Moyamoya disease is an unusual form of chronic, occlusive

Angiographic Dilatation and Branch Extension of the Anterior Choroidal and Posterior Communicating Arteries Are Predictors of Hemorrhage in Adult Moyamoya Patients Motohiro Morioka, MD; Jun-Ichiro Hamada, MD; Takayuki Kawano, MD, PhD; Tatemi Todaka, MD; Shigetoshi Yano, MD; Yutaka Kai, MD; Yukitaka Ushio, MD Background and Purpose The cause of intracranial bleeding in moyamoya disease patients is still unknown. To identify factors that contribute to bleeding, we assessed the angiographic findings of moyamoya disease patients. Methods We examined angiograms obtained from 107 moyamoya patients; 70 manifested ischemic and 37 had hemorrhagic lesions. Patients with intracerebral aneurysms or both hemorrhagic and ischemic lesions in the same cerebral hemisphere were not included. Patients were divided into those 20 years of age (n 47) and those 20 years of age (n 60). The right and left hemispheres in each patient were individually classified as hemorrhagic, ischemic, or asymptomatic. Each hemisphere was assessed for dilatation and branch extension of the anterior choroidal artery (AChA) and posterior communicating artery (P-CoM) and for the degree of proliferation of basal moyamoya vessels. These data were then statistically analyzed for correlation with intracranial bleeding events. Results The degree of proliferation of basal moyamoya vessels was not statistically correlated with hemorrhagic events. On the other hand, there was a correlation between hemorrhage and dilatation and abnormal branching of the AChA. In 27 of 37 hemorrhagic hemispheres (73.0%), this artery was dilated, and its abnormal branches served as collateral supply vessels to other regions. This phenomenon was observed in 4 of 5 hemorrhagic hemispheres from young patients; it was noted in fewer than one third of ischemic and asymptomatic hemispheres from this age group. Similarly, 71.9% of hemorrhagic hemispheres from adult patients manifested AChA dilatation and branching, and the difference between hemorrhagic hemispheres and those that were ischemic or asymptomatic was statistically significant (P 0.01). Although the incidence of dilatation and abnormal branching of the P-CoM was relatively low in hemorrhagic hemispheres from adult patients (18.8%), it was significantly higher than in the ischemic and asymptomatic hemispheres from this age group. Using dilatation and abnormal branching of the AChA and/or P-CoM as assessment criteria, we obtained high specificity (86.4%) and sensitivity (84.4%) for hemorrhagic events in adult moyamoya patients. Conclusions In adult moyamoya patients, dilatation and abnormal branching of the AChA and/or P-CoM are strong predictors of hemorrhagic events. (Stroke. 2003;34:90-95.) Key Words: angiography hemorrhage moyamoya disease Moyamoya disease is an unusual form of chronic, occlusive cerebrovascular disease characterized by bilateral stenosis or occlusion at the terminal portion of the internal carotid artery (ICA) and an abnormal vascular network (the so-called moyamoya vessels) at the base of the brain. 1 4 Many patients with moyamoya disease experience cerebral ischemic or hemorrhagic events; pediatric patients suffer primarily ischemic attacks, whereas hemorrhage is prevalent among adults. 1,3 Although revascularization surgery can prevent ischemic attacks, 5 8 the cause of intracranial bleeding is unclear, and strategies to prevent its occurrence remain to be developed. Because the site of intracranial bleeding in many moyamoya patients is the basal ganglia, thalamus, and near lateral ventricle wall, 9 11 basal moyamoya vessels have been suspected as its origin. 1,12 15 However, in some patients with hemorrhage, few basal moyamoya vessels are found, and their location is away from the bleeding site (Figure 1). We noted that among hemorrhagic moyamoya patients, including some exhibiting this phenomenon, the anterior choroidal artery (AChA) was frequently dilated and exhibited abnormal extension of many branches (Figure 1B, 1D, and 1E) and that the bleeding site was within the AChA territory. Therefore, we examined the arteries that normally supply the central or Received March 6, 2002; final revision received August 8, 2002; accepted August 13, 2002. From the Department of Neurosurgery, Kumamoto University, School of Medicine, Kumamoto, Japan. Reprint requests to Motohiro Morioka, Department of Neurosurgery, Kumamoto University School of Medicine, 1-1-1, Honjo Kumamoto 860-8556, Japan. E-mail morioka@kaiju.medic.kumamoto-u.ac.jp 2003 American Heart Association, Inc. Stroke is available at http://www.strokeaha.org DOI: 10.1161/01.STR.0000047120.67507.0D 90

Morioka et al Dilation and Branching of AChA/P-CoM in Moyamoya Disease 91 Figure 1. Demonstrative cases in which moyamoya vessels were not considered a bleeding vessel. A and B, A 33-year-old female. CT scan (A) shows right putaminal hematoma with intraventricular hemorrhage. Right internal carotid angiogram (B) showed fewer moyamoya vessels and dilated, abnormally branching AChA (arrowhead). C through E, A 52-year-old female. CT scan (C) shows massive right intraventricular hematoma and small intracerebral hemorrhage from posterior caudate nucleus to the near lateral ventricle wall. On right internal carotid angiogram (D and E), moyamoya vessels, far from the site of bleeding, are noted. AChA (arrowhead) was dilated and manifested abnormal branching. basal brain region in an effort to identify characteristic features of hemorrhagic moyamoya disease. Figure 2. Demonstrative angiograms. A, AChA appears normal; no proliferative vessels are apparent (grade 0). B, Note thickening of the AChA and staining of the proximal choroidal plexus. AChA is dilated, and distal vessels beyond the choroidal fissure are clearly visualized (grade 1). C and D, There is extension of other, not normally seen branches of AChA (grade 2). E and F, Moyamoya vessels classified as grades 1 (E) and 2 (F) are present. G, P-CoM, judged as positive, is dilated, and abnormal branches are clearly evident. Subjects and Methods A total of 170 patients with moyamoya disease underwent treatment at Kumamoto University Hospital and its affiliated hospitals beginning in 1969. Of these, 100 patients experienced ischemic events, including transient ischemic attacks or cerebral infarction; 47 presented with hemorrhage, including subarachnoid and intraventricular hemorrhage or intracerebral hematoma; and 23 had no or other Figure 3. Schematic illustrating the site of O/S of the ICA in patients with moyamoya disease. Right and left hemispheres were separately classified as ischemic (A), hemorrhagic (B), and asymptomatic (C), and the site of O/S of the ICA was identified. Circles represent the different age groups.

92 Stroke January 2003 symptoms. We focused only on patients with hemorrhagic or ischemic symptoms. Patients with intracerebral aneurysms and those with both hemorrhagic and ischemic lesions in the same hemisphere were excluded from this study. Finally, we could obtain 107 intra-arterial angiograms of 107 patients (ischemic, n 70; hemorrhagic, n 37) at the time of onset. We focused on vessels that supply the basal regions of the brain such as the basal ganglia, thalamus, and near lateral ventricle where intracranial bleeding frequently occurs in moyamoya patients. 1,4,9 11 Our focus was on the AChA, posterior communicating artery (P-CoM), and basal moyamoya vessels, except for the ethmoidal and vault moyamoya vessels because the territories they feed are not frequent bleeding sites. The right and left cerebral hemispheres (n 214) in each patient were separately identified as ischemic (including those with infarction and transient ischemic attacks, n 102), hemorrhagic (n 37), or asymptomatic (n 75). The AChA in each hemisphere was recorded as grade 0 (normal), 2 (dilated with distal branching), or 3 (dilated with abnormal branches serving as collateral supply vessels to other regions; Figure 2A through 2D). Basal moyamoya vessels were graded as absent (grade 0), few in number (grade 1), and densely proliferated (grade 2; Figure 2A, 2E, and 2F). Findings on the P-CoM were recorded as negative; normal, dilated, or positive; or dilated with abnormal branch extensions (Figure 2G). We also noted the site of occlusion or stenosis (O/S) of the ICA as following; site 1, ICA top or A1/M1; site 2, just distal to AChA; site 3, between the AChA and P-CoM; or site 4, proximal to P-CoM (Figure 3). The 107 patients were divided into a young ( 20 years of age; n 47) and an adult ( 20 years of age; n 60) group because childhood moyamoya patients tend to manifest ischemia and adults predominantly experience hemorrhage. We examined the correlation between angiographic findings and symptoms using the Mann- Whitney U and 2 tests. Differences of P 0.01 were considered statistically significant. Results We examined 107 angiograms (214 hemispheres) from 107 patients (ischemia, n 70; hemorrhage, n 37); the characteristics of these patients are shown in Table 1. The mean SD age of ischemic patients was 21.3 18.0 years (range, 1.6 to 67.8 years); it was 40.0 14.6 years (range, 5.3 to 66.8 years) for patients with hemorrhage. There were 102 ischemic, 37 hemorrhagic, and 75 asymptomatic hemispheres. The 37 hemorrhages were made up of 1 subarachnoid hemorrhage, 9 intraventricular hemorrhages, 14 intracerebral hematomas, and 13 lesions that were of both intracerebral hematoma and intraventricular hemorrhage origin. Among 47 young patients (94 hemispheres), only 5 patients (5 hemispheres) manifested hemorrhage; of 60 adult patients (120 hemispheres), 32 (32 hemispheres) had lesions of hemorrhagic origin. Angiographic Findings on Moyamoya Vessels and the AChA Compared with ischemic and asymptomatic hemispheres, those with hemorrhage tended to manifest a higher degree of moyamoya vessel proliferation, regardless of the age of the patient (Table 2). However, the difference was not statistically significant. Overall, in 33 of 37 hemorrhagic hemispheres (89.2%), the AChA was dilated and manifested branching (grades 1 and 2). More than 70% of the hemorrhagic hemispheres in both age groups had grade 2 AChA; the difference was statistically significant compared with ischemic and asymptomatic hemispheres (P 0.01). TABLE 1. Clinical Characteristics of 107 Moyamoya Disease Patients in This Study Ischemic Onset Cases (n 70) Hemorrhagic Onset Cases (n 37) Sex (male:female) All cases 26 44 11 26 Young group 15 27 (n 42) 1 4(n 5) Adult group 11 17 (n 28) 10 22 (n 32) Age at onset (mean SE) All cases* 21.3 18.0 40.0 14.6 Young group 8.0 3.7 (n 42) 11.5 5.1 (n 5) Adult group 41.2 10.9 (n 28) 44.3 11.1 (n 32) Complications at onset Mental retardation 5 (7.1%) 1 (2.7%) Hypertension 5 (7.1%) 4 (10.8%) Diabetes mellitus 2 (2.9%) 1 (2.7%) Seizure 4 (5.7%) 1 (2.7%) Neurological-radiological characterizations at onset No. of Cases (hemispheres) No. of Cases (hemispheres) Ischemic onset TIA 19 (21) Infarction 33 (62) TIA and infarction 18 (19) No symptom 0 (38) (lesion) Hemorrhagic onset SAH 1 (1) IVH 9 (9) ICH 14 (14) ICH and IVH 13 (13) No symptom (lesion) 0 (37) Statistical significant difference *P 0.01, chi-square test. TIA indicates transient ischemic attack; SAH, subarachnoid hemorrhage; IVH, intraventricular hematoma; ICH, intracerebral hemorrhage. Angiographic Findings on the P-COM As shown in Table 2, approximately one fifth of the hemorrhagic hemispheres in both age groups showed P-CoM dilatation and branching. The difference between hemorrhagic and nonhemorrhagic hemispheres was statistically significant at P 0.01 ( 2 test) in both age groups. Site of O/S of the ICA Figure 3 demonstrates the distribution of the O/S site in the ICA. In 80.6% of adult hemorrhagic hemispheres, the lesion was just distal to the AChA (site 2); this site was involved in 45.9% and 20.8% of ischemic and asymptomatic hemispheres, respectively. The incidence of site 4 and 3 O/S was highest in ischemic hemispheres, and site 4 O/S was not found in hemorrhagic hemispheres.

Morioka et al Dilation and Branching of AChA/P-CoM in Moyamoya Disease 93 TABLE 2. Distribution of the Grades of Anterior Choroidal Artery and Moyamoya Vessels, and of Posterior Communicating Artery in Each Hemispheric Group Arterial Grading Symptom of Hemisphere Total Number 0 1 2 Moyamoya vessels Hemorrhage 5 0 (0.0%) 1 (20.0%) 4 (80.0%) Ischemia 63 16 (25.4%) 17 (27.0%) 30 (47.6%) No symptom 26 4 (15.4%) 11 (42.3%) 11 (42.3%) Hemorrhage 32 1 (3.1%) 15 (46.9%) 16 (50.0%) Ischemia 39 11 (28.2%) 7 (17.9%) 21 (53.8%) No symptom 49 12 (24.5%) 20 (40.8%) 17 (34.7%) Anterior choroidal artery Hemorrhage 5 1 (20.0%) 0 (0.0%) 4 (80.0%) Ischemia* 63 31 (49.2%) 15 (23.8%) 17 (27.0%) No symptom* 26 13 (50.0%) 5 (19.2%) 8 (30.8%) Hemorrhage 32 3 (9.4%) 6 (18.8%) 23 (71.9%) Ischemia* 39 22 (56.4%) 10 (25.6%) 7 (17.9%) No symptom* 49 40 (81.6%) 6 (12.2%) 3 (6.1%) Posterior communicating artery Dilatation and Branch Extension No Yes Hemorrhage 5 4 (80.0%) 1 (20.0%) Ischemia 63 58 (92.1%) 5 (7.9%) No symptom 26 24 (92.3%) 2 (7.7%) Hemorrhage 32 26 (81.2%) 6 (18.8%) Ischemia 39 39 (100.0%) 0 (0.0%) No symptom 49 48 (98.0%) 1 (2.0%) Statistical significant difference compared to the hemorrhagic hemisphere group. *P 0.01, Mann-Whitney U test, P 0.01, chi-square test. Predictive Indicator(s) of a Hemorrhagic Event To determine the most important factor(s) for predicting a hemorrhagic event in adult moyamoya patients, we assessed different parameters for their positive or negative predictive value, specificity, and sensitivity for hemorrhagic events (Table 3). Although the findings of grade 1 or 2 AChA showed the highest sensitivity (90.6%), the specificity was not as high (70.5%). Finally, our findings suggest that the combination of a dilated AChA in which the branches provide collateral flow (grade 2) or dilated P-CoM with abnormal branch extensions represents an indicator with good sensitivity (84.4%) and specificity (86.4%) for predicting a hemorrhagic event. Discussion Our study shows a strong correlation between AChA dilatation and branching and hemorrhagic events in patients with moyamoya disease. Changes in the P-CoM were also correlated. In moyamoya patients without aneurysms, the main bleeding site has been thought to be the site of rupture of moyamoya vessels. 1,12 15 However, in some patients with hemorrhage, these vessels are few or are located away from the bleeding site (Figure 1). Bleeding was attributable to an intraventricular hematoma in 35% to 50% of patients reported by others 9 11 ; this was true in 22 (59.5%) of our 37 hemorrhagic moyamoya cases. However, because moyamoya vessels usually do not exist near the ventricle wall, it is difficult to accept that their rupture results in intraventricular hematoma. Suzuki and Kodama 3 suggested that there is a tendency for arteries near the ventricle wall to rupture. Under normal conditions, the AChA supplies areas such as the medial portion of the globus pallidus, anterior perforating substance, internal capsule, choroid plexus, tail of the caudate nucleus, and thalamus. The normal P-CoM gives off branches to the optic chiasm, oculomotor nerve, tuber cinereum, cerebral crura, ventral thalamus, and caudal portion of the

94 Stroke January 2003 TABLE 3. Positive/Negative Predictive Values, Sensitivity, and Specificity for Hemorrhagic Event Calculated With Various Conditions of Arterial Evaluation in the Adult Age Group Intracranial Bleeding Criteria of Arterial Evaluation* No. of Hemisphere No (%) Yes (%) Sensitivity, % Specificity, % AChA (grade 2) No 87 78 (89.7) 9 (10.3) Yes 33 10 (30.3) 23 (69.7) 71.9 89.7 AChA (grades 1&2) No 65 62(95.4) 3 (4.6) Yes 55 26 (47.3) 29 (52.7) 90.6 70.5 P-COM ( ) No 113 87 (77.0) 26 (23.0) Yes 7 1 (14.3) 6 (85.7) 18.8 98.9 AChA (grade 2) or P-COM ( ) No 81 76 (93.8) 5 (6.2) Yes 39 12 (30.8) 27 (69.2) 84.4 86.4 AChA (grades 1&2)orP-COM ( ) No 61 60 (98.4) 1 (1.6) Yes 59 28 (47.5) 31 (52.5) 96.9 68.2 AChA indicates anterior choroidal artery; P-COM, posterior communicating artery; ( ), dilatation and branch extension of P-COM were found. Statistical significant difference *P 0.01, chi-square test. caudate nucleus. 16,17 Thus, the normal branches of the AChA and P-CoM provide blood to areas near the lateral ventricle, basal ganglia, and thalamus. In moyamoya patients, these normal branches sometimes extend to other regions, and their function as collateral vessels results in blood flow increases. Rupture of dilated branches of the AChA and/or P-CoM may produce intraventricular or thalamic hematomas, hematomas near the lateral ventricle, and hematomas of the basal ganglia that are frequently found in hemorrhagic moyamoya patients. It is considered that the postmortem data may support (or disprove) our hypothesis. Thus, we examined 3 autopsy cases with hemorrhagic moyamoya disease and tried to identify the bleeding vessels. However, we could not identify the branches of AChA and P-CoM. Although it is difficult to pinpoint the bleeding vessels, in our series, hemorrhagic events coincided with dilatation and branch extension of the AChA and/or P-CoM (Table 3), suggesting that these vessels may have been the origin of bleeding. According to the morphometric analysis of Yamashita et al, 15 most dilated arteries show fibrosis and marked attenuation of the media with occasional segmentation of the elastic lamina. As a result of hemodynamic stress or aging, dilated arteries with attenuated walls may acquire a predisposition for focal protrusion (microaneurysm formation) of the arterial wall. Subsequent rupture is thought to be a mechanism resulting in hemorrhage in patients with moyamoya disease. Such microscopic arterial changes may occur in the branches of the AChA and P-CoM. The normal AChA is 0.5 mm in diameter and 3.0 cm in length. On angiograms, the last visible portion of the AChA enters the plexus of the temporal horn, visualized as the angiographic brush of the plexus. Furthermore, the fine vessels of the normal P-CoM are scarcely visible angiographically. 16,17 Thus, the angiographically evident dilatation and branching of the AChA and P-CoM recorded in our study may signal increased blood flow and hemodynamic stress in these vessels. In 30% of nonhemorrhagic hemispheres from our young moyamoya patients, the dilated AChA had branches that served as collateral vessels; in adult ischemic and asymptomatic hemispheres, this phenomenon was more rare (Table 2). This suggests that in young patients the AChA may function as a major collateral route and that it may play the same role for moyamoya vessels. In nonhemorrhagic hemispheres, blood flow in the AChA decreases or disappears as the O/S site gets closer to the area proximal to the P-CoM (Figure 3). Furthermore, if the stenotic lesion is located just proximal to the P-CoM, neither the dilated AChA nor the basal moyamoya vessels are visible on angiograms. We posit this as the reason that no basal moyamoya vessels were discernible in about one fourth of the ischemic and asymptomatic hemispheres examined (Table 2). We also suspect that O/S just distal to the AChA induces the greatest change in this vessel and results in severe hemodynamic stress. In adults with hemorrhagic moyamoya, the site of O/S may have stopped progressing at a younger age, and the presence of prolonged hemodynamic stress and/or some factors related to aging 18 may eventually have led to bleeding. Intracranial bleeding is a major prognostic factor in moyamoya patients, 9,11 and currently we have no reliable indicator(s) for predicting a hemorrhagic event. In our series, angiograms were obtained within a few days of the initial hemorrhagic event, and the findings reflect the status before any rebleeding episodes. Of 32 adult patients who suffered hemorrhage, 17 who did not undergo bypass surgery experienced rebleeding during the follow-up period. Of these, 16 (94.1%) manifested a dilated AChA whose branches served as collateral vessels and/or a dilated P-CoM on angiograms obtained before the rebleeding episode. From these findings and the data shown in Table 3, we suggest that dilatation and branch extension of the AChA and P-CoM are sensitive and specific predictive indicators of rebleeding. Direct bypass surgery is thought to prevent recurrent intracranial bleeding in moyamoya patients. 19 21 A direct bypass may decrease the blood flow in the AChA and P-CoM, and the findings reported here may help to identify moyamoya patients at greatest risk for hemorrhage and thus make it possible to apply preventive surgical therapy before the occurrence of a potentially lethal repeated hemorrhage.

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