Clinical characteristics and leptomeningeal collateral status in pediatric and adult patients with ischemic moyamoya disease

Summary Aim Previous studies have found significant differences in clinical characteristics between pediatric and adult moyamoya disease (MMD) patients, but few studies have focused on the factors underlying these differences. We aimed to investigate the differences in leptomeningeal collateral (LMC) status between pediatric and adult MMD patients and to analyze the effects of LMCs on clinical characteristics and therapeutic prognosis. Methods We retrospectively analyzed 214 MMD patients from January 2014 to January 2016. Clinical characteristics and LMC status were compared between the pediatric and adult patients. LMC status was graded as good or poor depending on the retrograde flow from the posterior cerebral artery (PCA) on digital subtraction angiography (DSA). Results A total of 83 pediatric and 131 adult (1:1.6) MMD patients were analyzed. Pediatric patients were more likely to experience a transient ischemic attack (81%), whereas adult patients were more likely to experience infarction (51%). Regarding the different MMD stages (the early, medium, and advanced stages corresponded to Suzuki stages 1‐2, 3‐4, and 5‐6, respectively), the prevalence of good LMC status was higher for pediatric patients than for adult patients in the early stage (P = 0.047) and the medium stage (P = 0.001), but there were no differences between these patient groups in the advanced stage (P = 0.547). Worse postoperative angiographic outcomes (P = 0.017) were found in adult patients than in pediatric patients in the medium stage. Poor LMC status had strong correlations with infarction (P < 0.001 and P = 0.017) and poor postoperative outcomes (P = 0.003 and P = 0.043) in both pediatric and adult patients. Conclusions Pediatric MMD patients have greater patency and a greater ability to establish good LMC status than adult patients, and poor LMC status has a strong correlation with severe clinical symptoms and poor postoperative outcomes. LMC status may be an important factor in the differences in clinical characteristics and prognosis between pediatric and adult MMD patients.


| INTRODUC TI ON
Moyamoya disease (MMD) is characterized by progressive stenosis or occlusion of the bilateral internal carotid arteries (ICAs) with unknown etiology, and numerous collateral vessels appear at the base of the brain. 1 There is a bimodal peak age at onset for MMD, with peaks in childhood and adulthood, and the clinical features differ between these patients. 2 In contrast to adult patients with MMD, who often present with cerebral infarction, pediatric patients with MMD typically exhibit transient ischemic attack (TIA). 3 However, relatively little attention has been devoted to the causes of these differences.
Moyamoya disease has a chronic, irreversible, and progressive natural course. For MMD, progressive stenosis and occlusion of the principal intracranial artery lead not only to disease progression but also to the development of collateral circulation. Many studies have indicated that leptomeningeal collateral (LMC) status is a strong predictor of long-term functional outcomes in stroke patients with large vessel intracranial occlusion [4][5][6] and plays the most important role in the collateral supply of the ischemic cortex of the anterior cerebral artery (ACA) and middle cerebral artery (MCA) territory in MMD patients. 7 Although aging is a major risk factor for poor LMC status, 8 relatively little attention has been devoted to the differences and effects of LMC status in pediatric and adult MMD patients. Therefore, in this work, we sought to elucidate these differences and analyze their clinical value.

| ME THODS
The authors declare that all supporting data are available within the article and its online-only Data Supplements.

| Subjects
The ethics committee of our institution granted ethical approval for this retrospective study (ky-2018-6-60) and waived written informed consent.
We retrospectively reviewed bilateral MMD patients who were treated in our department between January 2014 and January 2016.
The patients included in this study met the following criteria: (a) all of the patients underwent digital subtraction angiography (DSA) and met the current diagnostic criteria recommended by the moyamoya disease guidelines from 2012 9 ; (b) to exclude moyamoya syndrome, the patients were required to exhibit no history of systemic diseases, such as atherosclerosis or immune system disease 9 ; (c) the patients had no history of prior bypass surgery; (d) patients with two or more atherogenic risk factors, such as hypertension, diabetes mellitus, dyslipidemia, heavy smoking, heavy drinking, and congenital anomaly, were excluded because of unclear influences on collateral circulation 10 ; (e) patients with severe posterior cerebral artery (PCA) involvement (stage 3 and 4 according to the Mugikura staging system) were excluded because of disturbed blood supply to the LMCs 11 ; (f) the patients' symptoms at onset were transient ischemic attack (TIA) and infarction, and patients were excluded if the details of the first clinical event could not be confirmed or if their symptoms did not match the imaging findings; and (g) pediatric patients were defined as patients under 18 years old (≤18).

| Clinical data collection
Demographic and clinical data were collected according to a standard protocol during the patient's first visit to our institution. The data included age, sex, onset symptoms, and age at onset of initial symptoms. Infarction was verified by magnetic resonance imaging (MRI) or computed tomography (CT). The progression of MMD was stratified into three stages with a modified Suzuki staging system. 1 Suzuki stages 1-2, 3-4, and 5-6 were recorded as the early, medium, and advanced stages of MMD, respectively.

| Leptomeningeal collateral assessment
Because the lesions in MMD usually involve the bilateral cerebral hemispheres, many collateral grading methods for the healthy side do not apply to the side affected by MMD. In this study, LMC status was graded using DSA as follows: good LMC status was defined as  Follow-up was performed on a per-hemisphere basis until the occurrence of a primary or secondary event (in that hemisphere) or the end of the study (November 2017). A standardized script was used to screen for interval stroke in phone interviews. The primary endpoint was the occurrence of infarction or bleeding in the symptomatic hemispheres. The secondary endpoint was death. Endpoint determination was performed by an independent experienced physician who was blinded to the DSA data and was based on a review of clinical and imaging data.

| Statistical analyses
The Mann-Whitney U test was used to compare continuous variables. The Pearson chi-square test was used to compare categorical variables between groups. All analyses were performed with SPSS software, version 24.0 (International Business Machines Corp., Almond, NY, USA), and P < 0.05 was considered statistically significant.

| Difference in clinical characteristics between pediatric and adult patients with ischemic MMD
The clinical presentations were significantly different between pediatric and adult patients (P < 0.001). Pediatric patients were more

| Difference in leptomeningeal collateral status between pediatric and adult patients with ischemic MMD
A significant difference in LMC status was found between the two patient groups; the prevalence of good LMC status in pediatric patients with MMD was higher than that in adult patients (P = 0.002, Table 1). The LMC status in different stages was further compared in Table 2. There was no significant difference in LMC status in the advanced stage (Suzuki stage 5-6) between the two patient groups (P = 0.547), but in the early (Suzuki stage 1-2) and medium (Suzuki stage 3-4) stages, pediatric patients were more likely to have good LMCs (P = 0.047 and P = 0.001; Figure 2) than adult patients.

| Association between leptomeningeal collateral status and clinical characteristics
The associations of LMC status with clinical symptoms and prognosis in pediatric and adult patients with MMD are compared in Table 3.
Good LMC status was significantly correlated with TIA in pediatric and adult patients (P < 0.001 and P = 0.017).
The postoperative angiographic findings showed that there was no correlation between Matsushima stage and LMC status in pediatric (P = 0.285) or adult patients (P = 0.133, Table 2) with MMD.
However, poorer LMC status was associated with significantly higher postoperative stroke rates in pediatric (P = 0.003) and adult patients (P = 0.043) with MMD. Another epidemiological study in Japan (2012) showed that although TIA and infarction accounted for 60% of all cases, TIA mainly occurred in pediatric patients, while infarction had a higher incidence in adult patients. 15 In our study, we found that TIA was the major symptom in pediatric patients, whereas infarction was more prevalent among adult patients. Our results are consistent with those of previous studies and indicate that differences in clinical symptoms exist between pediatric and adult patients. The causes of these differences remain unclear, and few studies have investigated this issue.

| D ISCUSS I ON
The development of abundant collateral circulation is more common in MMD, a chronic progressive cerebrovascular disease, than in other ischemic cerebrovascular diseases. Previous studies have found that the collateral circulation, especially from the leptomeningeal system, plays the most important role in the collateral supply for MMD patients. 7 The presence of collateral flow via the posterior communicating artery is associated with a low prevalence of border zone infarcts, 16 while stenosis or occlusion of the PCA is often associated with a high stroke rate in MMD patients. 17 Almost no LMCs from the PCA were observed in normal hemispheres without ACA or MCA stenosis/occlusion. In our study, we found that the prevalence of good LMCs was higher in pediatric patients than in adult patients during the early and medium MMD stages, and poor LMC status had a strong correlation with severe clinical symptoms, such as infarction, in the medium stage. This finding reveals that the intracranial collateral circulation plays an important role in the differences in clinical symptoms between pediatric and adult MMD patients. Therefore, we conclude that good intracranial collateral compensation could improve cerebrovascular reserve and tolerance to cerebral ischemia and lead to milder symptoms at onset and lower incidence rates of stroke in pediatric patients.
The mechanism for the differences in LMC status between pediatric and adult MMD patients in the same stage remains unclear.
Experimental studies have shown that aging causes a significant decrease in LMCs, as well as increased tortuosity and vascular resistance in leptomeningeal vessels. 18,19 It is also well established from human studies that age has a detrimental effect on cerebrovascular reactivity. 20  TA B L E 3 Associations between clinical characteristics and leptomeningeal collateral status in pediatrics and adults with moyamoya disease potential selection bias related to regions and race may have occurred. Second, we did not consider the impact of other collateral pathways, such as transdural collaterals. However, because the LMCs from the PCAs to the anterior circulation are the earliest patent and most common collaterals 26 and due to the barriers of the cerebrospinal fluid and skull, it was difficult to establish collaterals between the external carotid artery (ECA) and the ICA. 27 Therefore, we believe that LMCs might be more important in the early and medium MMD stages in both pediatric and adult patients. In our study, we described only the association between LMCs and clinical characteristics. Further studies are needed to explore this relationship, such as investigations of cerebral hemodynamics in moyamoya disease using multiple inversion time arterial spin labeling MRI. Moreover, the mechanisms underlying the difference in the prevalence of good LMCs between pediatric and adult patients remain unclear and require further study.

| CON CLUS IONS
Pediatric MMD patients are more likely than adult patients to exhibit good LMC status in the early and medium stages, and poor LMC status has a strong correlation with severe clinical symptoms and poor postoperative outcomes. Assessments of systematic collateral circulation may help to better evaluate disease progression and prognosis in MMD patients. Further research on the mechanisms of collateral patency may help us understand how to improve collateral status and provide a novel potential therapeutic approach for MMD.

ACK N OWLED G EM ENTS
This study was supported by grants from the National Natural

CO N FLI C T S O F I NTE R E S T
The authors declare that there are no conflicts of interest.