researches have introduced several cerebral flow measurements in MMD to monitor hemodynamic status for perioperative evaluation (25, 26). Nevertheless, the requirement of expert knowledge may limit the operation of such technological advancements, and hence parameters that can be easily obtained to assess the risk of complications in patients with MMD who received revascularization are clinically needed. Complete blood count and biochemical analysis are routinely performed on each patient within initial admission and many contents are reflective of the valuable details about a patient's nutritional status (27). The association between aberrant nutrition and ischemia has been much discussed in both cardio- (28) and cerebrovascular diseases (29). Pathogenesis induced by altered nutritional status, including inflammation (30), oxidative stress (31), or lipid oxidation (32), generally contributes to the progression of vascular-ischemic events. Masahito et al. suggested that patients with MMD with preoperative malnutrition are prone to postoperative vascular complications via a possible vascular permeability impairment and increased inflammatory response (33). Based on exploration of nutritional blood parameters from complete blood count and biochemical analysis, we observed that patients developing postoperative cerebral ischemia had relatively lower WBC and higher TC levels before surgery.

A growing body of evidence from clinical and preclinical studies is in favor of the negative impacts of high TC level on vasculopathy, which highlights the risk of ischemic stroke (34, 35). Similar to previous studies, we assumed that inflammatory response was the underlying pathway triggered by excessive TC to provoke postoperative cerebral ischemia in patients with MMD, whereas the finding of WBC was intriguing because cerebral ischemic events are mostly reported to relate to elevated WBC level (36, 37). WBC, apart from a reliable biomarker for inflammation, was also measured as a possible indicator for the effects of immunonutrition (38, 39). In the case of such an interpretation, we took several composite indices into analysis and found that the level of WBC was positively correlated to PNI, an appliable biomarker quantifying both the nutritional and immunological status (40). The clinical values of PNI were generally explained by the two components of serum albumin concentration and total lymphocyte count in the peripheral blood (41). Low PNI might indicate lower cellular immune system activity that cannot function properly to decrease the patients' vulnerability to pathological noxae (42, 43). Since aberrant immune response can contribute to the pathogenesis of ischemic stroke (44), we hypothesized that patients with MMD with a relatively low WBC level had a relationship with aberrant immunomodulation around vessel walls, leading to altered vascular activity or disruption of the blood supply. This being the case, preoperative nutritional interventions to increase WBC as well as lower TC concentration are supposed to reduce the risk of cerebral ischemia after surgical revascularization.

Interestingly, the association between mRS on initial admission and cerebral ischemic complications after surgeries was contradictory to the clinical experience that patients with higher mRS scores are susceptible to an increased risk for complications. This finding was consistent with Li et al.'s research that admission mRS score was an independent protective factor (45). For such patients, new perfusion compensation might have been established due to experienced cerebral ischemic or hemorrhagic events, thus resulting in a relatively stable status. Hence, it is worthy to be noted that compared to patients with high mRS, perioperative managements should be carefully implemented on those who exhibited lower mRS score.

Notable strengths in our study were as follows:(1) in terms of nutritional parameters from routine blood tests, we determined that lower WBC and higher TC levels are independently associated with postoperative cerebral ischemic complications in patients with MMD who underwent revascularization. They are more practical, less expensive, and time-efficient biomarkers for clinical utility. Moreover, a predictive model incorporating these factors alongside with conventional baseline features was established in the form of nomogram, which could guide decisions on individualized and correct therapeutic strategies before surgery. Adding WBC and TC to model only covering the surgical side and mRS on admission showed a significant improvement in predicting the onset of postoperative cerebral ischemia; (2) to promote easy application in clinical practice, we translated this nomogram into a web-based calculator that may be well-adapted to a mobile device with feasible browsing. However, several limitations should be recognized:(1) this is a retrospective investigation based on single-centered data and hence potential bias may exist; (2) although the discriminative value of nomogram was good, the relatively small number of participants due to the merit of rarity and regional distribution of MMD was not easy to set up an external validation; (3) a variety of clinical factors were recorded in previously published reports, but they were not regularly measured in our preoperative measurement, which might compromise the statistical validity of our analysis. Prospective and multicenter trials are strongly recommended to support robust evidence to our findings.

The preoperative nutritional status of patients with MMD is closely linked to the onset of postoperative ischemic complications. High concentration of TC and low WBC, as novel nutritional blood parameters, are independent risk factors for cerebral ischemic complications following surgical revascularization. The utility of nomogram, composed of surgical side, mRS on admission, WBC, and TC levels in preoperative management, is expected to effectively identify patients at high risk of developing cerebral ischemic complications and guide clinicians to implement appropriate nutritional interventions for prevention.

The original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.

The studies involving human participants were reviewed and approved by Ethnic Committee of Qingdao Municipal Hospital. Written informed consent for participation was not provided by the participants' legal guardians/next of kin because: this is a retrospective study and all data were anonymous. Written informed consent was not obtained from the individual(s), nor the minor(s)' legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.

LL and TL were responsible for conceptualizing this study, design, data interpretation, and critical revision of the manuscript. FL and CL were joint contributors who participated in revascularization surgeries and played a major role in acquisition of clinical records, data analyzing, figures, and manuscript drafting. YS, YB, WJ, ZS, YW, ML, and WW participated in acquisition and interpretation of data. All authors read and approved the final manuscript.

This work was supported by grants from the National Natural Science Foundation of China (82001253 to TL and 82001184 to ML).

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.

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