Acute Preoperative Infarcts and Poor Cerebrovascular Reserve Are Independent Risk Factors for Severe Ischemic Complications following Direct Extracranial-Intracranial Bypass for Moyamoya Disease

Discussion

While the risk of developing a large infarct is very low following STA-MCA bypass, a small subset of patients do experience this complication shortly after the operation. Our results suggest that certain features evident on preoperative imaging may be related to this clinical outcome. While baseline CBF does not differ between the index and control groups, both univariate and multivariate regression analyses demonstrated that CVR is significantly lower in patients who develop large postoperative infarcts. Multiple prior studies suggest that reduced CVR is an independent risk factor for stroke.^20,21 A recent meta-analysis demonstrated a significant positive relationship between reduced CVR and stroke risk in patients with carotid stenosis or occlusion, with an odds ratio of 3.86.²² Despite this relationship, it is not immediately clear why patients would experience strokes so soon after revascularization.

One potential explanation for the observed infarcts is that any surgical procedure represents a physiologic stress that portends an elevated risk of ischemic complications. Indeed, for this reason, a cardiac stress test is routinely performed in patients considered at high risk before surgical intervention. Similarly, patients with reduced CVR may be at an elevated risk of ischemic complications following any operation. Schoof et al²³ explored this concept in patients who underwent a coronary artery bypass graft and were screened with carotid sonography. If stenosis was identified, CVR was calculated by using transcranial Doppler before and after carbon dioxide administration. Patients with reduced CVR had a 27.3% stroke rate following cardiothoracic surgery, compared with a 1.5% risk in patients with normal CVR. Patients with reduced CVR may similarly have an elevated stroke risk following cerebral revascularization.

The rationale behind operative intervention in patients with Moyamoya disease is that for the long term, the risk of ischemic events will be lowered. As such, patients with reduced CVR may benefit the most. Indeed, the presence of reduced CVR appears to promote the success of revascularization. In a study assessing the postoperative course of patients with Moyamoya disease who underwent bilateral encephaloduroarteriosynangiosis, revascularization occurred selectively in areas of reduced CVR,²⁴ suggesting that abnormal CVR may itself promote angiogenesis. With time, this possibility is obviously advantageous. However, during an operation or in the immediate postoperative period, during which mean flow through the microanastomosis increases 5-fold (from 4.4 to 22.2 mL/min),⁹ the balance of cerebral hemodynamics may be very fragile. Increased flow related to the bypass may paradoxically represent a new hemodynamic stress and induce altered perfusion parameters by competing with the underlying stenotic vasculature and the native collateral network. This concept has been explored in prior studies, in part to account for the presence of postoperative perfusion abnormalities contralateral to the bypass.^1,6 Indeed, it has previously been shown that increased STA flow following bypass is correlated with a higher incidence of postoperative infarct,⁹ though it is not clear whether this association is causative or correlative.

As in our study, infarcts have been reported both ipsilateral and contralateral to the most recently revascularized hemisphere. The concept of competitive flow might further explain the prominent changes in vascular flow dynamics following bypass in several of the index cases. For instance, a postoperative MR angiogram obtained in 1 patient (Fig 5) demonstrated new decreased flow-related enhancement in the bilateral anterior and right posterior communicating/posterior cerebral artery territories, which was confirmed as a change on cerebral angiography. It is possible that such rapid progression could arise in response to hemodynamic changes related to the flow through the new bypass in conjunction with altered perfusion parameters in the setting of a large acute infarct.

Most of the index cases demonstrated small acute infarcts on MR imaging examinations performed shortly before the operation. On univariate and multivariate analyses, the presence of a preoperative acute infarct was found to be a significant and independent predictor of infarct in the postoperative period. Most interesting, although the DWI lesions predicted the vascular territory in 5 of 8 anterior circulation territories, 2 anterior circulation infarcts occurred contralateral to the preoperative DWI lesion. These occurred in patients with large infarcts after the first bypass but who had significant contralateral stenosis and poor CVR. While such spatially removed infarcts may be explained by the hemodynamic changes described above, systemic factors (such as alterations in platelet function) may render a patient with recent infarcts more generally susceptible to a postoperative infarct than would be expected on the basis of vascular pathology alone. In addition, while hypotension was strictly avoided during the operation, other operative stresses, such as cortisol release and platelet activation, may collectively contribute to perioperative ischemia. Whether delaying operative revascularization to allow infarct evolution/stabilization in such high-risk patients would have altered the postoperative course is presently unknown because our data were collected as part of the preoperative work-up of operative patients and similar data were not available to assess the effect of acute infarct and impaired CVR on a matched nonoperative patient cohort. Nonetheless, the risks and benefits of delaying the operation in patients with ongoing ischemic change must be carefully weighed, given the inherently progressive nature of Moyamoya disease.

Prior researchers have noted the association between preoperative infarct and perioperative complications in Moyamoya disease. In a review of 165 adult patients (undergoing 265 revascularization procedures), Hyun et al²⁵ found that the presence of a preoperative diffusion abnormality was significantly correlated with 19 perioperative infarcts. However, most of these complications were transient in nature and occurred primarily in indirect revascularization procedures. By comparison, our series assesses variables associated with large, clinically significant infarctions in patients undergoing direct bypass, a distinctly less well-studied patient population.

There are several potential limitations to our study. The first is its retrospective design and the relatively small number of index cases. Our institutional morbidity associated with cerebral revascularization is low, and despite a large number of bypasses, only a small number of patients with large postoperative infarcts were available for analysis. To maximize the power of this small patient cohort, we analyzed multiple vascular territories in each patient independently, while correcting for clustering. We also performed multivariate analysis, maximizing our ability to detect meaningful predictors of postoperative infarct. Second, this analysis focused on 2 smaller subsets of a larger group of patients with Moyamoya disease. The study was specifically designed in this manner to identify factors associated with profound operative morbidity relative to the optimal clinical outcome.

While prior studies have assessed factors associated with transient postoperative neurologic deficits,²⁶ our index patients represent a small, relatively unstudied subgroup. Given the low risk of postoperative stroke in this patient population and the fact that most of these strokes tend to be small, investigation of the factors that lead to severe infarcts was deemed most clinically relevant. Nonetheless, additional patients who underwent bypass at our institution included those with either small postoperative diffusion abnormalities (often clinically asymptomatic) or those with mild or transient neurologic symptoms. Further studies are ongoing to address contributors to adverse outcomes in these larger patient cohorts. Only acute (DWI with positive findings) preoperative infarcts were considered in the evaluation of preoperative risk factors because only acute infarcts could be consistently evaluated in all patients. Although 4 of the 6 index cases had acute preoperative infarcts, another index patient had a small infarct on a 3-month preoperative scan, which was subacute on immediate preoperative MR imaging. Although the presence of subacute infarcts could not be consistently evaluated for all patients in this study, we cannot exclude the possibility that the presence of subacute infarcts could also portend a worse prognosis.

Finally, we used XeCT CBF measurements for the CVR measurements. While XeCT is considered a reference standard method, others have proposed the use of MR imaging–based perfusion measurements.²⁷ Regardless of the methodology, our results underscore the importance of quantitative assessment of CVR to identify patients at high risk for stroke. Thus, we are now investigating the use of MR perfusion with and without acetazolamide, which, if comparable, may represent a technique more amenable to widespread use outside specialized centers.