Moyamoya disease (MMD) is a rare, chronic, and progressive cerebrovascular disorder characterized by stenosis and occlusion of the distal carotid and proximal middle and anterior cerebral arteries. MMD is also accompanied by the development of small collateral vessel networks at the base of the brain17). Ischemia is the most common sign of this disease, and surgical revascularization seems to be helpful for this MMD patient subgroup1316).

The hemorrhagic subtype is found in 20% of MMD patients1). This subtype is associated with a poor clinical course compared with other MMD subtypes1519). Only half of patients experience adequate recovery after the first hemorrhagic event7). Furthermore, poorer clinical outcomes can be expected after recurrent bleeding19). Currently, limited data is available regarding the clinical course of hemorrhagic MMD (hMMD)14). Additionally, no definitive treatment method has been recognized as effective for preventing recurrent bleeding. Until recently, risk factors for recurrent bleeding were poorly understood. In a few studies, microbleeding observed on magnetic resonance imaging (MRI) or angiographic scans indicated the existence of dilated anterior choroidal and posterior communicating arteries deemed as hMMD predictors611). To the best of our knowledge, and despite hemodynamic insufficiency being the main pathophysiologic MMD finding, there have been no studies examining the effect of hemodynamic insufficiency on rebleeding risk in hMMD. Furthermore, even though a hemodynamic abnormality is a key pathologic feature of MMD, ischemic events are poorly recognized12).

Further verification regarding an hMMD clinical course and the role of hemodynamic insufficiency and other parameters on recurrent stroke is necessary. The current study reviewed the clinical course of adult patients with hMMD who were treated at our sponsoring institution. The goal of the present study was to rigorously clarify the clinical course and identify potential risk factors for recurrent stroke in hMMD.

Five of 52 patients were categorized as unilateral MMD. The median age at diagnosis was 36 (range, 21–60) years for all patients. Eight patients were male and 5 (9.6%) had a family history of MMD. Nine patients (17.3%) experienced TIA-like symptoms before the hemorrhagic event. Patient characteristics are detailed in Table 1.

The types of hemorrhage according to location were pure intraventricular hemorrhage (IVH, n=22), basal ganglia or periventricular hemorrhage with IVH (n=22), lobar hemorrhage (n=5), basal ganglia hemorrhage (n=2), and subarachnoid hemorrhage (n=1). Thirty-three patients (63.5%) had transdural collaterals at initial evaluation. SPECT results showed that 44 (84.6%) patients had impaired cerebral hemodynamics, 35 (67.3%) had decreased basal perfusion, and 34 (65.4%) had impaired vascular reserve. Twelve out of 52 hemorrhagic MMD patients were unable to determine the site of bleeding due to bilateral IVH which showed similar amount between each side of lateral ventricle. Other than these 12 patients, 31 out of 40 showed impaired cerebral hemodynamics on SPECT study. All of these patients showed ipsilateral perfusion abnormality.

A recent study demonstrated that surgical revascularization could reduce recurrent bleeding910). Here, direct revascularization seemed to be more beneficial than indirect bypass surgery. Dilated anterior choroidal, posterior communicating artery, and moyamoya vessels are suspected as risk factors for a hemorrhagic event in MMD because these factors are thought to reflect the hemodynamic stress in that area11). However, these aforementioned angiographic factors have no clear definition. Therefore, interpretation of angiographic findings can vary depending on the evaluator. The present study hypothesized that hemodynamic impairment could more precisely reflect hemodynamic stress. Theoretically, impaired perfusion results in hemodynamic stress on the vessel wall and facilitates dilation or microaneurysm formation in collateral vessels. Surgical treatment can reduce the development of abnormal collateral vessels by rectifying the hemodynamics. Considering this, surgical treatment seems to be helpful in hMMD10). Although a recent prospective randomized trial demonstrated that direct bypass could lower rebleeding risk, the role of surgical treatment in hMMD is still controversial25915). Kawaguchi et al.5) reported that direct bypass is effective to prevent recurrent hemorrhage or ischemic events. However, Okada's long-term follow-up study found that despite significant improvement in cerebral hemodynamics and decreased abnormal collateral vessel development, around 20% of patients developed recurrent bleeding after surgical revascularizations13).

Our univariate analysis could not demonstrate fewer hemorrhagic events in the surgically treated group compared to the non-surgery group. Half (n=6) of recurrent bleeding patients have received indirect revascularization. However, multivariate analysis suggested that surgery could reduce rebleeding risk. According to our strategy, surgical treatment was performed on patients with impaired hemodynamics. Since there was a lack of sufficient evidence regarding the preventive role of surgery on recurrent bleeding in hMMD, the main surgical goal was to prevent subsequent ischemic events among patients who were recovering without any significant neurologic deficits after the initial hemorrhagic event. According to our results, hemodynamic insufficiency seems to be an important predictor after initial bleeding. Based on the results of our revascularization strategy in hMMD, surgery was usually performed on patients with a high rebleeding risk. Therefore, the present results might reflect our treatment strategy. None of the patients treated with revascularization surgery experienced an ischemic event, while 5/30 non-surgery patients had a recurrent TIA during follow-up. Additionally, a considerable proportion (17.6%) of our hMMD patients had a history of ischemic events before the hemorrhage. Moreover, around 80% of our patients showed a hemodynamic abnormality. These findings suggest that the hemorrhagic subtype cannot be free from ischemic events, indicating that revascularization can provide beneficial effects in hMMD, even if only a marginally decreased risk of rebleeding is present. However, revascularization surgery should be applied with caution for selected hMMD patients with a hemodynamic abnormality.

Other concerns regarding disparities with previous studies could be related to the bleeding site. In MMD, the most common bleeding sites are deep in the brain, such as intraventricular sites or the basal ganglia, rather than at cortical and subcortical sites413). Among 12 patients with recurrent bleeding, half of the patients have received indirect revascularization. All the sites of recurrent bleeding were located in the deep side of the brain as described above. Furthermore bleeding sites were similar with the previous bleeding sites. Considering that direct or indirect bypass surgery usually provides additional blood flow to the fronto-temporo-parietal cortical and subcortical areas, surgery may have a limited role until revascularized vessels are able to influence deeper brain sites. Indirect revascularization might need a relatively extended time period in order to influence deeper brain site. Additionally, MMD is a rare disease and has a dynamic disease course, making it difficult to gather controlled data818).

Several limitations should be noted in this study. First, this study only investigated half of the patients with hMMD in our institute. We did not perform a detailed examination on patients with poor clinical outcomes (mRS >4) during recovery after the initial hemorrhagic event. And we excluded patients with early stage MMD and included those with unilateral (probable) MMD to reduce the diagnostic ambiguity. Therefore, a significant selection bias was likely present. It is possible that the subset of hMMD patients assessed just happened to be experiencing good recovery after the initial event. Nevertheless, these patients should be acknowledged since subsequent events occur in a high proportion of these patients, resulting in poor outcomes even after satisfactory recovery from the first hemorrhagic event7). Second, the present study used a qualitative analysis of previous hemodynamic studies, and follow-up SPECT and DSA were rarely used in our study population. This was the case even though such analyses could provide more detailed information regarding hemodynamic effects on hMMD. Finally, the present study was limited by a small sample size, relatively short follow-up periods, and retrospective analyses.

In conclusion, hemodynamic abnormalities seem to be associated with recurrent bleeding in MMD. Furthermore, ischemic events are common in hMMD, which result from hemodynamic insufficiency. To reduce the risk of further stroke in hMMD with hemodynamic insufficiency, revascularization should be considered.