J Neurosurg 121:1048–1055, 2014 ©AANS, 2014
Outcome in adult patients with hemorrhagic moyamoya disease after combined extracranial-intracranial bypass Clinical article *Hanqiang Jiang, M.D., Ph.D., Wei Ni, M.D., Ph.D., Bin Xu, M.D., Ph.D., Yu Lei, M.D., Yanlong Tian, M.D., Feng Xu, M.D., Yuxiang Gu, M.D., Ph.D., and Ying Mao, M.D., Ph.D. Division of Cerebrovascular Surgery and Interventional Neuroradiology, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China Object. The outcome of patients with hemorrhagic moyamoya disease (MMD) after cerebral revascularization is uncertain. The purpose of this study was to delineate the efficacy of this surgical method in the treatment of hemorrhagic MMD. Methods. Between January 2007 and August 2011, a consecutive cohort of 113 patients with hemorrhagic MMD was enrolled into this prospective single-center cohort study. The surgical method was combined direct and indirect bypass. The cumulative probability of the primary end point (all stroke and deaths from surgery through 30 days after surgery and ipsilateral recurrent hemorrhage afterward) was analyzed. The angiographic outcome was measured by the following parameters: bypass patency, reduction of basal MMD vessels, improved degree of dilation, and branch extension of the anterior choroidal and posterior communicating arteries (AChA-PCoA). Results. Of the 113 enrolled cases, CT scans revealed pure intraventricular hemorrhage (IVH) in 63 cases (55.7%), pure intracranial hemorrhage (ICH) in 14 cases (12.4%), and ICH with IVH in 36 cases (31.9%). In 74 of 113 hemorrhagic hemispheres (65.5%), the AChA-PCoA was extremely dilated with extensive branches beyond the choroidal fissure. A total of 114 surgeries were performed. No patient suffered ischemic or hemorrhagic stroke through 30 days after surgery. Ipsilateral rebleeding occurred in 5 patients, 4 of whom died of the rebleeding event. The cumulative probability of the primary end point was 0% at 1 year and 1.9% at 2 years. The annual rebleeding rate was 1.87%/person/year. The improvement in AChA-PCoA extension was observed in 75 of 107 operated hemispheres (70.1%), which was higher than that in 7 of 105 unoperated hemispheres (35.2%). Conclusions. Revascularization may provide a benefit over conservative therapy for hemorrhagic MMD patients. The improvement of dilation and branch extension of AChA-PCoA might be correlated with the low rebleeding rate. (http://thejns.org/doi/abs/10.3171/2014.7.JNS132434)
Key Words • vascular disorders • hemorrhagic moyamoya disease • revascularization • rebleeding rate
M
disease (MMD) is an uncommon cerebrovascular disease characterized by an unusual vascular network at the base of the brain due to progressive stenosis or occlusion of the supraclinoid internal carotid artery (ICA) and its main branches within the circle of Willis.15 The symptoms and signs of MMD can be classified into 2 major etiological categooyamoya
Abbreviations used in this paper: AChA = anterior choroidal artery; DSA = digital subtraction angiography; DTA = deep temporal artery; ICA = internal carotid artery; ICG = indocyanine green; ICH = intracranial hemorrhage; IVH = intraventricular hemorrhage; MCA = middle cerebral artery; MMA = middle meningeal artery; MMD = moyamoya disease; mRS = modified Rankin Scale; PCoA = posterior communicating artery; STA = superficial temporal artery; TIA = transient ischemic attack. * Drs. Jiang and Ni contributed equally to this work.
1048
ries: those caused by brain ischemia (ischemic type) and those caused by the deleterious consequences of the compensatory fragile collateral vessels (hemorrhagic type). The ischemic type is prevalent among pediatric patients with MMD, whereas the hemorrhagic type dominates in adults.5 In previous reports, it is well recognized that surgical revascularization using direct and/or indirect bypass provides an improved outcome in patients presenting with the ischemic type.1,11 In patients with the hemorrhagic type, extracranial-to-intracranial bypass has also been performed based on the hypothesis that bypass surgery reduces the hemodynamic stress on the pathological vessels and prevents recurrent hemorrhage.24,25 However, This article contains some figures that are displayed in color online but in black-and-white in the print edition.
J Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD there are limited reports on the surgical outcome in patients with hemorrhagic MMD. The goal of this study was to determine whether extracranial-to-intracranial bypass would improve hemodynamic impairment and provide a benefit for patients with hemorrhagic MMD.
Methods Study Population
The research ethics board of our institution approved the protocol for this prospective single-center study. During the study period (January 2007 to August 2011), all patients who were admitted to our center because of spontaneous intracranial hemorrhage (ICH) were evaluated as potential candidates for the study. The inclusion criteria were angiographically verified MMD (under the guidelines of the Research Committee on MMD according to the Ministry of Health and Welfare in Japan4), hemorrhagic attack identified by CT scanning, patient age of 18–75 years, preoperative modified Rankin scale score (mRS) ≤ 2, and from 1 month to 1 year after the last ictus of hemorrhage. The exclusion criteria were MMD with ruptured aneurysm in the main stem of the intracranial arteries, other concurrent intracranial lesions, and life expectancy less than 1 year because of another medical condition. Patients whose MMD was with associated aneurysms in the peripheral portion of the MMD vessels were not excluded from the study. Each patient or family member signed an informed consent for patients enrolled in this study. The patients’ demographics, clinical data, images, and follow-up information were prospectively collected. Periprocedural Management, Surgical Procedure, and Follow-Up
Angiographic staging was based on the published guidelines of Suzuki’s 6-stage classification.27 Each hemisphere was assessed for the association of the angiographic changes of the anterior choroidal and posterior communicating arteries (AChA-PCoA) with hemorrhagic ictus. The modified grading system for the angiographic findings of the AChA-PCoA was based on the criteria suggested by Morioka et al.21 and modified by Liu et al.16 Generally, we revascularized the hemorrhagic side visualized on CT scanning. The surgical method was revascularization using combined direct and indirect bypass. The direct bypass procedure was a microsurgical endto-side anastomosis of 1 or 2 superficial temporal artery (STA) branches to identical cortical branches of the middle cerebral artery (MCA). The choice of a single or double bypass depended on how well the feeding artery matched the recipient artery. An encephalo-dura-myo-synangiosis (EDMS) was used as the indirect bypass procedure, which we described in our previous study.7,29 After the direct bypass, indocyanine green (ICG) fluorescence imaging or Doppler ultrasound was regularly used to provide a reliable and rapid intraoperative assessment of the bypass patency. In general, antiplatelet therapy was not used for fear of potential rebleeding after revascularization. CT and J Neurosurg / Volume 121 / November 2014
MR scanning were performed if the patient had a new neurological event. After discharge, each patient had a follow-up visit at 90 days. The subsequent follow-ups were completed as clinic visits, by telephone, or by letter once a year until July 2013. An independent neurologist evaluated the neurological status of the patients by using the mRS. CT and MRI scans were obtained if a new neurological event occurred. Angiographic follow-up was scheduled at 6 months after the operation for the assessment of disease and effectiveness of the revascularization. The angiographic progress of MMD was evaluated according to the decreased numbers in basal MMD vessels and the improvement of dilation of AChA-PCoA. The method to evaluate numbers of MMD vessels was to measure the area with pathological basal vessels and calculate the relative percentage of the pathological moyamoya area compared with the area of the MCA feeding territory in the capillary phase of the anteroposterior view in the internal carotid angiogram. Improvement of the angiographic characteristics of AChA-PCoA was defined as reduction of dilation and branch extension of AChA-PCoA on follow-up digital subtraction angiography (DSA). The anastomosis was evaluated by 2 independent neurosurgeons who were not involved in the surgery, with reference to the criteria proposed by Matsushima and Inaba for the evaluation of transdural collaterals after revascularization.18 End Point Assessment
The mRS score at the most recent follow-up or the end point event after enrollment was independently assessed by neurologists. The primary end point for all participants was the combined total of all strokes and death from surgery within 30 days after the procedure and ipsilateral recurrent hemorrhage afterward. The secondary end points included rebleeding on the contralateral side, ischemic stroke beyond 30 days, and transient ischemic attack (TIA) on the surgically treated side at any time.
Statistical Analysis
The patient demographic data, angiographic outcomes, and clinical outcomes were presented as the mean ± SD for the continuous variables. The cumulative probability of the occurrence of a primary end point over time was estimated by the product-limit method at 1 year and 2 years. The correlation between angiographic findings and clinical findings was examined using the chi-square test. Differences of a p value < 0.05 were considered statistically significant.
Results Baseline Demographic Data
A consecutive cohort of 113 patients was enrolled in this study. The baseline demographic data are presented in Table 1. The average age was 37.3 ± 9.46 years (range 21–58 years), with 16 (15.0% [14.2%]) of patients experiencing more than 1 episode of bleeding. Of the 113 enrolled cases, CT scans revealed the presence of pure intraventricular hemorrhage (IVH) in 63 cases (55.8%), pure 1049
H. Jiang et al. TABLE 1: Baseline demographics in 113 patients with hemorrhagic MMD Variable
TABLE 3: Distribution of AChA-PCoA extension in 113 cases Modified Morioka Grading*
Value*
age in yrs mean range no. of females no. of males symptoms prior to bleeding ipsilat TIA/stroke contralat TIA/stroke type of 1st bleeding IVH ICH ICH w/ IVH total no. of bleeding episodes 1 2 3 4
37.3 ± 9.46 21–58 65 48 8/2 2/0 63 14 36
No. of Hemispheres
1
2†
3
hemorrhagic nonhemorrhagic
113 113
39 72
74 41
0 0
* Grading system: 1 = normal or slight-moderate dilation of AChAPCoA (with stenosed or occluded ICA and proliferation around circle of the Willis); 2 = extreme dilation of AChA-PCoA (with abnormal branches beyond the choroidal fissure, serving as collateral blood supply to the anterior circulation via posterior pericallosal arteries and/or leptomeningeal collateral vessels); 3 = nonvisualization of AChA-PCoA on DSA (with occluded ICA proximal to the PCoA level). † p < 0.05, chi-square test.
Surgical Results
97 13 2 1
* Values are number of patients unless stated otherwise.
ICH in 14 cases (12.4%), and ICH with IVH in 36 cases (31.9%). One hundred one of the patients were asymptomatic prior to their first bleeding episodes, whereas 12 of the patients had ischemic symptoms prior to their first episodes. TIA was the most common symptom, occurring in 8 of the 12 patients in the ipsilateral hemisphere and in 2 in the contralateral hemisphere. Ischemic stroke occurred in the other 2 patients and was verified by MRI in the ipsilateral hemisphere. Seven of these 12 patients received antiplatelet therapy thereafter. Table 2 summarizes the lesion characteristics (Suzuki grade). Table 3 describes the angiographic dilation and extension of AChA-PCoA (modified Morioka grade) in 226 hemispheres. In 74 of 113 hemorrhagic hemispheres (65.5%), the AChA-PCoA was extremely dilated with extensive branches beyond the choroidal fissure (modified Morioka Grade 2), which only occurred in 41 of 113 nonhemorrhagic hemispheres (36.3%). The difference was statistically significant between hemorrhagic and nonhemorrhagic hemispheres in this cohort (Table 3, p < 0.05). TABLE 2: Lesion characteristics in 113 patients based on the Suzuki grading system Suzuki Stage
Description
No. of Patients
I II III IV V VI
narrowing of the ICA bifurcation w/o collaterals initiation of moyamoya collaterals intensification of moyamoya collaterals minimization of moyamoya collaterals reduction of moyamoya collaterals disappearance of moyamoya collaterals
0 9 51 30 23 0
1050
Hemisphere
The surgical procedure was performed at 46.7 ± 10.6 days (range 31–92 days) from the last ictus. A total of 114 surgeries were performed; 1 patient underwent staged bilateral surgery due to rebleeding in the contralateral hemisphere. All hemispheres were treated with direct bypass combined with indirect bypass. In 60 cases a double bypass was performed in the hemispheres, and in 54 cases a single bypass was performed in the hemispheres. The ICG demonstrated a 100% patency rate for each anastomotic stoma during the procedure. Surgical complications occurred in 14 patients. Five suffered intracranial infection and recovered after antibiotic therapy. Two experienced epileptic seizures within 3 days after surgery. One had asymptomatic epidural hematoma on the day after the surgery and underwent immediate evacuation. The bypass was preserved well during the procedure. The other 6 patients manifested disorientation or focal neurological deficit (fluctuating aphasia, weakness or numbness in the contralateral limbs, and facial palsy) related to the surgically treated hemisphere on the postoperative 2nd to 5th days without any evidence of stroke on CT or MRI. The symptoms lasted about 3–4 weeks and resolved spontaneously and completely with the use of a free radical scavenger and calcium channel antagonist. Cerebral hyperperfusion syndrome was considered to occur in these 6 patients.
Primary End Point
In this cohort, 7 patients were lost to follow-up. The remaining patients underwent clinical follow-ups at a mean of 30.33 ± 10.7 months (range 21–72 months). No patient suffered ischemic or hemorrhagic stroke within 30 days of surgery. During the follow-up period, the primary end point event of ipsilateral rebleeding occurred in 5 patients, 4 of whom died from the rebleeding event. The cumulative probability of the occurrence of a primary end point was 0% at 1 year and 1.9% at 2 years (Fig. 1 left). The annual rebleeding rate was 1.87% according to the person-year method. The Kaplan-Meier curve for rebleeding-free survival during the mean follow-up period is shown in Fig. 1 right.
Secondary End Point
Sixteen secondary end point events were observed J Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD
Fig. 1. Left: The cumulative probability of stroke and death from surgery within 30 days of surgery and ipsilateral recurrent hemorrhage afterward was 0% at 1 year and 1.9% (95% CI 3.5%–9.06%) at 2 years. Right: The Kaplan-Meier curve for rebleeding-free survival in 106 patients with hemorrhagic MMD during the mean follow-up period of 30.33 months. Cum = cumulative.
in this cohort, including 2 contralateral recurrent hemorrhages after surgery and 14 TIAs on the operated side (2 within 30 days and 12 beyond 30 days). Of 2 patients suffering contralateral recurrent hemorrhage, 1 experienced contralateral rebleeding and underwent revascularization 1 month later. No rebleeding was observed subsequently. The other patient suffered contralateral rebleeding 16 months after the operation, and he is now stably recovering from this ictus. Clinical Outcome
The patients’ mRS scores at the latest follow-up are listed in Table 4. Of the 106 patients, 4 died of ipsilateral rebleeding. Three patients had severe neurological deficits (mRS Scores 3–5) due to the brain damage caused by the second ictus of intracranial hemorrhage, including 1 patient who suffered ipsilateral rebleeding after the revascularization and 2 patients who suffered contralateral rebleeding. The remaining 99 patients attained good outcomes with or without mild neurological deficits (mRS Scores 0–2), including 6 patients suffering new TIAs in the unoperated hemispheres beyond 30 days. Among the 12 patients who suffered ischemic symptoms prior to their last bleeding episodes, 2 of 8 patients with ipsilateral TIAs suffered recurrent TIAs in the same hemisphere beTABLE 4: Clinical outcome for 106 patients who underwent surgery and follow-up mRS Score
No. of Patients
0 1 2 3 4 5 6
67 24 8 1 0 2 4
J Neurosurg / Volume 121 / November 2014
yond 30 days after surgery (calculated as secondary end point). One of 2 patients with contralateral TIAs did not experience TIAs in the follow-up period; the other suffered TIAs in the unoperated hemisphere until the most recent follow-up visit. No recurrent stroke occurred in the 2 patients with ipsilateral ischemic stroke prior to the bleeding ictus. Angiographic Outcome
Efficacy of Bypass. Postoperative angiograms were obtained for 107 hemispheres in 106 patients with 167 anastomotic stomas (60 double bypass and 47 single bypass) at a mean of 10.6 ± 2.7 months (range 6–16 months). All the bypass grafts were confirmed to be patent. Transdural and transpial collaterals on the operated site were graded according to the Matsushima criteria. Table 5 summarizes the results of this variable. The revascularization established from the middle meningeal artery (MMA) and deep temporal artery (DTA) via the indirect procedure was also evaluated by DSA. Sixty-two (57.9%) of 107 operated hemispheres showed that both the MMA and DTA had spontaneous anastomosis with cortical branches. In the other 44 patients (41.1%), spontaneous anastomosis in the operated hemisphere was observed only in the DTA. Only 1 operated hemisphere showed TABLE 5: Angiographic change of moyamoya vessels and postoperative collateral grading Matsushima Grading A B C
Description area perfused by the synangiosis is greater than 2/3 of the MCA territory area perfused by the synangiosis is btwn 1/3 & 2/3 of the MCA territory area perfused by the synangiosis is less than 1/3 of the MCA territory
No. of Hemispheres 87 17 3
1051
H. Jiang et al. that neither MMA nor DTA had established spontaneous collaterals in the MCA feeding territory.
Decrease in Number of MMD Vessels. Table 6 describes the distribution of angiographic grading for decrease of MMD vessels in the operated hemispheres and no operated hemispheres. No statistical difference was observed in the decrease in the number of MMD vessels between surgical and nonsurgical hemispheres (p > 0.05).
Improvement in AChA-PCoA Extension. Among the 212 hemispheres (107 operated and 105 unoperated) in 106 patients, the improvement in AChA-PCoA extension was evaluated in comparison with preoperative DSA; the characteristics of these patients are shown in Table 7. Overall, the improvement in AChA-PCoA extension was observed in 75 of 107 operated hemispheres (70.1%) and 37 of 105 unoperated hemispheres (35.2%). The difference was statistically significant between surgical and nonsurgical hemispheres in this cohort (p < 0.05).
Discussion Clinical Manifestation and Angiographic Patterns
The mechanisms of MMD-related intracranial hemorrhage are always under discussion. Some authors have suggested that hemodynamic stress on the fragile MMD vessels might be correlated with the hemorrhagic ictus,10,12,15 and others have supported that dilation and branch extension of the AChA-PCoA was the strong factor.16,21 In our study period, there were 113 patients with hemorrhagic MMD; 63 (55.7%) presented with pure IVH and 36 (31.9%) presented with IVH with ICH. Intraventricular hemorrhage seemed to be more frequent in hemorrhagic MMD. Most of the patients (81 of 113 patients, 71.7%) harbored Grade III or IV lesions based on the Suzuki grading system. These patterns of the hemorrhagic locations and lesion characteristics were consistent with those previously reported in the literature.23 We also reviewed distribution of the AChA-PCoA changes, which showed that bleeding events were related to angiographic changes of the AChA-PCoA. Grade 2 lesions according to the modified Morioka scale were predominantly associated with the hemorrhagic ictus. In addition, the dilated and extended AChA-PCoA might produce preferential development of IVH due to the rupture of focal protruTABLE 6: Distribution of number reduction of basal moyamoya vessels on follow-up DSA in 212 hemispheres Decrease in No. of Moyamoya Vessels* Hemisphere
No. of Hemispheres
0
1
2
hemorrhagic nonhemorrhagic
107 105
46 55
25 28
36 22
* 0 = no evidence of decrease (50%). No statistical difference was observed in the decrease in the number of MMD vessels between surgical and nonsurgical hemispheres, according to the chi-square test.
1052
TABLE 7: Distribution of AChA-PCoA extension improvement in all 212 hemispheres
Hemisphere surgical nonsurgical
AChA-PCoA Extension Improvement No. of Hemispheres Improved* Not improved 107 105
75 37
32 68
* p < 0.05, chi-square test.
sions or microaneurysm formation in the distal branches. The findings were also consistent with the previous study.23 Low Rebleeding Rate After Surgical Procedure
The clinical outcome of the extracranial-intracranial bypass for patients with hemorrhagic MMD in this single high-volume center study compares favorably with that of conservative therapy reported previously in the literature. So far, there have been 4 published studies investigating the natural history of hemorrhagic MMD. Two Japanese studies reported annual hemorrhage rates ranging from 6% to 7% in adults.14,22 However, the other 2 studies reported a relatively low risk of rehemorrhage, ranging from 0% to 1.7% after conservative therapy for a small sample of hemorrhagic MMD patients.2,6 The shared limitation of these studies was the small sample size. The low rebleeding rate might be related to the aggressive surgical strategy for the patients in this cohort. Direct bypass procedures are often performed in patients with MMD,3,11,19,26 whereas the options for indirect bypass are controversial.8,9,28 Our indirect revascularization technique, termed encephalo-dura-myo-synangiosis (EDMS), which is distinguished from encephalo-duro-arteriosynangiosis (EDAS), encephalo-myo-synangiosis (EMS), and encephalo-duro-arterio-myo-synangiosis (EDAMS), produced a definite therapeutic effect on MMD. As shown in postoperative DSA images, Matsushima Grade A transpial and transdural collaterals were present in 84.1% of the hemispheres with synangiosis sites, indicating that this procedure generally resulted in well-developed collateralization of the brain. From the obtained DS angiogram, we found that the collaterals from the MMA or DTA developed in most of the surgically treated patients, which demonstrates that these 2 arteries played an important role in the establishment of the collateral circulation. In our surgical strategy published in the previous reports, the integrity of these 2 arteries was carefully preserved during craniotomy, which guaranteed the further established cortical network from MMA and DTA. How to Reduce Rebleeding Events
In the past decades, attempts have been made to determine the potential mechanisms of lower rebleeding risk after revascularization. Some authors believe that revascularization might cause a lower degree of proliferation of basal MMD vessels.13,30 In this cohort, 61 (57%) of 107 hemispheres had fewer MMD vessels after revascularization. This proportion was not higher than that in the unoperated hemispheres, indicating that revascularJ Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD ization may not promote the spontaneous occlusion of pathological MMD vessels. Due to the finding that dilated and extended AChAPCoA was a significant cause of bleeding, we presumed that the improvement of AChA-PCoA dilation in the surgically treated hemispheres might be correlated with the low rebleeding rate. In our cohort, we found that extracranial-to-intracranial revascularization could lead to improvement in AChA-PCoA dilation rather than reduction in basal MMD vessels (Fig. 2). Of note, our cohort included 2 patients harboring a distal AChA aneurysm, which disappeared after revascularization.24 These 2 cases suggest that revascularization may relieve the hemodynamic stress in AChA-PCoA. We compared the angiographic changes of the AChA-PCoA between the patients who suffered rebleeding in the surgical hemispheres and those who did not (Table 8). Improvement in AChA-PCoA dilation and extension occurred in 73 (71.6%) of 102 hemispheres that did not have rehemorrhage and in 2 (40%) of 5 hemispheres that did have rehemorrhage; thus, improvement tended to occur more frequently in patients who do not experience hemorrhage and might be the most pos-
TABLE 8: Distribution of AChA-PCoA extension improvement in 107 surgical hemispheres
Hemisphere no rebleeding rebleeding
AChA-PCoA Extension Improvement No. of Hemispheres Improved Not Improved 102 5
73 2
29 3
sible predictive factor for the low rebleeding rate. In addition, we reviewed the patients who encountered ipsilateral rebleeding in the surgically treated hemisphere (Table 9). Three patients with improvement in AChA-PCoA extension presented with ICH and the other 2 patients without it presented with IVH, which indicated that AChA-PCoA system was closely correlated with IVH rather than ICH in hemorrhagic MMD. High Mortality in Rebleeding Patients
The 80% mortality rate due to postoperative ipsilateral rehemorrhage in this cohort was extremely high.
Fig. 2. Radiological changes of AChA-PCoA extension after STA-MCA bypass surgery in a patient with MMD. A: CT scan demonstrating intraventricular hemorrhage. B: Preoperative right ICA angiogram (lateral view) revealing MMD with Grade 2 dilation of the AChA-PCoA. C: Right STA-MCA bypass was performed. D: The bypass patency demonstrated by ICG. E: The follow-up DSA confirming patency of the anastomosis. F: DSA revealing great improvement of AChA-PCoA dilation and extension in the operated hemisphere.
J Neurosurg / Volume 121 / November 2014
1053
H. Jiang et al. TABLE 9: Angiography characteristics and clinical outcome in 5 surgically treated cases with ipsilateral rebleeding Case No.
Graft Patency
1 2 3 4 5
yes yes yes yes yes
Matsushima Moyamoya Vessel AChA-PCoA Grade Decrease Extension Improvement Rebleeding Type A A A A A
>50% 25–50% >50% 25–50% 25–50%
Liu et al. conducted an extensive study of 97 consecutive patients with hemorrhagic MMD.17 The results revealed that mortality from rebleeding in the surgery group (50%) tended to be higher than that in the conservatively treated group, but this was not statistically significant. These findings indicate that the mortality rate was higher if rebleeding occurred in the patients who had undergone revascularization. The mechanisms of this phenomenon have not been fully elucidated. We presume that revascularization provides additional collaterals for the operated hemisphere, resulting in immediate reperfusion and long-lasting restoration of the blood supply, which might penetrate the fragile MMD vessels if the pathological process is not stopped by the surgery. Limitations
The current study has several limitations. First, it was not a randomized controlled study. There may have been bias in patient selection and demographics. Second, the conservative treatment methods used in different cohorts were not identical in the previous studies. With the development of medication in the current years, it is noted that the rebleeding rate after conservative therapy was much lower in the latest study. Thus, our results should be interpreted with more caution to deduce a likely benefit of surgery versus conservative treatment. The other main limitation of this research is the midterm follow-up period. MMD is a gradually progressive lesion, and therefore much longer-term follow-up is necessary to investigate the progress of MMD after revascularization.
Conclusions
Our results indicate that revascularization may provide a benefit for patients with hemorrhagic MMD. The improvement of dilation and branch extension of AChAPCoA might be correlated with the low rebleeding rate. A randomized controlled trial comparing revascularization with conservative therapy, conducted at multiple highvolume institutions, is needed to confirm the efficacy of surgery. The results of the Japan Adult MMD Trial are highly anticipated.20 Acknowledgments We gratefully express our gratitude and appreciation to Prof. Donglei Song for his great contribution for this work. We also thank Dr. Ping He for his excellent assistance in statistical analysis in this paper.
1054
1 0 1 0 0
ICH IVH ICH IVH IVH
Clinical Outcome death death severe disability death death
Disclosure This study was supported by grant 2011BAI08B00 from the Ministry of Health of the People’s Republic of China, grant 81371307 from the National Natural Science Foundation of China, and grant SHDC12010118 from the Shanghai Hospital Developing Center. The authors declare 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: Jiang, Ni, Mao. Acquisition of data: Gu, Ni, B Xu. Analysis and interpretation of data: Ni, Tian, F Xu. Drafting the article: Gu, Ni, B Xu, Lei. 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: Gu. Statistical analysis: Lei, F Xu. Administrative/technical/material support: Jiang, B Xu. Study supervision: Lei, Mao. References 1. Czabanka M, Peña-Tapia P, Scharf J, Schubert GA, Münch E, Horn P, et al: Characterization of direct and indirect cerebral revascularization for the treatment of European patients with moyamoya disease. Cerebrovasc Dis 32:361–369, 2011 2. Duan L, Bao XY, Yang WZ, Shi WC, Li DS, Zhang ZS, et al: Moyamoya disease in China: its clinical features and outcomes. Stroke 43:56–60, 2012 3. Fujimura M, Kaneta T, Tominaga T: Efficacy of superficial temporal artery-middle cerebral artery anastomosis with routine postoperative cerebral blood flow measurement during the acute stage in childhood moyamoya disease. Childs Nerv Syst 24:827–832, 2008 4. Fukui M: Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 99 (Suppl 2):S238– S240, 1997 5. Fukui M, Kono S, Sueishi K, Ikezaki K: Moyamoya disease. Neuropathology 20 (Suppl):S61–S64, 2000 6. Gross BA, Du R: The natural history of moyamoya in a North American adult cohort. J Clin Neurosci 20:44–48, 2013 7. Gu Y, Ni W, Jiang H, Ning G, Xu B, Tian Y, et al: Efficacy of extracranial-intracranial revascularization for non-moyamoya steno-occlusive cerebrovascular disease in a series of 66 patients. J Clin Neurosci 19:1408–1415, 2012 8. Houkin K, Kuroda S, Ishikawa T, Abe H: Neovascularization (angiogenesis) after revascularization in moyamoya disease. Which technique is most useful for moyamoya disease? Acta Neurochir (Wien) 142:269–276, 2000 9. Houkin K, Nakayama N, Kuroda S, Ishikawa T, Nonaka T: How does angiogenesis develop in pediatric moyamoya disease after surgery? A prospective study with MR angiography. Childs Nerv Syst 20:734–741, 2004
J Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD 10. Irikura K, Miyasaka Y, Kurata A, Tanaka R, Yamada M, Kan S, et al: The effect of encephalo-myo-synangiosis on abnormal collateral vessels in childhood moyamoya disease. Neurol Res 22:341–346, 2000 11. Ishikawa T, Kamiyama H, Kuroda S, Yasuda H, Nakayama N, Takizawa K: Simultaneous superficial temporal artery to middle cerebral or anterior cerebral artery bypass with pansynangiosis for Moyamoya disease covering both anterior and middle cerebral artery territories. Neurol Med Chir (Tokyo) 46:462–468, 2006 12. Iwama T, Hashimoto N, Tsukahara T, Miyake H: Superficial temporal artery to anterior cerebral artery direct anastomosis in patients with moyamoya disease. Clin Neurol Neurosurg 99 (Suppl 2):S134–S136, 1997 13. Kashiwagi S, Yamashita T, Katoh S, Kitahara T, Nakashima K, Yasuhara S, et al: Regression of moyamoya vessels and hemodynamic changes after successful revascularization in childhood moyamoya disease. Acta Neurol Scand Suppl 166:85– 88, 1996 14. Kobayashi E, Saeki N, Oishi H, Hirai S, Yamaura A: Longterm natural history of hemorrhagic moyamoya disease in 42 patients. J Neurosurg 93:976–980, 2000 15. Kuroda S, Houkin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:1056–1066, 2008 16. Liu W, Zhu S, Wang X, Yue X, Zhou Z, Wang H, et al: Evaluation of angiographic changes of the anterior choroidal and posterior communicating arteries for predicting cerebrovascular lesions in adult moyamoya disease. J Clin Neurosci 18:374–378, 2011 17. Liu X, Zhang D, Shuo W, Zhao Y, Wang R, Zhao J: Long term outcome after conservative and surgical treatment of haemorrhagic moyamoya disease. J Neurol Neurosurg Psychiatry 84:258–265, 2013 18. Matsushima Y, Inaba Y: Moyamoya disease in children and its surgical treatment. Introduction of a new surgical procedure and its follow-up angiograms. Childs Brain 11:155–170, 1984 19. Miyamoto S, Akiyama Y, Nagata I, Karasawa J, Nozaki K, Hashimoto N, et al: Long-term outcome after STA-MCA anastomosis for moyamoya disease. Neurosurg Focus 5(5):E5, 1998 20. Miyamoto S, Japan Adult Moyamoya Trial Group: Study design for a prospective randomized trial of extracranial-intracranial bypass surgery for adults with moyamoya disease and hemorrhagic onset—the Japan Adult Moyamoya Trial Group. Neurol Med Chir (Tokyo) 44:218–219, 2004 21. Morioka M, Hamada J, Kawano T, Todaka T, Yano S, Kai Y, et al: Angiographic dilatation and branch extension of the anterior choroidal and posterior communicating arteries are
J Neurosurg / Volume 121 / November 2014
predictors of hemorrhage in adult moyamoya patients. Stroke 34:90–95, 2003 22. Morioka M, Hamada J, Todaka T, Yano S, Kai Y, Ushio Y: High-risk age for rebleeding in patients with hemorrhagic moyamoya disease: long-term follow-up study. Neurosurgery 52:1049–1055, 2003 23. Nah HW, Kwon SU, Kang DW, Ahn JS, Kwun BD, Kim JS: Moyamoya disease-related versus primary intracerebral hemorrhage: [corrected] location and outcomes are different. Stroke 43:1947–1950, 2012 (Erratum in Stroke 44:e119, 2013) 24. Ni W, Xu F, Xu B, Liao Y, Gu Y, Song D: Disappearance of aneurysms associated with moyamoya disease after STAMCA anastomosis with encephaloduro myosynangiosis. J Clin Neurosci 19:485–487, 2012 25. Ryan RW, Chowdhary A, Britz GW: Hemorrhage and risk of further hemorrhagic strokes following cerebral revascularization in Moyamoya disease: a review of the literature. Surg Neurol Int 3:72, 2012 26. Starke RM, Komotar RJ, Hickman ZL, Paz YE, Pugliese AG, Otten ML, et al: Clinical features, surgical treatment, and long-term outcome in adult patients with moyamoya disease. Clinical article. J Neurosurg 111:936–942, 2009 27. Suzuki J, Takaku A: Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20:288–299, 1969 28. Veeravagu A, Guzman R, Patil CG, Hou LC, Lee M, Steinberg GK: Moyamoya disease in pediatric patients: outcomes of neurosurgical interventions. Neurosurg Focus 24(2):E16, 2008 29. Xu B, Song DL, Mao Y, Gu YX, Xu H, Liao YJ, et al: Superficial temporal artery-middle cerebral artery bypass combined with encephalo-duro-myo-synangiosis in treating moyamoya disease: surgical techniques, indications and midterm followup results. Chin Med J (Engl) 125:4398–4405, 2012 30. Yoshida Y, Yoshimoto T, Shirane R, Sakurai Y: Clinical course, surgical management, and long-term outcome of moyamoya patients with rebleeding after an episode of intracerebral hemorrhage: an extensive follow-up study. Stroke 30: 2272–2276, 1999 Manuscript submitted November 2, 2013. Accepted July 9, 2014. Please include this information when citing this paper: published online August 15, 2014; DOI: 10.3171/2014.7.JNS132434. Address correspondence to: Yuxiang Gu, M.D., Ph.D., Department of Neurosurgery, Huashan Hospital, Fudan University, No. 12 Mid Wulumuqi Road, Shanghai 200040, P.R. China. email: [email protected].
1055
Outcome in adult patients with hemorrhagic moyamoya disease after combined extracranial-intracranial bypass Clinical article *Hanqiang Jiang, M.D., Ph.D., Wei Ni, M.D., Ph.D., Bin Xu, M.D., Ph.D., Yu Lei, M.D., Yanlong Tian, M.D., Feng Xu, M.D., Yuxiang Gu, M.D., Ph.D., and Ying Mao, M.D., Ph.D. Division of Cerebrovascular Surgery and Interventional Neuroradiology, Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, P.R. China Object. The outcome of patients with hemorrhagic moyamoya disease (MMD) after cerebral revascularization is uncertain. The purpose of this study was to delineate the efficacy of this surgical method in the treatment of hemorrhagic MMD. Methods. Between January 2007 and August 2011, a consecutive cohort of 113 patients with hemorrhagic MMD was enrolled into this prospective single-center cohort study. The surgical method was combined direct and indirect bypass. The cumulative probability of the primary end point (all stroke and deaths from surgery through 30 days after surgery and ipsilateral recurrent hemorrhage afterward) was analyzed. The angiographic outcome was measured by the following parameters: bypass patency, reduction of basal MMD vessels, improved degree of dilation, and branch extension of the anterior choroidal and posterior communicating arteries (AChA-PCoA). Results. Of the 113 enrolled cases, CT scans revealed pure intraventricular hemorrhage (IVH) in 63 cases (55.7%), pure intracranial hemorrhage (ICH) in 14 cases (12.4%), and ICH with IVH in 36 cases (31.9%). In 74 of 113 hemorrhagic hemispheres (65.5%), the AChA-PCoA was extremely dilated with extensive branches beyond the choroidal fissure. A total of 114 surgeries were performed. No patient suffered ischemic or hemorrhagic stroke through 30 days after surgery. Ipsilateral rebleeding occurred in 5 patients, 4 of whom died of the rebleeding event. The cumulative probability of the primary end point was 0% at 1 year and 1.9% at 2 years. The annual rebleeding rate was 1.87%/person/year. The improvement in AChA-PCoA extension was observed in 75 of 107 operated hemispheres (70.1%), which was higher than that in 7 of 105 unoperated hemispheres (35.2%). Conclusions. Revascularization may provide a benefit over conservative therapy for hemorrhagic MMD patients. The improvement of dilation and branch extension of AChA-PCoA might be correlated with the low rebleeding rate. (http://thejns.org/doi/abs/10.3171/2014.7.JNS132434)
Key Words • vascular disorders • hemorrhagic moyamoya disease • revascularization • rebleeding rate
M
disease (MMD) is an uncommon cerebrovascular disease characterized by an unusual vascular network at the base of the brain due to progressive stenosis or occlusion of the supraclinoid internal carotid artery (ICA) and its main branches within the circle of Willis.15 The symptoms and signs of MMD can be classified into 2 major etiological categooyamoya
Abbreviations used in this paper: AChA = anterior choroidal artery; DSA = digital subtraction angiography; DTA = deep temporal artery; ICA = internal carotid artery; ICG = indocyanine green; ICH = intracranial hemorrhage; IVH = intraventricular hemorrhage; MCA = middle cerebral artery; MMA = middle meningeal artery; MMD = moyamoya disease; mRS = modified Rankin Scale; PCoA = posterior communicating artery; STA = superficial temporal artery; TIA = transient ischemic attack. * Drs. Jiang and Ni contributed equally to this work.
1048
ries: those caused by brain ischemia (ischemic type) and those caused by the deleterious consequences of the compensatory fragile collateral vessels (hemorrhagic type). The ischemic type is prevalent among pediatric patients with MMD, whereas the hemorrhagic type dominates in adults.5 In previous reports, it is well recognized that surgical revascularization using direct and/or indirect bypass provides an improved outcome in patients presenting with the ischemic type.1,11 In patients with the hemorrhagic type, extracranial-to-intracranial bypass has also been performed based on the hypothesis that bypass surgery reduces the hemodynamic stress on the pathological vessels and prevents recurrent hemorrhage.24,25 However, This article contains some figures that are displayed in color online but in black-and-white in the print edition.
J Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD there are limited reports on the surgical outcome in patients with hemorrhagic MMD. The goal of this study was to determine whether extracranial-to-intracranial bypass would improve hemodynamic impairment and provide a benefit for patients with hemorrhagic MMD.
Methods Study Population
The research ethics board of our institution approved the protocol for this prospective single-center study. During the study period (January 2007 to August 2011), all patients who were admitted to our center because of spontaneous intracranial hemorrhage (ICH) were evaluated as potential candidates for the study. The inclusion criteria were angiographically verified MMD (under the guidelines of the Research Committee on MMD according to the Ministry of Health and Welfare in Japan4), hemorrhagic attack identified by CT scanning, patient age of 18–75 years, preoperative modified Rankin scale score (mRS) ≤ 2, and from 1 month to 1 year after the last ictus of hemorrhage. The exclusion criteria were MMD with ruptured aneurysm in the main stem of the intracranial arteries, other concurrent intracranial lesions, and life expectancy less than 1 year because of another medical condition. Patients whose MMD was with associated aneurysms in the peripheral portion of the MMD vessels were not excluded from the study. Each patient or family member signed an informed consent for patients enrolled in this study. The patients’ demographics, clinical data, images, and follow-up information were prospectively collected. Periprocedural Management, Surgical Procedure, and Follow-Up
Angiographic staging was based on the published guidelines of Suzuki’s 6-stage classification.27 Each hemisphere was assessed for the association of the angiographic changes of the anterior choroidal and posterior communicating arteries (AChA-PCoA) with hemorrhagic ictus. The modified grading system for the angiographic findings of the AChA-PCoA was based on the criteria suggested by Morioka et al.21 and modified by Liu et al.16 Generally, we revascularized the hemorrhagic side visualized on CT scanning. The surgical method was revascularization using combined direct and indirect bypass. The direct bypass procedure was a microsurgical endto-side anastomosis of 1 or 2 superficial temporal artery (STA) branches to identical cortical branches of the middle cerebral artery (MCA). The choice of a single or double bypass depended on how well the feeding artery matched the recipient artery. An encephalo-dura-myo-synangiosis (EDMS) was used as the indirect bypass procedure, which we described in our previous study.7,29 After the direct bypass, indocyanine green (ICG) fluorescence imaging or Doppler ultrasound was regularly used to provide a reliable and rapid intraoperative assessment of the bypass patency. In general, antiplatelet therapy was not used for fear of potential rebleeding after revascularization. CT and J Neurosurg / Volume 121 / November 2014
MR scanning were performed if the patient had a new neurological event. After discharge, each patient had a follow-up visit at 90 days. The subsequent follow-ups were completed as clinic visits, by telephone, or by letter once a year until July 2013. An independent neurologist evaluated the neurological status of the patients by using the mRS. CT and MRI scans were obtained if a new neurological event occurred. Angiographic follow-up was scheduled at 6 months after the operation for the assessment of disease and effectiveness of the revascularization. The angiographic progress of MMD was evaluated according to the decreased numbers in basal MMD vessels and the improvement of dilation of AChA-PCoA. The method to evaluate numbers of MMD vessels was to measure the area with pathological basal vessels and calculate the relative percentage of the pathological moyamoya area compared with the area of the MCA feeding territory in the capillary phase of the anteroposterior view in the internal carotid angiogram. Improvement of the angiographic characteristics of AChA-PCoA was defined as reduction of dilation and branch extension of AChA-PCoA on follow-up digital subtraction angiography (DSA). The anastomosis was evaluated by 2 independent neurosurgeons who were not involved in the surgery, with reference to the criteria proposed by Matsushima and Inaba for the evaluation of transdural collaterals after revascularization.18 End Point Assessment
The mRS score at the most recent follow-up or the end point event after enrollment was independently assessed by neurologists. The primary end point for all participants was the combined total of all strokes and death from surgery within 30 days after the procedure and ipsilateral recurrent hemorrhage afterward. The secondary end points included rebleeding on the contralateral side, ischemic stroke beyond 30 days, and transient ischemic attack (TIA) on the surgically treated side at any time.
Statistical Analysis
The patient demographic data, angiographic outcomes, and clinical outcomes were presented as the mean ± SD for the continuous variables. The cumulative probability of the occurrence of a primary end point over time was estimated by the product-limit method at 1 year and 2 years. The correlation between angiographic findings and clinical findings was examined using the chi-square test. Differences of a p value < 0.05 were considered statistically significant.
Results Baseline Demographic Data
A consecutive cohort of 113 patients was enrolled in this study. The baseline demographic data are presented in Table 1. The average age was 37.3 ± 9.46 years (range 21–58 years), with 16 (15.0% [14.2%]) of patients experiencing more than 1 episode of bleeding. Of the 113 enrolled cases, CT scans revealed the presence of pure intraventricular hemorrhage (IVH) in 63 cases (55.8%), pure 1049
H. Jiang et al. TABLE 1: Baseline demographics in 113 patients with hemorrhagic MMD Variable
TABLE 3: Distribution of AChA-PCoA extension in 113 cases Modified Morioka Grading*
Value*
age in yrs mean range no. of females no. of males symptoms prior to bleeding ipsilat TIA/stroke contralat TIA/stroke type of 1st bleeding IVH ICH ICH w/ IVH total no. of bleeding episodes 1 2 3 4
37.3 ± 9.46 21–58 65 48 8/2 2/0 63 14 36
No. of Hemispheres
1
2†
3
hemorrhagic nonhemorrhagic
113 113
39 72
74 41
0 0
* Grading system: 1 = normal or slight-moderate dilation of AChAPCoA (with stenosed or occluded ICA and proliferation around circle of the Willis); 2 = extreme dilation of AChA-PCoA (with abnormal branches beyond the choroidal fissure, serving as collateral blood supply to the anterior circulation via posterior pericallosal arteries and/or leptomeningeal collateral vessels); 3 = nonvisualization of AChA-PCoA on DSA (with occluded ICA proximal to the PCoA level). † p < 0.05, chi-square test.
Surgical Results
97 13 2 1
* Values are number of patients unless stated otherwise.
ICH in 14 cases (12.4%), and ICH with IVH in 36 cases (31.9%). One hundred one of the patients were asymptomatic prior to their first bleeding episodes, whereas 12 of the patients had ischemic symptoms prior to their first episodes. TIA was the most common symptom, occurring in 8 of the 12 patients in the ipsilateral hemisphere and in 2 in the contralateral hemisphere. Ischemic stroke occurred in the other 2 patients and was verified by MRI in the ipsilateral hemisphere. Seven of these 12 patients received antiplatelet therapy thereafter. Table 2 summarizes the lesion characteristics (Suzuki grade). Table 3 describes the angiographic dilation and extension of AChA-PCoA (modified Morioka grade) in 226 hemispheres. In 74 of 113 hemorrhagic hemispheres (65.5%), the AChA-PCoA was extremely dilated with extensive branches beyond the choroidal fissure (modified Morioka Grade 2), which only occurred in 41 of 113 nonhemorrhagic hemispheres (36.3%). The difference was statistically significant between hemorrhagic and nonhemorrhagic hemispheres in this cohort (Table 3, p < 0.05). TABLE 2: Lesion characteristics in 113 patients based on the Suzuki grading system Suzuki Stage
Description
No. of Patients
I II III IV V VI
narrowing of the ICA bifurcation w/o collaterals initiation of moyamoya collaterals intensification of moyamoya collaterals minimization of moyamoya collaterals reduction of moyamoya collaterals disappearance of moyamoya collaterals
0 9 51 30 23 0
1050
Hemisphere
The surgical procedure was performed at 46.7 ± 10.6 days (range 31–92 days) from the last ictus. A total of 114 surgeries were performed; 1 patient underwent staged bilateral surgery due to rebleeding in the contralateral hemisphere. All hemispheres were treated with direct bypass combined with indirect bypass. In 60 cases a double bypass was performed in the hemispheres, and in 54 cases a single bypass was performed in the hemispheres. The ICG demonstrated a 100% patency rate for each anastomotic stoma during the procedure. Surgical complications occurred in 14 patients. Five suffered intracranial infection and recovered after antibiotic therapy. Two experienced epileptic seizures within 3 days after surgery. One had asymptomatic epidural hematoma on the day after the surgery and underwent immediate evacuation. The bypass was preserved well during the procedure. The other 6 patients manifested disorientation or focal neurological deficit (fluctuating aphasia, weakness or numbness in the contralateral limbs, and facial palsy) related to the surgically treated hemisphere on the postoperative 2nd to 5th days without any evidence of stroke on CT or MRI. The symptoms lasted about 3–4 weeks and resolved spontaneously and completely with the use of a free radical scavenger and calcium channel antagonist. Cerebral hyperperfusion syndrome was considered to occur in these 6 patients.
Primary End Point
In this cohort, 7 patients were lost to follow-up. The remaining patients underwent clinical follow-ups at a mean of 30.33 ± 10.7 months (range 21–72 months). No patient suffered ischemic or hemorrhagic stroke within 30 days of surgery. During the follow-up period, the primary end point event of ipsilateral rebleeding occurred in 5 patients, 4 of whom died from the rebleeding event. The cumulative probability of the occurrence of a primary end point was 0% at 1 year and 1.9% at 2 years (Fig. 1 left). The annual rebleeding rate was 1.87% according to the person-year method. The Kaplan-Meier curve for rebleeding-free survival during the mean follow-up period is shown in Fig. 1 right.
Secondary End Point
Sixteen secondary end point events were observed J Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD
Fig. 1. Left: The cumulative probability of stroke and death from surgery within 30 days of surgery and ipsilateral recurrent hemorrhage afterward was 0% at 1 year and 1.9% (95% CI 3.5%–9.06%) at 2 years. Right: The Kaplan-Meier curve for rebleeding-free survival in 106 patients with hemorrhagic MMD during the mean follow-up period of 30.33 months. Cum = cumulative.
in this cohort, including 2 contralateral recurrent hemorrhages after surgery and 14 TIAs on the operated side (2 within 30 days and 12 beyond 30 days). Of 2 patients suffering contralateral recurrent hemorrhage, 1 experienced contralateral rebleeding and underwent revascularization 1 month later. No rebleeding was observed subsequently. The other patient suffered contralateral rebleeding 16 months after the operation, and he is now stably recovering from this ictus. Clinical Outcome
The patients’ mRS scores at the latest follow-up are listed in Table 4. Of the 106 patients, 4 died of ipsilateral rebleeding. Three patients had severe neurological deficits (mRS Scores 3–5) due to the brain damage caused by the second ictus of intracranial hemorrhage, including 1 patient who suffered ipsilateral rebleeding after the revascularization and 2 patients who suffered contralateral rebleeding. The remaining 99 patients attained good outcomes with or without mild neurological deficits (mRS Scores 0–2), including 6 patients suffering new TIAs in the unoperated hemispheres beyond 30 days. Among the 12 patients who suffered ischemic symptoms prior to their last bleeding episodes, 2 of 8 patients with ipsilateral TIAs suffered recurrent TIAs in the same hemisphere beTABLE 4: Clinical outcome for 106 patients who underwent surgery and follow-up mRS Score
No. of Patients
0 1 2 3 4 5 6
67 24 8 1 0 2 4
J Neurosurg / Volume 121 / November 2014
yond 30 days after surgery (calculated as secondary end point). One of 2 patients with contralateral TIAs did not experience TIAs in the follow-up period; the other suffered TIAs in the unoperated hemisphere until the most recent follow-up visit. No recurrent stroke occurred in the 2 patients with ipsilateral ischemic stroke prior to the bleeding ictus. Angiographic Outcome
Efficacy of Bypass. Postoperative angiograms were obtained for 107 hemispheres in 106 patients with 167 anastomotic stomas (60 double bypass and 47 single bypass) at a mean of 10.6 ± 2.7 months (range 6–16 months). All the bypass grafts were confirmed to be patent. Transdural and transpial collaterals on the operated site were graded according to the Matsushima criteria. Table 5 summarizes the results of this variable. The revascularization established from the middle meningeal artery (MMA) and deep temporal artery (DTA) via the indirect procedure was also evaluated by DSA. Sixty-two (57.9%) of 107 operated hemispheres showed that both the MMA and DTA had spontaneous anastomosis with cortical branches. In the other 44 patients (41.1%), spontaneous anastomosis in the operated hemisphere was observed only in the DTA. Only 1 operated hemisphere showed TABLE 5: Angiographic change of moyamoya vessels and postoperative collateral grading Matsushima Grading A B C
Description area perfused by the synangiosis is greater than 2/3 of the MCA territory area perfused by the synangiosis is btwn 1/3 & 2/3 of the MCA territory area perfused by the synangiosis is less than 1/3 of the MCA territory
No. of Hemispheres 87 17 3
1051
H. Jiang et al. that neither MMA nor DTA had established spontaneous collaterals in the MCA feeding territory.
Decrease in Number of MMD Vessels. Table 6 describes the distribution of angiographic grading for decrease of MMD vessels in the operated hemispheres and no operated hemispheres. No statistical difference was observed in the decrease in the number of MMD vessels between surgical and nonsurgical hemispheres (p > 0.05).
Improvement in AChA-PCoA Extension. Among the 212 hemispheres (107 operated and 105 unoperated) in 106 patients, the improvement in AChA-PCoA extension was evaluated in comparison with preoperative DSA; the characteristics of these patients are shown in Table 7. Overall, the improvement in AChA-PCoA extension was observed in 75 of 107 operated hemispheres (70.1%) and 37 of 105 unoperated hemispheres (35.2%). The difference was statistically significant between surgical and nonsurgical hemispheres in this cohort (p < 0.05).
Discussion Clinical Manifestation and Angiographic Patterns
The mechanisms of MMD-related intracranial hemorrhage are always under discussion. Some authors have suggested that hemodynamic stress on the fragile MMD vessels might be correlated with the hemorrhagic ictus,10,12,15 and others have supported that dilation and branch extension of the AChA-PCoA was the strong factor.16,21 In our study period, there were 113 patients with hemorrhagic MMD; 63 (55.7%) presented with pure IVH and 36 (31.9%) presented with IVH with ICH. Intraventricular hemorrhage seemed to be more frequent in hemorrhagic MMD. Most of the patients (81 of 113 patients, 71.7%) harbored Grade III or IV lesions based on the Suzuki grading system. These patterns of the hemorrhagic locations and lesion characteristics were consistent with those previously reported in the literature.23 We also reviewed distribution of the AChA-PCoA changes, which showed that bleeding events were related to angiographic changes of the AChA-PCoA. Grade 2 lesions according to the modified Morioka scale were predominantly associated with the hemorrhagic ictus. In addition, the dilated and extended AChA-PCoA might produce preferential development of IVH due to the rupture of focal protruTABLE 6: Distribution of number reduction of basal moyamoya vessels on follow-up DSA in 212 hemispheres Decrease in No. of Moyamoya Vessels* Hemisphere
No. of Hemispheres
0
1
2
hemorrhagic nonhemorrhagic
107 105
46 55
25 28
36 22
* 0 = no evidence of decrease (50%). No statistical difference was observed in the decrease in the number of MMD vessels between surgical and nonsurgical hemispheres, according to the chi-square test.
1052
TABLE 7: Distribution of AChA-PCoA extension improvement in all 212 hemispheres
Hemisphere surgical nonsurgical
AChA-PCoA Extension Improvement No. of Hemispheres Improved* Not improved 107 105
75 37
32 68
* p < 0.05, chi-square test.
sions or microaneurysm formation in the distal branches. The findings were also consistent with the previous study.23 Low Rebleeding Rate After Surgical Procedure
The clinical outcome of the extracranial-intracranial bypass for patients with hemorrhagic MMD in this single high-volume center study compares favorably with that of conservative therapy reported previously in the literature. So far, there have been 4 published studies investigating the natural history of hemorrhagic MMD. Two Japanese studies reported annual hemorrhage rates ranging from 6% to 7% in adults.14,22 However, the other 2 studies reported a relatively low risk of rehemorrhage, ranging from 0% to 1.7% after conservative therapy for a small sample of hemorrhagic MMD patients.2,6 The shared limitation of these studies was the small sample size. The low rebleeding rate might be related to the aggressive surgical strategy for the patients in this cohort. Direct bypass procedures are often performed in patients with MMD,3,11,19,26 whereas the options for indirect bypass are controversial.8,9,28 Our indirect revascularization technique, termed encephalo-dura-myo-synangiosis (EDMS), which is distinguished from encephalo-duro-arteriosynangiosis (EDAS), encephalo-myo-synangiosis (EMS), and encephalo-duro-arterio-myo-synangiosis (EDAMS), produced a definite therapeutic effect on MMD. As shown in postoperative DSA images, Matsushima Grade A transpial and transdural collaterals were present in 84.1% of the hemispheres with synangiosis sites, indicating that this procedure generally resulted in well-developed collateralization of the brain. From the obtained DS angiogram, we found that the collaterals from the MMA or DTA developed in most of the surgically treated patients, which demonstrates that these 2 arteries played an important role in the establishment of the collateral circulation. In our surgical strategy published in the previous reports, the integrity of these 2 arteries was carefully preserved during craniotomy, which guaranteed the further established cortical network from MMA and DTA. How to Reduce Rebleeding Events
In the past decades, attempts have been made to determine the potential mechanisms of lower rebleeding risk after revascularization. Some authors believe that revascularization might cause a lower degree of proliferation of basal MMD vessels.13,30 In this cohort, 61 (57%) of 107 hemispheres had fewer MMD vessels after revascularization. This proportion was not higher than that in the unoperated hemispheres, indicating that revascularJ Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD ization may not promote the spontaneous occlusion of pathological MMD vessels. Due to the finding that dilated and extended AChAPCoA was a significant cause of bleeding, we presumed that the improvement of AChA-PCoA dilation in the surgically treated hemispheres might be correlated with the low rebleeding rate. In our cohort, we found that extracranial-to-intracranial revascularization could lead to improvement in AChA-PCoA dilation rather than reduction in basal MMD vessels (Fig. 2). Of note, our cohort included 2 patients harboring a distal AChA aneurysm, which disappeared after revascularization.24 These 2 cases suggest that revascularization may relieve the hemodynamic stress in AChA-PCoA. We compared the angiographic changes of the AChA-PCoA between the patients who suffered rebleeding in the surgical hemispheres and those who did not (Table 8). Improvement in AChA-PCoA dilation and extension occurred in 73 (71.6%) of 102 hemispheres that did not have rehemorrhage and in 2 (40%) of 5 hemispheres that did have rehemorrhage; thus, improvement tended to occur more frequently in patients who do not experience hemorrhage and might be the most pos-
TABLE 8: Distribution of AChA-PCoA extension improvement in 107 surgical hemispheres
Hemisphere no rebleeding rebleeding
AChA-PCoA Extension Improvement No. of Hemispheres Improved Not Improved 102 5
73 2
29 3
sible predictive factor for the low rebleeding rate. In addition, we reviewed the patients who encountered ipsilateral rebleeding in the surgically treated hemisphere (Table 9). Three patients with improvement in AChA-PCoA extension presented with ICH and the other 2 patients without it presented with IVH, which indicated that AChA-PCoA system was closely correlated with IVH rather than ICH in hemorrhagic MMD. High Mortality in Rebleeding Patients
The 80% mortality rate due to postoperative ipsilateral rehemorrhage in this cohort was extremely high.
Fig. 2. Radiological changes of AChA-PCoA extension after STA-MCA bypass surgery in a patient with MMD. A: CT scan demonstrating intraventricular hemorrhage. B: Preoperative right ICA angiogram (lateral view) revealing MMD with Grade 2 dilation of the AChA-PCoA. C: Right STA-MCA bypass was performed. D: The bypass patency demonstrated by ICG. E: The follow-up DSA confirming patency of the anastomosis. F: DSA revealing great improvement of AChA-PCoA dilation and extension in the operated hemisphere.
J Neurosurg / Volume 121 / November 2014
1053
H. Jiang et al. TABLE 9: Angiography characteristics and clinical outcome in 5 surgically treated cases with ipsilateral rebleeding Case No.
Graft Patency
1 2 3 4 5
yes yes yes yes yes
Matsushima Moyamoya Vessel AChA-PCoA Grade Decrease Extension Improvement Rebleeding Type A A A A A
>50% 25–50% >50% 25–50% 25–50%
Liu et al. conducted an extensive study of 97 consecutive patients with hemorrhagic MMD.17 The results revealed that mortality from rebleeding in the surgery group (50%) tended to be higher than that in the conservatively treated group, but this was not statistically significant. These findings indicate that the mortality rate was higher if rebleeding occurred in the patients who had undergone revascularization. The mechanisms of this phenomenon have not been fully elucidated. We presume that revascularization provides additional collaterals for the operated hemisphere, resulting in immediate reperfusion and long-lasting restoration of the blood supply, which might penetrate the fragile MMD vessels if the pathological process is not stopped by the surgery. Limitations
The current study has several limitations. First, it was not a randomized controlled study. There may have been bias in patient selection and demographics. Second, the conservative treatment methods used in different cohorts were not identical in the previous studies. With the development of medication in the current years, it is noted that the rebleeding rate after conservative therapy was much lower in the latest study. Thus, our results should be interpreted with more caution to deduce a likely benefit of surgery versus conservative treatment. The other main limitation of this research is the midterm follow-up period. MMD is a gradually progressive lesion, and therefore much longer-term follow-up is necessary to investigate the progress of MMD after revascularization.
Conclusions
Our results indicate that revascularization may provide a benefit for patients with hemorrhagic MMD. The improvement of dilation and branch extension of AChAPCoA might be correlated with the low rebleeding rate. A randomized controlled trial comparing revascularization with conservative therapy, conducted at multiple highvolume institutions, is needed to confirm the efficacy of surgery. The results of the Japan Adult MMD Trial are highly anticipated.20 Acknowledgments We gratefully express our gratitude and appreciation to Prof. Donglei Song for his great contribution for this work. We also thank Dr. Ping He for his excellent assistance in statistical analysis in this paper.
1054
1 0 1 0 0
ICH IVH ICH IVH IVH
Clinical Outcome death death severe disability death death
Disclosure This study was supported by grant 2011BAI08B00 from the Ministry of Health of the People’s Republic of China, grant 81371307 from the National Natural Science Foundation of China, and grant SHDC12010118 from the Shanghai Hospital Developing Center. The authors declare 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: Jiang, Ni, Mao. Acquisition of data: Gu, Ni, B Xu. Analysis and interpretation of data: Ni, Tian, F Xu. Drafting the article: Gu, Ni, B Xu, Lei. 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: Gu. Statistical analysis: Lei, F Xu. Administrative/technical/material support: Jiang, B Xu. Study supervision: Lei, Mao. References 1. Czabanka M, Peña-Tapia P, Scharf J, Schubert GA, Münch E, Horn P, et al: Characterization of direct and indirect cerebral revascularization for the treatment of European patients with moyamoya disease. Cerebrovasc Dis 32:361–369, 2011 2. Duan L, Bao XY, Yang WZ, Shi WC, Li DS, Zhang ZS, et al: Moyamoya disease in China: its clinical features and outcomes. Stroke 43:56–60, 2012 3. Fujimura M, Kaneta T, Tominaga T: Efficacy of superficial temporal artery-middle cerebral artery anastomosis with routine postoperative cerebral blood flow measurement during the acute stage in childhood moyamoya disease. Childs Nerv Syst 24:827–832, 2008 4. Fukui M: Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Research Committee on Spontaneous Occlusion of the Circle of Willis (Moyamoya Disease) of the Ministry of Health and Welfare, Japan. Clin Neurol Neurosurg 99 (Suppl 2):S238– S240, 1997 5. Fukui M, Kono S, Sueishi K, Ikezaki K: Moyamoya disease. Neuropathology 20 (Suppl):S61–S64, 2000 6. Gross BA, Du R: The natural history of moyamoya in a North American adult cohort. J Clin Neurosci 20:44–48, 2013 7. Gu Y, Ni W, Jiang H, Ning G, Xu B, Tian Y, et al: Efficacy of extracranial-intracranial revascularization for non-moyamoya steno-occlusive cerebrovascular disease in a series of 66 patients. J Clin Neurosci 19:1408–1415, 2012 8. Houkin K, Kuroda S, Ishikawa T, Abe H: Neovascularization (angiogenesis) after revascularization in moyamoya disease. Which technique is most useful for moyamoya disease? Acta Neurochir (Wien) 142:269–276, 2000 9. Houkin K, Nakayama N, Kuroda S, Ishikawa T, Nonaka T: How does angiogenesis develop in pediatric moyamoya disease after surgery? A prospective study with MR angiography. Childs Nerv Syst 20:734–741, 2004
J Neurosurg / Volume 121 / November 2014
Combined bypass for hemorrhagic MMD 10. Irikura K, Miyasaka Y, Kurata A, Tanaka R, Yamada M, Kan S, et al: The effect of encephalo-myo-synangiosis on abnormal collateral vessels in childhood moyamoya disease. Neurol Res 22:341–346, 2000 11. Ishikawa T, Kamiyama H, Kuroda S, Yasuda H, Nakayama N, Takizawa K: Simultaneous superficial temporal artery to middle cerebral or anterior cerebral artery bypass with pansynangiosis for Moyamoya disease covering both anterior and middle cerebral artery territories. Neurol Med Chir (Tokyo) 46:462–468, 2006 12. Iwama T, Hashimoto N, Tsukahara T, Miyake H: Superficial temporal artery to anterior cerebral artery direct anastomosis in patients with moyamoya disease. Clin Neurol Neurosurg 99 (Suppl 2):S134–S136, 1997 13. Kashiwagi S, Yamashita T, Katoh S, Kitahara T, Nakashima K, Yasuhara S, et al: Regression of moyamoya vessels and hemodynamic changes after successful revascularization in childhood moyamoya disease. Acta Neurol Scand Suppl 166:85– 88, 1996 14. Kobayashi E, Saeki N, Oishi H, Hirai S, Yamaura A: Longterm natural history of hemorrhagic moyamoya disease in 42 patients. J Neurosurg 93:976–980, 2000 15. Kuroda S, Houkin K: Moyamoya disease: current concepts and future perspectives. Lancet Neurol 7:1056–1066, 2008 16. Liu W, Zhu S, Wang X, Yue X, Zhou Z, Wang H, et al: Evaluation of angiographic changes of the anterior choroidal and posterior communicating arteries for predicting cerebrovascular lesions in adult moyamoya disease. J Clin Neurosci 18:374–378, 2011 17. Liu X, Zhang D, Shuo W, Zhao Y, Wang R, Zhao J: Long term outcome after conservative and surgical treatment of haemorrhagic moyamoya disease. J Neurol Neurosurg Psychiatry 84:258–265, 2013 18. Matsushima Y, Inaba Y: Moyamoya disease in children and its surgical treatment. Introduction of a new surgical procedure and its follow-up angiograms. Childs Brain 11:155–170, 1984 19. Miyamoto S, Akiyama Y, Nagata I, Karasawa J, Nozaki K, Hashimoto N, et al: Long-term outcome after STA-MCA anastomosis for moyamoya disease. Neurosurg Focus 5(5):E5, 1998 20. Miyamoto S, Japan Adult Moyamoya Trial Group: Study design for a prospective randomized trial of extracranial-intracranial bypass surgery for adults with moyamoya disease and hemorrhagic onset—the Japan Adult Moyamoya Trial Group. Neurol Med Chir (Tokyo) 44:218–219, 2004 21. Morioka M, Hamada J, Kawano T, Todaka T, Yano S, Kai Y, et al: Angiographic dilatation and branch extension of the anterior choroidal and posterior communicating arteries are
J Neurosurg / Volume 121 / November 2014
predictors of hemorrhage in adult moyamoya patients. Stroke 34:90–95, 2003 22. Morioka M, Hamada J, Todaka T, Yano S, Kai Y, Ushio Y: High-risk age for rebleeding in patients with hemorrhagic moyamoya disease: long-term follow-up study. Neurosurgery 52:1049–1055, 2003 23. Nah HW, Kwon SU, Kang DW, Ahn JS, Kwun BD, Kim JS: Moyamoya disease-related versus primary intracerebral hemorrhage: [corrected] location and outcomes are different. Stroke 43:1947–1950, 2012 (Erratum in Stroke 44:e119, 2013) 24. Ni W, Xu F, Xu B, Liao Y, Gu Y, Song D: Disappearance of aneurysms associated with moyamoya disease after STAMCA anastomosis with encephaloduro myosynangiosis. J Clin Neurosci 19:485–487, 2012 25. Ryan RW, Chowdhary A, Britz GW: Hemorrhage and risk of further hemorrhagic strokes following cerebral revascularization in Moyamoya disease: a review of the literature. Surg Neurol Int 3:72, 2012 26. Starke RM, Komotar RJ, Hickman ZL, Paz YE, Pugliese AG, Otten ML, et al: Clinical features, surgical treatment, and long-term outcome in adult patients with moyamoya disease. Clinical article. J Neurosurg 111:936–942, 2009 27. Suzuki J, Takaku A: Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 20:288–299, 1969 28. Veeravagu A, Guzman R, Patil CG, Hou LC, Lee M, Steinberg GK: Moyamoya disease in pediatric patients: outcomes of neurosurgical interventions. Neurosurg Focus 24(2):E16, 2008 29. Xu B, Song DL, Mao Y, Gu YX, Xu H, Liao YJ, et al: Superficial temporal artery-middle cerebral artery bypass combined with encephalo-duro-myo-synangiosis in treating moyamoya disease: surgical techniques, indications and midterm followup results. Chin Med J (Engl) 125:4398–4405, 2012 30. Yoshida Y, Yoshimoto T, Shirane R, Sakurai Y: Clinical course, surgical management, and long-term outcome of moyamoya patients with rebleeding after an episode of intracerebral hemorrhage: an extensive follow-up study. Stroke 30: 2272–2276, 1999 Manuscript submitted November 2, 2013. Accepted July 9, 2014. Please include this information when citing this paper: published online August 15, 2014; DOI: 10.3171/2014.7.JNS132434. Address correspondence to: Yuxiang Gu, M.D., Ph.D., Department of Neurosurgery, Huashan Hospital, Fudan University, No. 12 Mid Wulumuqi Road, Shanghai 200040, P.R. China. email: [email protected].
1055
