J Neurosurg 119:961–965, 2013 ©AANS, 2013
Assessment of the difference in posterior circulation involvement between pediatric and adult patients with moyamoya disease Clinical article Tomohito Hishikawa, M.D., Koji Tokunaga, M.D., Kenji Sugiu, M.D., and Isao Date, M.D. Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan Object. There is no description of the change in the posterior cerebral artery (PCA) in the diagnostic criteria of moyamoya disease (MMD). However, PCAs are often involved in the clinical setting, and an understanding of the significance of PCA lesions is therefore of great importance when evaluating the disease progression and predicting prognosis. The aim of this study was to assess the difference in posterior circulation involvement in pediatric and adult patients with MMD. Methods. The records of 120 consecutive patients with MMD were reviewed. The clinical manifestations at diagnosis were evaluated on the basis of symptoms and CT and MRI findings. The degree of steno-occlusive internal carotid artery (ICA) lesions and the existence of steno-occlusive PCA lesions were evaluated by observing a total of 240 ICAs and PCAs on angiography. Angiographic correlation between anterior and posterior circulation was assessed in pediatric and adult patients with MMD. Results. Seventeen (26%) of 66 pediatric patients and 18 (33%) of 54 adult patients exhibited steno-occlusive PCA lesions. There was no significant difference in the prevalence of PCA lesions between pediatric and adult patients with MMD (p = 0.36). The prevalence of infarction in pediatric and adult patients with PCA involvement was significantly higher than that in pediatric and adult patients without PCA involvement (p = 0.0003 and p = 0.003, respectively). There was no significant difference in the distribution of infarction areas between pediatric and adult patients with PCA involvement (p = 0.62). On the basis of the staging system used, steno-occlusive lesions in ICAs ipsilateral to PCAs with lesions were in significantly advanced stages compared with lesions in ICAs ipsilateral to PCAs without lesions in both pediatric and adult cases (p < 0.0001 and p = 0.0008, respectively). Pediatric patients had less advanced steno-occlusive lesions in ICAs ipsilateral to PCAs with lesions compared with adults (p < 0.05). Conclusions. The clinical significance of posterior circulation involvement in MMD was similar between pediatric and adult patients. The only significant difference was that less advanced ICA lesions could complicate posterior circulation involvement in pediatric patients. (http://thejns.org/doi/abs/10.3171/2013.6.JNS122099)
Key Words • adult • child • moyamoya disease • posterior cerebral artery • vascular disorders
disease is a chronic, progressive disease characterized by stenosis or occlusion of the bilateral supraclinoid ICAs along with the development of an abnormal vascular network called moyam oya at the base of the brain. In the guidelines of the research committee on MMD set forth by the Japanese Ministry of Health and Welfare, both the existence of bilateral ICA steno-occlusive lesions and the development of moyamoya vessels are necessary for a definitive diagoyamoya
Abbreviations used in this paper: ACA = anterior cerebral artery; ICA = internal carotid artery; IQR = interquartile range; MCA = middle cerebral artery; MMD = moyamoya disease; PCA = posterior cerebral artery; PWS = posterior watershed; TIA = transient ischemic attack.
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nosis of MMD.2 The presence and appearance of stenoocclusive PCA lesions are not included in the diagnostic criteria of MMD. However, PCAs are often involved after progression of ICA lesions, and the clinical significance of steno-occlusive PCA lesions in MMD has been demonstrated.4,5,7,9–12,15 The clinical characteristics of pediatric patients with MMD are quite different from those of adult patients. Most pediatric patients with MMD develop ischemic complications, and approximately half of adult patients suffer intracranial hemorrhage and half suffer ischemic complications.6 Understanding the difference in angioarchitecture of MMD between pediatric and adult patients is of great importance when explaining the difference in clinical presentation and evaluating disease progression. It has been 961
T. Hishikawa et al. reported that there is a difference in angiographic progression in ICA lesions between pediatric and adult patients.1 To the best of our knowledge, there have been no previous reports comparing the character of PCA steno-occlusive lesions associated with MMD between pediatric and adult patients in a large-scale study. Therefore, in this study, we reviewed 120 patients with MMD and retrospectively assessed the difference in posterior circulation involvement between pediatric and adult patients.
bral, intraventricular, and subarachnoid hemorrhage (n = 8); combined ischemic and hemorrhagic complication (n = 10); asymptomatic (n = 1); and other (headache or epilepsy [n = 5]). Clinical presentation of a TIA with asymptomatic infarction was considered as a cerebral infarction. Computed tomography and MR images were reviewed for parenchymal ischemic and hemorrhagic changes. Infarctions were diagnosed on MRI using diffusion-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Infarction location was classified as ACA territory, MCA territory, PCA territory, anterior watershed (that is, ACA-MCA border zone infarction), PWS (that is, MCAPCA border zone infarction), and deep white matter.
Between January 1989 and December 2011, observing the guidelines of the research committee on MMD set forth by the Japanese Ministry of Health and Welfare,2 we diagnosed 120 patients with definite MMD at Okayama University Hospital on the basis of the results of cerebral angiograms. Forty-one patients were male and 79 were female with an age range at the onset of symptoms of 1–69 years (median age 12 years [IQR 6–34 years]). This study was approved by the Institutional Review Board of Okayama University Hospital, and all patients provided written informed consent.
A total of 120 angiograms (240 hemispheres) obtained in 120 patients were examined in this study (66 pediatric and 54 adult patients with MMD). Seventeen (26%) of 66 pediatric patients and 18 (33%) of 54 adult patients had steno-occlusive PCA lesions. Of 240 PCAs in the 120 patients with MMD, 47 (20%) exhibited stenoocclusive lesions. Twenty-four (18%) of 132 PCAs in pediatric patients and 23 (21%) of 108 PCAs in adult patients contained lesions. The steno-occlusive PCA lesions were located in the P2 segment in 2 children and 4 adults, the P4 segment in 22 children and 18 adults, and in the P1 segment in 1 adult. There was no significant difference in the prevalence of steno-occlusive PCA lesions between pediatric and adult patients with MMD (26% vs 33%, p = 0.36). Table 1 shows the baseline characteristics of patients in this investigation. There was no significant difference in age at onset between pediatric patients with and without PCA involvement and adult patients with and without PCA involvement (p = 0.13 and p = 0.92, respectively). Pediatric patients with PCA involvement tended to be female compared with those without PCA involvement (p = 0.08). In adult cases, however, there was no sex difference between patients with and without PCA involvement (p > 0.99).
All 120 patients underwent cerebral angiography that included bilateral internal and external carotid arteriography and bilateral or unilateral vertebral arteriography using the transfemoral catheterization technique. We used angiography to observe a total of 240 ICAs and PCAs. Using the angiographic staging system as defined by Mugikura et al.,13 we evaluated the degree of steno-occlusive ICA lesions (Stages 1–4) and checked for the existence of steno-occlusive PCA lesions. This system is a modification of Suzuki’s staging system14 and was reclassified not on the basis of the degree of the development of moya moya vessels but mainly on the severity of steno-occlusive lesions in the proximal part of the ACA/MCA and the degree of antegrade opacification of their branches.13 This grading system is more useful in the precise staging of ICAs on a single angiogram without the use of temporally serial angiograms as is required by Suzuki’s grading system. The interobserver agreement of this staging system has been reported to be 91%.13 The classification of ICA stage is as follows: Stage 1, mild to moderate stenosis around the carotid bifurcation with absent or slightly developed basal moyamoya; Stage 2, severe stenosis around the carotid bifurcation or occlusion of the proximal ACA or MCA with well-developed basal moyamoya; Stage 3, occlusion of both the proximal ACA and MCA with welldeveloped basal moyamoya; and Stage 4, complete occlusion of both the proximal ACA and MCA with absence of or a small amount of basal moyamoya.13 None of the patients had undergone previous surgical treatment. Clinical Manifestation and Evaluation of CT and MRI
In all 120 patients, we reviewed the clinical manifestations at diagnosis on the basis of symptoms and CT and MRI findings. We classified the clinical manifestations as TIA (n = 56); cerebral infarction (n = 40); intracere-
Quantitative variables are presented as a percentage or as the median and IQRs. Statistical analysis was performed using the Fisher exact probability test, the chisquare test, and the Mann-Whitney U-test, as appropriate. All statistical analyses were performed using StatView (SAS Institute). Differences were considered to be significant with p values < 0.05.
Difference in the Impact of PCA Involvement on Clinical Presentation Between Pediatric and Adult Patients With MMD
The prevalence of pediatric patients with PCA involvement who presented with infarction was significantly higher than that for those without PCA involvement (76% vs 24%, p = 0.0003). Similarly, there was a significantly higher frequency of infarction in adult patients with PCA involvement than in adult patients without PCA involvement (67% vs 25%, p = 0.003). In contrast, for hemorrhagic complications, there was no significant difference in the prevalence between pediatric patients with PCA J Neurosurg / Volume 119 / October 2013
Posterior circulation in moyamoya disease TABLE 1: Baseline characteristics for 120 patients with MMD in this study* Pediatric Cases (n = 66) Characteristic age at initial onset in yrs† male/female‡ clinical presentation TIA infarction hemorrhage TIA & hemorrhage infarction & hemorrhage asymptomatic other location of infarctions ACA territory AWS MCA territory PWS PCA territory DWM total distribution of ICA stages 1 2 3 4 total no. of PCAs w/ lesions no. of PCAs w/o lesions
w/ PCA Involvement (n = 17)
Adult Cases (n = 54)
w/o PCA Involvement (n = 49)
7 (7–10) 3:14
6 (4–10) 22:27
w/ PCA Involvement (n = 18)
w/o PCA Involvement (n = 36)
34 (26–41) 5:13
35 (24–46) 11:25
4 12 0 0 1 0 0
31 12 1 1 0 0 4
4 9 1 0 3 1 0
17 7 6 3 2 0 1
2 (8) 4 (16) 4 (16) 9 (36) 2 (8) 4 (16) 25 (100)
2 (13) 1 (7) 4 (27) 1 (7) 0 (0) 7 (46) 15 (100)
0 (0) 4 (18) 2 (9) 7 (32) 4 (18) 5 (23) 22 (100)
2 (18) 1 (9) 0 (0) 3 (27) 0 (0) 5 (46) 11 (100)
6 (18) 14 (41) 13 (38) 1 (3) 34 (100) 24 10
56 (57) 33 (34) 6 (6) 3 (3) 98 (100) 0 98
8 (22) 12 (33) 7 (20) 9 (25) 36 (100) 23 13
25 (35) 31 (43) 8 (11) 8 (11) 72 (100) 0 72
* Age values are presented as the median (IQR). Other values represent raw numbers (%). AWS = anterior watershed; DWM = deep white matter. † No statistical significance for age at initial onset between pediatric patients with and without PCA lesions (p = 0.13) and between adult patients with and without PCA lesions (p = 0.92) according to the Mann-Whitney U-test. ‡ No statistical significance of sex distribution between pediatric patients with and without PCA lesions (p = 0.08) and between adult patients with and without PCA lesions (p > 0.99) according to the Fisher exact probability test.
involvement (6%) and without PCA involvement (4%) (p > 0.99) and in adult patients with PCA involvement (22%) and without PCA involvement (31%) (p = 0.75).
ence in the distribution of infarction areas between pediatric and adult patients with PCA involvement (p = 0.62; Table 1).
Distribution of Infarction Areas
Distribution of ICA Stage
A total of 25 and 15 infarction areas were observed in pediatric patients with and without PCA involvement, respectively, and 22 and 11 infarction areas were seen in adult patients with and without PCA involvement, respectively. The frequency of a combination of PWS and PCA territory infarction in pediatric patients with PCA involvement (44%) was significantly higher than that in pediatric patients without PCA involvement (7%) (p = 0.02; Table 1). However, adult patients with PCA involvement had a greater tendency to suffer from PWS and PCA territory infarction (50%) than those without PCA involvement (27%) (p = 0.28; Table 1). There was no significant differ-
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In pediatric cases, patients with PCA involvement had more advanced ICA lesions according to the staging system than those without PCA involvement (Table 1; p < 0.0001). However, in adult cases, patients with PCA involvement had a greater tendency to have advanced ICA stages, compared with those without PCA involvement (Table 1; p = 0.11).
Relation of Ipsilateral ICA Stage and PCA Lesions in Pediatric and Adult Patients
In 17 pediatric patients with PCA involvement, 7 had 963
T. Hishikawa et al. bilateral and 10 had unilateral PCA lesions. Of 34 PCAs in this group, 24 PCAs contained lesions and the remaining 10 did not have lesions. To clarify the relationship between ipsilateral ICA stage and PCA lesions, we separately analyzed 24 PCAs with lesions and 108 PCAs without lesions in pediatric cases. Similarly, we assessed 23 PCAs with lesions and 85 PCAs without lesions in adult cases. In pediatric cases, lesions in ICAs ipsilateral to PCAs with lesions were significantly advanced compared with those in ICAs ipsilateral to PCAs without lesions (Table 2; p < 0.0001). Also, in adult cases, lesions in ICAs ipsilateral to PCAs with lesions were more advanced than those ipsilateral to PCAs without lesions (Table 2; p = 0.0008). Moreover, lesions in ICAs ipsilateral to PCAs with lesions in pediatric cases were significantly less advanced than those in ICAs ipsilateral to PCAs with lesions in adult cases (Table 2; p < 0.05).
Miyamoto et al. first reported the clinical significance of posterior circulation involvement in MMD. Since then, studies have demonstrated that PCAs also undergo a similar obstructive process that occurs simultaneously with the occlusion of ICAs and that cerebral ischemia is significantly correlated with the severity of steno-occlusive PCA lesions in MMD.12,15 This is the first report to evaluate the difference in posterior circulation involvement between pediatric and adult patients with MMD in a large cohort. 9
Impact of Posterior Circulation Involvement on Ischemia
From a symptomatological point of view, this study revealed that a significantly higher prevalence of pediatric and adult MMD patients with steno-occlusive PCA lesions presented with cerebral infarctions (76% and 67%, respectively) compared with pediatric and adult MMD patients without PCA lesions (24% and 25%, respectively). The areas of infarction tended to be found in the posterior part of the brain, such as the PWS and PCA territory, in MMD patients with PCA involvement. This ischemic lesion pattern tendency was found in both pediatric and adult MMD patients with PCA involvement. The pathophysiology of severe cerebral ischemia may be explained mainly by a decrease in the leptomeningeal collaterals from the PCA TABLE 2: Relationship between ipsilateral ICA stage and PCA steno-occlusive lesions in pediatric and adult patients with MMD* Pediatric Cases
PCA w/ Lesions
PCA w/o Lesions
PCA w/ Lesions
PCA w/o Lesions
1 2 3 4 total
2 (8) 9 (38) 12 (50) 1 (4) 24 (100)
60 (56) 38 (35) 7 (6) 3 (3) 108 (100)
1 (4) 8 (35) 6 (26) 8 (35) 23 (100)
32 (38) 35 (42) 9 (10) 9 (10) 85 (100)
* Values represent the raw numbers (%).
to the anterior circulation.10,12 Previous investigations of pediatric and adult patients with MMD have demonstrated that ischemic lesions tend to occur in the watershed area initially and then spread to a wider area involving the posterior part of the brain as the PCA narrows.5,12 Our data show that steno-occlusive PCA lesions have a significant impact on the severity of ischemia and could be an important landmark for both pediatric and adult patients at high risk for infarctions. In clinical settings, symptoms derived from PCA territory ischemia, such as visual impairment or visual field defects, are rare,3 and it is also uncommon for patients with MMD to require posterior circulation revascularization. Our study revealed that only 5 (4%) of 120 patients had PCA territory infarctions. This is probably because many patients are diagnosed with MMD in a timely manner, and surgical revascularization is promptly performed before progression to posterior circulation involvement. Miyamoto et al.8 reported that revascularization of the MCA territory as a standard surgical procedure for MMD indirectly improved cerebral blood flow in the PCA distribution by decreasing the vascular steal of the collateral vessels supplying the anterior circulation. Interaction Between ICAs and PCAs in MMD
Our investigation found a correlation between the stage of the lesion in the ICA and the existence of steno-occlusive PCA lesions in pediatric and adult patients with MMD. This indicates that there are significant interactions between ICAs and PCAs in MMD. Although the mechanisms of interaction between ICAs and PCAs remain unknown, there are some proposed hypotheses, such as hemodynamic stress to the vascular endotheli um of the PCAs and the propagation of hypertonicity of the ICAs to the PCAs via adrenergic nerve fibers.13 In this investigation, the only significant difference between pediatric and adult patients was that in pediatric patients with PCA lesions the ICA lesions were significantly less advanced than in adult patients. Mugikura et al.11 demonstrated that, particularly in children diagnosed before 4 years of age, steno-occlusive changes involved the PCA aggressively, even in hemispheres with less advanced ICA lesions. Thus, the vascular changes might progress more rapidly in pediatric patients with MMD than in adult patients. In their angiographic follow-up of childhood-onset MMD, Ezura et al.1 showed on angiography that the disease advanced in the stage between childhood and adolescence but that it stabilized or almost stabilized between adolescence and adulthood. These findings underline the importance of periodic and careful observation in pediatric patients with MMD. Study Limitations
This study is limited by its retrospective nature. Also, in this study, we assessed the difference in morphological characteristics between pediatric and adult patients with MMD from an angiographic point of view, focusing on the posterior circulation. However, these morphological characteristics do not always directly reflect functional outcomes. The prediction of functional outcomes is very important in determining how to manage MMD patients J Neurosurg / Volume 119 / October 2013
Posterior circulation in moyamoya disease with posterior circulation involvement. Future studies need to prospectively compare the functional outcomes between pediatric and adult patients with MMD with or without posterior circulation involvement.
In our patient cohort, the clinical significance of posterior circulation involvement in MMD was similar between pediatric and adult patients. Posterior circulation involvement may be an important landmark for both pediatric and adult patients with MMD who are at high risk for infarctions. The only significant difference was that pediatric patients with posterior circulation involvement had significantly less advanced ICA lesions than adult patients. Disclosure The authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper. Author contributions to the study and manuscript preparation include the following. Conception and design: Hishikawa. Acquisition of data: Hishikawa. Analysis and interpretation of data: Hishikawa. Drafting the article: Hishikawa. Critically revising the article: all authors. Reviewed submitted version of manuscript: all authors. Approved the final version of the manuscript on behalf of all authors: Hishikawa. Statistical analysis: Hishikawa. Study supervision: Date. References 1. Ezura M, Yoshimoto T, Fujiwara S, Takahashi A, Shirane R, Mizoi K: Clinical and angiographic follow-up of childhoodonset moyamoya disease. Childs Nerv Syst 11:591–594, 1995 2. Fukui M: Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Clin Neurol Neurosurg 99 Suppl 2:S238–S240, 1997 3. Hasimoto N, Tominaga T, Miyamoto S, Nagata I, Houkin K, Suzuki N, et al: Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 52:245–266, 2012 4. Hishikawa T, Tokunaga K, Sugiu K, Date I: Clinical and radiographic features of moyamoya disease in patients with both cerebral ischaemia and haemorrhage. Br J Neurosurg 27:198–201, 2013 5. Kim JM, Lee SH, Roh JK: Changing ischaemic lesion patterns
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in adult moyamoya disease. J Neurol Neurosurg Psychiatry 80:36–40, 2009 6. Kuroda S, Houkin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:1056–1066, 2008 7. Kuroda S, Ishikawa T, Houkin K, Iwasaki Y: [Clinical significance of posterior cerebral artery stenosis/occlusion in moyamoya disease.] No Shinkei Geka 30:1295–1300, 2002 (Jpn) 8. Miyamoto S, Kikuchi H, Karasawa J, Nagata I, Ihara I, Yamagata S: Study of the posterior circulation in moyamoya disease. Part 2: Visual disturbances and surgical treatment. J Neurosurg 65:454–460, 1986 9. Miyamoto S, Kikuchi H, Karasawa J, Nagata I, Ikota T, Takeuchi S: Study of the posterior circulation in moyamoya disease. Clinical and neuroradiological evaluation. J Neurosurg 61: 1032–1037, 1984 10. Morioka M, Hamada J, Kai Y, Yano S, Kawano T, Omori Y, et al: [Contributing factors to long-term outcome and type of onset in young aged moyamoya disease patients with ischemic onset.] Surg Cereb Stroke (Jpn) 37:338–344, 2009 (Jpn) 11. Mugikura S, Higano S, Shirane R, Fujimura M, Shimanuki Y, Takahashi S: Posterior circulation and high prevalence of ischemic stroke among young pediatric patients with Moyamoya disease: evidence of angiography-based differences by age at diagnosis. AJNR Am J Neuroradiol 32:192–198, 2011 12. Mugikura S, Takahashi S, Higano S, Shirane R, Kurihara N, Furuta S, et al: The relationship between cerebral infarction and angiographic characteristics in childhood moyamoya disease. AJNR Am J Neuroradiol 20:336–343, 1999 13. Mugikura S, Takahashi S, Higano S, Shirane R, Sakurai Y, Yamada S: Predominant involvement of ipsilateral anterior and posterior circulations in moyamoya disease. Stroke 33: 1497–1500, 2002 14. Suzuki J, Takaku A: Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20:288–299, 1969 15. Yamada I, Himeno Y, Suzuki S, Matsushima Y: Posterior circulation in moyamoya disease: angiographic study. Radiology 197:239–246, 1995 Manuscript submitted November 4, 2012. Accepted June 24, 2013. Please include this information when citing this paper: published online August 2, 2013; DOI: 10.3171/2013.6.JNS122099. Address correspondence to: Tomohito Hishikawa, M.D., Department of Neurological Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama City, Okayama 700-8558, Japan. email: [email protected]