Acta Neurochir DOI 10.1007/s00701-014-2136-3
CLINICAL ARTICLE - VASCULAR
Long-term outcomes in adult patients with ischemic-type moyamoya disease involving posterior circulation Tomohito Hishikawa & Koji Tokunaga & Kenji Sugiu & Isao Date
Received: 14 February 2014 / Accepted: 16 May 2014 # Springer-Verlag Wien 2014
Abstract Background The object of this study was to compare the longterm outcomes in adult patients with moyamoya disease (MMD) with posterior circulation involvement (PCi) treated through surgical revascularization with those in adult patients without PCi. Methods The records of 32 consecutive adult patients with ischemic-type MMD who were treated with revascularization were reviewed. Twelve of these patients (38 %) had PCi at initial onset. Clinical characteristics of the patients with PCi were compared to those without PCi. Neurological outcomes were assessed using the modified Rankin Scale (mRS) in the preoperative and postoperative follow-up periods. A five-year Kaplan-Meier stroke risk was calculated. Results The frequency of presenting with infarction was significantly higher among patients with PCi than among those without PCi (p=0.006). mRS scores in the preoperative period were significantly higher in patients with PCi than in patients without PCi (p=0.0004). There were no significant differences in mRS scores between the preoperative and postoperative follow-up period in patients with PCi (p=0.3), nor were there any between the preoperative and postoperative followup periods in patients without PCi (p=0.2). The five-year Kaplan-Meier risk of surgical morbidity and ipsilateral stroke was 14.3 % in surgically treated hemispheres with PCi versus 14.9 % in surgically treated hemispheres without PCi (p=0.96). Conclusions PCi at initial onset was significantly correlated with poor outcome. Revascularization for the middle cerebral artery territory in patients with PCi was effective at preventing recurrent ischemic stroke. T. Hishikawa (*) : K. Tokunaga : K. Sugiu : I. Date Department of Neurological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan e-mail: [email protected]
Keywords Adult . Moyamoya disease . Outcomes . Posterior cerebral artery . Revascularization surgery
Introduction Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disorder characterized by bilateral stenosis of the internal carotid arteries (ICAs) with compensatory enlargement of the perforating vessels at the base of the brain. It has been reported that there is a significant correlation between the degree of ICA lesions and the existence of steno-occlusive posterior cerebral artery (PCA) lesions in MMD [4, 12, 14]. About one-third of adult MMD patients have posterior circulation involvement (PCi) [4]. PCi in MMD has been reported to be significantly related to the reduction of cerebral blood flow and the occurrence of anterior and posterior circulation infarction [4, 14, 23]. Surgical revascularization is recommended in ischemictype adult patients with MMD because medical treatment alone has been reported to be associated with a high risk of recurrent stroke [2]; however, no previous reports have investigated the long-term outcomes or effectiveness of revascularization surgery in adult patients with ischemic-type MMD with PCi. Therefore, in this study, we reviewed 32 ischemictype MMD patients who underwent revascularization surgery and retrospectively assessed the impact of PCi on revascularization surgery and its outcome.
Patients and methods Patients Between January 1989 and December 2011, following the guidelines of the Research Committee on MMD set forth by
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the Japanese Ministry of Health and Welfare [1], we diagnosed 120 patients with definite MMD at Okayama University Hospital on the basis of the results of cerebral angiograms. Of 120 patients, 32 adult (age> 15 years) patients with ischemic-type MMD were treated with revascularization surgery. This study was approved by the ethics committee of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences. Nine patients were male, and 23 were female, with an age range at the onset of symptoms of 16 to 54 years (median age, 33 years [interquartile range (IQR) 24–38.5 years]). Angiographic evaluation All 32 patients underwent cerebral angiography that included bilateral internal and external carotid arteriography, and bilateral or unilateral vertebral arteriography, using the transfemoral catheterization technique. We checked for the existence of steno-occlusive PCA lesions, observing a total of 64 PCAs. Evaluation of MRI Infarctions were diagnosed on MRI using diffusion-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Infarction location was classified according to our previous report [4]: ACA territory, MCA territory, PCA territory, anterior watershed (AWS, that is, ACA-MCA border zone infarction), posterior watershed (PWS, that is, MCA-PCA border zone infarction), and deep white matter.
combination of direct and indirect bypass techniques consisting of superficial temporal artery (STA)-MCA anastomosis with encephalo-duro-myo-synangiosis (EDMS) or encephalo-myo-synangiosis (EMS) for the symptomatic MCA territory, was the standard procedure in our institute. In three hemispheres belonging to two patients, indirect bypass alone, specifically, encephalo-duro-arterio-myosynangiosis (EDAMS), was performed [6]. A total of 41 surgeries in 41 hemispheres were performed in 32 patients. Five of the 32 patients were treated with the ‘ribbon’ technique for ACA territories with severe hemodynamic compromise together with the revascularization of one side of the MCA territories [7]. Statistical analysis Statistical analysis was performed using Fisher’s exact probability test, the Mann–Whitney U test, and a paired t-test as appropriate. Kaplan-Meier stroke risk was calculated for the incidence of surgical morbidity and any ipsilateral stroke in surgically treated hemispheres with PCi during the follow-up period relative to the incidence of stroke in surgically-treated hemispheres without PCi. Kaplan-Meier stroke risk limited to the incidence of any ipsilateral stroke was also calculated. All statistical analyses were performed using StatView (SAS Institute, Cary, NC, USA). Differences were considered to be significant when p values were less than 0.05.
Neurological evaluation
Results
A neurosurgeon in our institute assessed the neurological status of all patients using the modified Rankin Scale (mRS) [20] in the preoperative period. We classified the clinical manifestations as TIA (n=21) or cerebral infarction (n=11). Surgical morbidity was defined as new neurological deficits lasting 24 h or longer after revascularization surgery and associated with a new infarction or hemorrhage on MR or CT imaging in the first 14 days after the revascularization procedure. After discharge, stroke was defined as any new infarction or hemorrhage on follow-up radiographic imaging regardless of the presence of new neurological deficits. Longterm outcomes were ascertained through biannual or annual in-person follow-up examinations.
A total of 32 ischemic-type adult MMD patients who were treated with revascularization surgery were examined in this study. Twelve (38 %) of these patients had steno-occlusive PCA lesions. Table 1 shows the baseline characteristics of patients in this investigation. In the 12 patients with PCi, two had bilateral PCA lesions, and 10 had unilateral lesions. There were three stenotic and one occlusive lesions in the P2 segment, and six stenotic and four occlusive lesions in the P4 segment. There was no significant difference in age at initial onset between adult patients with and without PCi (p=0.8). There was also no gender difference between patients with and without PCi (p>0.99). The prevalence of presenting with infarction was significantly higher among patients with PCi than among patients without PCi (67 % vs. 15 %, p=0.006). A total of 13 and 8 infarction areas were observed in patients with and without PCi, respectively. The distribution of infarction areas was shown in Table 1. The median follow-up period (months) in patients with and without PCi was 61.5 and 40.5 months, respectively.
Surgical treatment The indications for surgical treatment for patients with MMD in our institute are as follows: patients with ischemic symptoms and patients with decreased hemodynamic reserve as measured in a cerebral blood flow (CBF) study [18]. A
Acta Neurochir Table 1 Summary of demographic and clinical characteristics of 32 patients with MMD No. of patients w. PCi (12 patients) w/o. PCi (20 patients) Age at initial onset * 31 (25.75-38.5) 34.5 (23.25-38.5) Sex (male : female) ** 3:9 6 : 14 Type of clinical presentation TIA Infarction Location of infarctions ACA territory AWS MCA territory PWS PCA territory DWM total Surgery (no. of procedures) STA-MCA bypass with EDMS (EMS) STA-MCA bypass without EDMS (EMS) EDAMS Ribbon technique Surgical morbidity (no. of patients) *** Infarction Hemorrhage Follow-up period, months, mean (range)
4 8
17 3
0 3 1 3 3 3 13
1 1 0 1 0 5 8
12
21
2
3
1 0
2 5
2 0 61.5 (39.5–98.75)
3 1 40.5 (15–58.5)
period were significantly higher in patients with PCi than in patients without PCi (median 1 [IQR 0–2.25] vs 0 [IQR 0–0], p=0.0004). In the postoperative follow-up period, mRS scores were likewise significantly higher in patients with PCi than in patients without PCi (median 1 [IQR 0–2] vs 0 [IQR 0–1], p=0.04). There were no significant differences in mRS scores between the preoperative and postoperative follow-up periods either among patients with PCi (p=0.3) or among patients without PCi (p=0.2). Surgical results
MMD indicates moyamoya disease; PCi, posterior circulation involvement; TIA, transient ischemic attack; AWS, anterior watershed; PWS, posterior watershed; DWM, deep white matter; STA, superficial temporal artery; MCA, middle cerebral artery; EDMS, encephalo-duro-myosynangiosis; EMS, encephalo-myo-synangiosis; EDAMS, encephalo-duro-arterio-myo-synangiosis * indicates no statistical significance of age at initial onset between the cases with and without PCi (p=0.80) according to the Mann–Whitney Utest ** indicates no statistical significance of sex distribution between the cases with and without PCi (p>0.99) according to Fisher’s exact probability test *** indicates no statistical significance of prevalence of surgical morbidity between the cases with and without PCi (p>0.99) according to the paired t-test Age and follow-up period values represent medians (interquartile range); other values represent raw numbers
Clinical outcome Figure 1 shows the distribution of patients and their modified Rankin Scale (mRS) scores in the preoperative and postoperative follow-up periods. mRS scores in the preoperative
Of the 12 patients with PCi, two experienced infarctions in the first 14 days after surgery (Table 1). Of the 20 patients without PCi, infarctions occurred in three patients and hemorrhage in one (Table 1). There was no significant difference in the prevalence of surgical morbidities between patients with and without PCi (17 % vs 20 %, p>0.99). The five-year KaplanMeier risk of surgical morbidity and ipsilateral stroke was 14.3 % in the 14 surgically treated hemispheres with PCi versus 14.9 % in the 27 surgically treated hemispheres without PCi (p=0.96, Fig. 2). According to the five-year KaplanMeier risk analysis limited to the incidence of any ipsilateral stroke, the risk was 0 % in the 14 surgically treated hemispheres with PCi versus 3.7 % in the 27 surgically treated hemispheres without PCi (Fig. 3). Most of postoperative events were attributable to surgical morbidities in patients both with and without PCi, and only one patient suffered asymptomatic infarction in the hemisphere without PCi six months after the surgery. Illustrative case A 40-year-old woman experienced motor aphasia and weakness of the right upper and lower limbs when she was 25 years of age. She had been diagnosed as MMD and followed up in another clinic. She experienced a TIA of motor aphasia six months before visiting our clinic. An MRI showed a left frontal lobe infarction (Fig. 4a). Cerebral angiography revealed occlusion of the terminal portion of the left ICA and the development of moyamoya vessels (Fig. 4b). There was severe stenosis in the P4 segment of the left PCA (Fig. 4c). She underwent left STA-MCA anastomosis without indirect bypass. Cerebral angiography three months after the surgery demonstrated a good collateral flow through the STA-MCA bypass (Fig. 4d). Preoperative single-photon emission computed tomography (SPECT) findings at rest showed the perfusion in the left MCA territory was decreased (Fig. 4e). There was a remarkable improvement in the perfusion in the left MCA territory according to the SPECT study three days after surgery (Fig. 4f). She did not have any further stroke during the follow-up period of 38 months.
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Fig. 1 Bar graph showing modified rankin scale (mRS) distribution in the preoperative and postoperative follow-up periods. mRS scores in the preoperative period were significantly higher in patients with PCi than in patients without PCi (median 1 [IQR 0–2.25] vs 0 [IQR 0–0], p=0.0004, Mann–Whitney U-test). In the postoperative follow-up period, likewise, mRS scores were significantly higher in patients with PCi than in patients
without PCi (median 1 [IQR 0–2] vs 0 [IQR 0–1], p=0.04, Mann– Whitney U-test). There were no significant differences between the preoperative and postoperative follow-up periods in patients with PCi (p=0.3, paired t-test) or in patients without PCi (p=0.2, paired t-test). The broken horizontal line indicates the 50th percentile of patients
Discussion
relation between PCi and clinical outcomes in adult patients with MMD. Our data showed that the patients with PCi at initial onset had significantly worse outcomes compared with those without PCi. According to Suzuki’s grading system, PCi was involved in Stage 4 [22]. It has been reported that there was a significant positive correlation between Suzuki’s grade and the number of infarctions [14]. This is probably because there are significant interactions between ICAs and PCAs, and a decrease in the leptomeningeal collaterals from the PCA to the anterior circulation could cause severe cerebral ischemia [4, 14]. Given the significant correlation between PCi and cerebral infarction in this study, neurological deficit due to cerebral infarction is supposed to be a leading cause of the poor outcomes in patients with PCi. Only the progression of steno-occlusive ICA lesions does not affect the CBF, because PCAs can compensate in order to maintain the CBF [24]. Once steno-occlusive PCA lesions appear along with the progression of ICA lesions, the CBF of the total hemisphere ipsilateral to the PCA lesions is significantly reduced [24]. Especially, the medial frontal lobe is usually supplied by PCA as a collateral pathway in MMD. It has been reported that long-standing hemodynamic ischemia in the medial frontal lobe could lead to cognitive dysfunction in adult patients with MMD [17]. Cognitive dysfunction due to the medial frontal lobe ischemia may be related to the higher mRS scores in patients with PCi. Taking the significant correlation between PCi at initial onset and poor outcomes into consideration, it is thought to be important to detect PCi before the symptoms occur in the
Impact of PCi on clinical outcomes in adult patients with MMD The prevalence of PCi in MMD was reported to be 27 % in pediatric cases and 33 % in adult cases [4]. PCi is thus relatively common in MMD, yet its pathophysiology is assessed mainly from a radiological point of view [3, 4, 9, 12, 14–16, 23, 24]. This paper is the first to evaluate the
Fig. 2 Kaplan-Meier survival curve showing cumulative event-free rate. The five-year Kaplan-Meier risk of surgical morbidity and any ipsilateral stroke was 14.3 % in the 14 surgically treated hemispheres with PCi versus 14.9 % in the 27 surgically treated hemispheres without PCi (p= 0.96)
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Preventive effect of revascularization surgery on recurrent stroke
Fig. 3 Kaplan-Meier survival curve showing cumulative event-free rate. The five-year Kaplan-Meier risk limited to any ipsilateral stroke was 0 % in the 14 surgically treated hemispheres with PCi versus 3.7 % in the 27 surgically treated hemispheres without PCi
clinical setting. Recently, the opportunity to identify asymptomatic patients with MMD has increased due to advancements in noninvasive diagnostic modalities such as MR examination [8]. Serial follow-up using MR examination is needed to achieve the early identification of PCi in asymptomatic patients with MMD. Moreover, it has been reported that RNF213 is a susceptibility gene [10] and that one of the variants of the RNF213 gene could be a good biomarker for predicting PCi [13]. This genetic screening method could help assess the risk of developing PCi for asymptomatic patients with MMD.
Fig. 4 An illustrative case with PCi. An MRI revealed a left frontal lobe infarction (A). Left common carotid angiography (B) showed occlusion of the terminal portion of the left ICA (black arrow) and development of moyamoya vessels, and right vertebral angiography (C) demonstrated severe stenosis in the P4 segment of the left PCA (black arrow). A good collateral flow through the bypass graft (open circle) was observed on left internal carotid angiography after the surgery (D). Preoperative SPECT at rest showed decreased perfusion in the left MCA territory (E). A SPECT at rest performed three days after surgery revealed the remarkable improvement in the perfusion in the left MCA territory (F)
Revascularization surgery has been reported to be an effective means of preventing recurrent ischemic events in ischemictype adult patients with MMD [2, 21]. Our investigation distinguished the MMD patients with PCi from those without PCi and revealed that the revascularization surgeries for the MCA territory maintained the mRS scores equally well in patients with and without PCi. Hallemeier et al. revealed that the five-year risk of recurrent ipsilateral stroke was 65 % in medically treated symptomatic hemispheres [2]. The Kaplan– Meier analysis in this study demonstrated that the five-year risk of recurrent ipsilateral stroke was very low in patients both with and without PCi if surgical morbidity could be avoided. This indicates that the preventive effect of the revascularization surgery on recurrent stroke is remarkably high in patients both with and without PCi. Our investigation demonstrated that only 2 (6 %) of 32 patients with and without PCi and 2 (17 %) of 12 patients with PCi had PCA territory infarction at initial presentation. There was no posterior circulation revascularization as first-line or additional treatment in this study. Miyamoto et al. [12] reported that revascularization in the MCA territory as a standard surgical procedure for MMD indirectly improved CBF in the PCA distribution by decreasing the vascular steal of the collateral vessels supplying the anterior circulation. They considered this phenomenon to be an indirect redistribution effect of revascularization in the MCA territory on the posterior circulation. The revascularization surgery in the MCA territory in patients with PCi
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could have a preventive effect not only on anterior circulation but also on posterior circulation through this mechanism. As surgical morbidity in patients with PCi was similar to that in patients without PCi and the prevalence of PCA territory infarction was low at initial presentation in this cohort, revascularization in the MCA territory should be employed as a first-line treatment for patients with PCi. On the other hand, the fact remains that some MMD patients are refractory to revascularization surgery for the MCA territory [5, 11, 19]. Almost every case in previous reports has been reported to need a second operation for the MCA territory after indirect revascularization surgery for the MCA territory. The mechanism of this refractory response is poorly understood, and its relation to PCi in MMD is unclear. These findings underline the importance of periodic and careful observation in patients with MMD who undergo revascularization surgery. Study limitations There are certain limitations to this study that should be noted. First, this study had a retrospective nature and limited sample size, and incorporated data from only one institute. Second, we employed mRS score as an index of clinical outcomes in MMD patients. Starke et al. [21] pointed out that mRS score does not measure higher cortical function and emphasized the importance of neuropsychological testing in patients with MMD. Third, this study demonstrates the preventive effect of revascularization surgery against recurrent stroke in adult MMD patients with and without PCi, but the effect of revascularization surgery on asymptomatic MMD patients is unknown. In the future, a prospective study is warranted to evaluate the effect of revascularization surgery on asymptomatic MMD patients with PCi who are at risk of becoming symptomatic.
Conclusions PCi at initial onset had an adverse impact on clinical outcomes in adult MMD patients. Revascularization surgery in the MCA territory in patients with PCi was effective at preserving the preoperative clinical outcome and preventing recurrent ischemic stroke. It will be an important issue to identify PCi in asymptomatic patients with MMD in order to prevent the patients from suffering severe ischemic damage.
Conflicts of interest None.
References 1. Fukui M (1997) Guidelines for the diagnosis and treatment of spontaneous occlusion of the circle of Willis (‘moyamoya’ disease). Clin Neurol Neurosurg 99:S238–S240 2. Hallemeier CL, Rich KM, Grubb RL, Chicoine MR, Moran CJ, Cross DW III, Zipfel GJ, Dacey RJ, Derdeyn CP Jr (2006) Clinical features and outcome in North American adults with moyamoya phenomenon. Stroke 37:1490–1496 3. Hishikawa T, Tokunaga K, Sugiu K, Date I (2013) Clinical and radiographic features of moyamoya disease in patients with both cerebral ischaemia and haemorhage. Br J Neurosurg 27:198–201 4. Hishikawa T, Tokunaga K, Sugiu K, Date I (2013) Assessment of the difference in posterior circulation involvement between pediatric and adult patients with moyamoya disease. J Neurosurg 119:961–965 5. Horiuchi T, Kusano Y, Asanuma M, Hongo K (2012) Posterior auricular artery–middle cerebral artery bypass for additional surgery of moyamoya disease. Acta Neurochir 154:455–456 6. Kinugasa K, Mandai S, Kamata I, Sugiu K, Ohmoto T (1993) Surgical treatment of moyamoya disease: Operative technique for encephalo-duro-arterio-myo-synangiosis, its follow-up, clinical results, and angiograms. Neurosurgery 32:527–531 7. Kinugasa K, Mandai S, Tokunaga K, Kamata I, Sugiu K, Handa A, Ohmoto T (1994) Ribbon encephalo-duro-arterio-myo-synangiosis for moyamoya disease. Surg Neurol 41:455–461 8. Kuroda S, Hashimoto N, Yoshimoto T, Iwasaki Y (2007) Research committee on moyamoya disease in Japan: Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 38:1430–1435 9. Lee JY, Kim SK, Cheon JE, Choi JW, Phi JH, Kim IO, Cho BK, Wang KC (2013) Posterior cerebral artery involvement in moyamoya disease: initial infarction and angle between PCA and basilar artery. Child’s Nerv Syst 29:2263–2269 10. Liu W, Morito D, Takashima S, Mineharu Y, Kobayashi H, Hitomi T, Hashikata H, Matsuura N, Yamazaki S, Toyoda A, Kikuta K, Takagi Y, Harada KH, Fujiyama A, Herzig R, Krischek B, Zou L, Kim JE, Kitakaze M, Miyamoto S, Nagata K, Hashimoto N, Koizumi A (2011) Identification of RNF213 as a susceptibility gene for moyamoya disease and its possible role in vascular development. PLoS One 6:e22542 11. Miyamoto S, Kikuchi H, Kawasawa J, Nagata I, Yamazoe N, Akiyama Y (1988) Pitfalls in the surgical treatment of moyamoya disease. Operative techniques for refractory cases. J Neurosurg 68:537–543 12. Miyamoto S, Kikuchi H, Karasawa J, Nagata I, Ikota T, Takeuchi S (1984) Study of the posterior circulation in moyamoya disease. Clinical and neuroradiological evaluation. J Neurosurg 61:1032–1037 13. Miyatake S, Miyake N, Touho H, Nishimura-Tadaki A, Kondo Y, Okada I, Tsurusaki Y, Doi H, Sasaki H, Saitsu H, Shimojima K, Yamamoto T, Higurashi M, Kawahara N, Kawauchi H, Nagasaka K, Okamoto N, Mori T, Koyano S, Kuroiwa Y, Taguri M, Morita S, Matsubara Y, Kure S, Matsumoto N (2012) Homozygous c. 14576G>A variant of RNF213 predicts early-onset and severe form of moyamoya disease. Neurology 78:803–810 14. Mugikura S, Takahashi S, Higano S, Shirane R, Kurihara N, Furuta S, Ezura M, Takahashi A (1999) The relationship between cerebral infarction and angiographic characteristics in childhood moyamoya disease. Am J Neuroradiol 20:336–343 15. Mugikura S, Takahashi S, Higano S, Shirane R, Sakurai Y, Yamada S (2002) Predominant involvement of ipsilateral anterior and posterior circulations in moyamoya disease. Stroke 33:1497–1500 16. Mugikura S, Higano S, Shirane R, Fujimura M, Shimanuki Y, Takahashi S (2011) Posterior circulation and high prevalence of ischemic stroke among young pediatric patients with moyamoya disease: Evidence of angiography-based differences by age at diagnosis. Am J Neuroradiol 32:192–198
Acta Neurochir 17. Nakagawara J, Osato T, Kamiyama K, Honjo K, Sugio H, Fumoto K, Murahashi T, Takada H, Watanabe T, Nakamura H (2012) Diagnostic imaging of higher brain dysfunction in patients with adult moyamoya disease using statistical imaging analysis for [123I] Iomazenil single photon emission computed tomography. Neurol Med Chir (Tokyo) 52:318–326 18. Nakashima H, Meguro T, Kawada S, Hirotsune N, Ohmoto T (1997) Long-term results of surgically treated moyamoya disease. Clin Neurol Neurosurg 99:S156–S161 19. Pandey P, Steinberg GK (2011) Outcome of repeat revascularization surgery for moyamoya disease after an unsuccessful indirect revascularization. J Neurosurg 115:328–336 20. Rankin J (1957) Cerebral vascular accidents in patients over the age of 60. III. Diagnosis and treatment. Scott Med J 2:254–268
21. Starke RM, Komotar RJ, Hickman ZL, Paz YE, Pugliese AG, Otten ML, Garrett MC, Elkind MSV, Marshall RS, Festa JR, Meyers PM, Connolly ES Jr (2009) Clinical features, surgical treatment, and longterm outcome in adult patients with moyamoya disease. J Neurosurg 111:936–942 22. Suzuki J, Takaku A (1969) Cerebrovascular “moyamoya” disease. Disease showing abnormal net-like vessels in the base of brain. Arch Neurol 20:288–299 23. Yamada I, Himeno Y, Suzuki S, Matsushima Y (1995) Posterior circulation in moyamoya disease: angiography study. Radiology 197:239–246 24. Yamada I, Murata Y, Umehara I, Suzuki S, Matsushima Y (1996) SPECT and MRI evaluations of the posterior circulation in moyamoya disease. J Nucl Med 37:1613–1617
CLINICAL ARTICLE - VASCULAR
Long-term outcomes in adult patients with ischemic-type moyamoya disease involving posterior circulation Tomohito Hishikawa & Koji Tokunaga & Kenji Sugiu & Isao Date
Received: 14 February 2014 / Accepted: 16 May 2014 # Springer-Verlag Wien 2014
Abstract Background The object of this study was to compare the longterm outcomes in adult patients with moyamoya disease (MMD) with posterior circulation involvement (PCi) treated through surgical revascularization with those in adult patients without PCi. Methods The records of 32 consecutive adult patients with ischemic-type MMD who were treated with revascularization were reviewed. Twelve of these patients (38 %) had PCi at initial onset. Clinical characteristics of the patients with PCi were compared to those without PCi. Neurological outcomes were assessed using the modified Rankin Scale (mRS) in the preoperative and postoperative follow-up periods. A five-year Kaplan-Meier stroke risk was calculated. Results The frequency of presenting with infarction was significantly higher among patients with PCi than among those without PCi (p=0.006). mRS scores in the preoperative period were significantly higher in patients with PCi than in patients without PCi (p=0.0004). There were no significant differences in mRS scores between the preoperative and postoperative follow-up period in patients with PCi (p=0.3), nor were there any between the preoperative and postoperative followup periods in patients without PCi (p=0.2). The five-year Kaplan-Meier risk of surgical morbidity and ipsilateral stroke was 14.3 % in surgically treated hemispheres with PCi versus 14.9 % in surgically treated hemispheres without PCi (p=0.96). Conclusions PCi at initial onset was significantly correlated with poor outcome. Revascularization for the middle cerebral artery territory in patients with PCi was effective at preventing recurrent ischemic stroke. T. Hishikawa (*) : K. Tokunaga : K. Sugiu : I. Date Department of Neurological Surgery, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558, Japan e-mail: [email protected]
Keywords Adult . Moyamoya disease . Outcomes . Posterior cerebral artery . Revascularization surgery
Introduction Moyamoya disease (MMD) is a chronic occlusive cerebrovascular disorder characterized by bilateral stenosis of the internal carotid arteries (ICAs) with compensatory enlargement of the perforating vessels at the base of the brain. It has been reported that there is a significant correlation between the degree of ICA lesions and the existence of steno-occlusive posterior cerebral artery (PCA) lesions in MMD [4, 12, 14]. About one-third of adult MMD patients have posterior circulation involvement (PCi) [4]. PCi in MMD has been reported to be significantly related to the reduction of cerebral blood flow and the occurrence of anterior and posterior circulation infarction [4, 14, 23]. Surgical revascularization is recommended in ischemictype adult patients with MMD because medical treatment alone has been reported to be associated with a high risk of recurrent stroke [2]; however, no previous reports have investigated the long-term outcomes or effectiveness of revascularization surgery in adult patients with ischemic-type MMD with PCi. Therefore, in this study, we reviewed 32 ischemictype MMD patients who underwent revascularization surgery and retrospectively assessed the impact of PCi on revascularization surgery and its outcome.
Patients and methods Patients Between January 1989 and December 2011, following the guidelines of the Research Committee on MMD set forth by
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the Japanese Ministry of Health and Welfare [1], we diagnosed 120 patients with definite MMD at Okayama University Hospital on the basis of the results of cerebral angiograms. Of 120 patients, 32 adult (age> 15 years) patients with ischemic-type MMD were treated with revascularization surgery. This study was approved by the ethics committee of the Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences. Nine patients were male, and 23 were female, with an age range at the onset of symptoms of 16 to 54 years (median age, 33 years [interquartile range (IQR) 24–38.5 years]). Angiographic evaluation All 32 patients underwent cerebral angiography that included bilateral internal and external carotid arteriography, and bilateral or unilateral vertebral arteriography, using the transfemoral catheterization technique. We checked for the existence of steno-occlusive PCA lesions, observing a total of 64 PCAs. Evaluation of MRI Infarctions were diagnosed on MRI using diffusion-weighted, T2-weighted, and fluid-attenuated inversion recovery images. Infarction location was classified according to our previous report [4]: ACA territory, MCA territory, PCA territory, anterior watershed (AWS, that is, ACA-MCA border zone infarction), posterior watershed (PWS, that is, MCA-PCA border zone infarction), and deep white matter.
combination of direct and indirect bypass techniques consisting of superficial temporal artery (STA)-MCA anastomosis with encephalo-duro-myo-synangiosis (EDMS) or encephalo-myo-synangiosis (EMS) for the symptomatic MCA territory, was the standard procedure in our institute. In three hemispheres belonging to two patients, indirect bypass alone, specifically, encephalo-duro-arterio-myosynangiosis (EDAMS), was performed [6]. A total of 41 surgeries in 41 hemispheres were performed in 32 patients. Five of the 32 patients were treated with the ‘ribbon’ technique for ACA territories with severe hemodynamic compromise together with the revascularization of one side of the MCA territories [7]. Statistical analysis Statistical analysis was performed using Fisher’s exact probability test, the Mann–Whitney U test, and a paired t-test as appropriate. Kaplan-Meier stroke risk was calculated for the incidence of surgical morbidity and any ipsilateral stroke in surgically treated hemispheres with PCi during the follow-up period relative to the incidence of stroke in surgically-treated hemispheres without PCi. Kaplan-Meier stroke risk limited to the incidence of any ipsilateral stroke was also calculated. All statistical analyses were performed using StatView (SAS Institute, Cary, NC, USA). Differences were considered to be significant when p values were less than 0.05.
Neurological evaluation
Results
A neurosurgeon in our institute assessed the neurological status of all patients using the modified Rankin Scale (mRS) [20] in the preoperative period. We classified the clinical manifestations as TIA (n=21) or cerebral infarction (n=11). Surgical morbidity was defined as new neurological deficits lasting 24 h or longer after revascularization surgery and associated with a new infarction or hemorrhage on MR or CT imaging in the first 14 days after the revascularization procedure. After discharge, stroke was defined as any new infarction or hemorrhage on follow-up radiographic imaging regardless of the presence of new neurological deficits. Longterm outcomes were ascertained through biannual or annual in-person follow-up examinations.
A total of 32 ischemic-type adult MMD patients who were treated with revascularization surgery were examined in this study. Twelve (38 %) of these patients had steno-occlusive PCA lesions. Table 1 shows the baseline characteristics of patients in this investigation. In the 12 patients with PCi, two had bilateral PCA lesions, and 10 had unilateral lesions. There were three stenotic and one occlusive lesions in the P2 segment, and six stenotic and four occlusive lesions in the P4 segment. There was no significant difference in age at initial onset between adult patients with and without PCi (p=0.8). There was also no gender difference between patients with and without PCi (p>0.99). The prevalence of presenting with infarction was significantly higher among patients with PCi than among patients without PCi (67 % vs. 15 %, p=0.006). A total of 13 and 8 infarction areas were observed in patients with and without PCi, respectively. The distribution of infarction areas was shown in Table 1. The median follow-up period (months) in patients with and without PCi was 61.5 and 40.5 months, respectively.
Surgical treatment The indications for surgical treatment for patients with MMD in our institute are as follows: patients with ischemic symptoms and patients with decreased hemodynamic reserve as measured in a cerebral blood flow (CBF) study [18]. A
Acta Neurochir Table 1 Summary of demographic and clinical characteristics of 32 patients with MMD No. of patients w. PCi (12 patients) w/o. PCi (20 patients) Age at initial onset * 31 (25.75-38.5) 34.5 (23.25-38.5) Sex (male : female) ** 3:9 6 : 14 Type of clinical presentation TIA Infarction Location of infarctions ACA territory AWS MCA territory PWS PCA territory DWM total Surgery (no. of procedures) STA-MCA bypass with EDMS (EMS) STA-MCA bypass without EDMS (EMS) EDAMS Ribbon technique Surgical morbidity (no. of patients) *** Infarction Hemorrhage Follow-up period, months, mean (range)
4 8
17 3
0 3 1 3 3 3 13
1 1 0 1 0 5 8
12
21
2
3
1 0
2 5
2 0 61.5 (39.5–98.75)
3 1 40.5 (15–58.5)
period were significantly higher in patients with PCi than in patients without PCi (median 1 [IQR 0–2.25] vs 0 [IQR 0–0], p=0.0004). In the postoperative follow-up period, mRS scores were likewise significantly higher in patients with PCi than in patients without PCi (median 1 [IQR 0–2] vs 0 [IQR 0–1], p=0.04). There were no significant differences in mRS scores between the preoperative and postoperative follow-up periods either among patients with PCi (p=0.3) or among patients without PCi (p=0.2). Surgical results
MMD indicates moyamoya disease; PCi, posterior circulation involvement; TIA, transient ischemic attack; AWS, anterior watershed; PWS, posterior watershed; DWM, deep white matter; STA, superficial temporal artery; MCA, middle cerebral artery; EDMS, encephalo-duro-myosynangiosis; EMS, encephalo-myo-synangiosis; EDAMS, encephalo-duro-arterio-myo-synangiosis * indicates no statistical significance of age at initial onset between the cases with and without PCi (p=0.80) according to the Mann–Whitney Utest ** indicates no statistical significance of sex distribution between the cases with and without PCi (p>0.99) according to Fisher’s exact probability test *** indicates no statistical significance of prevalence of surgical morbidity between the cases with and without PCi (p>0.99) according to the paired t-test Age and follow-up period values represent medians (interquartile range); other values represent raw numbers
Clinical outcome Figure 1 shows the distribution of patients and their modified Rankin Scale (mRS) scores in the preoperative and postoperative follow-up periods. mRS scores in the preoperative
Of the 12 patients with PCi, two experienced infarctions in the first 14 days after surgery (Table 1). Of the 20 patients without PCi, infarctions occurred in three patients and hemorrhage in one (Table 1). There was no significant difference in the prevalence of surgical morbidities between patients with and without PCi (17 % vs 20 %, p>0.99). The five-year KaplanMeier risk of surgical morbidity and ipsilateral stroke was 14.3 % in the 14 surgically treated hemispheres with PCi versus 14.9 % in the 27 surgically treated hemispheres without PCi (p=0.96, Fig. 2). According to the five-year KaplanMeier risk analysis limited to the incidence of any ipsilateral stroke, the risk was 0 % in the 14 surgically treated hemispheres with PCi versus 3.7 % in the 27 surgically treated hemispheres without PCi (Fig. 3). Most of postoperative events were attributable to surgical morbidities in patients both with and without PCi, and only one patient suffered asymptomatic infarction in the hemisphere without PCi six months after the surgery. Illustrative case A 40-year-old woman experienced motor aphasia and weakness of the right upper and lower limbs when she was 25 years of age. She had been diagnosed as MMD and followed up in another clinic. She experienced a TIA of motor aphasia six months before visiting our clinic. An MRI showed a left frontal lobe infarction (Fig. 4a). Cerebral angiography revealed occlusion of the terminal portion of the left ICA and the development of moyamoya vessels (Fig. 4b). There was severe stenosis in the P4 segment of the left PCA (Fig. 4c). She underwent left STA-MCA anastomosis without indirect bypass. Cerebral angiography three months after the surgery demonstrated a good collateral flow through the STA-MCA bypass (Fig. 4d). Preoperative single-photon emission computed tomography (SPECT) findings at rest showed the perfusion in the left MCA territory was decreased (Fig. 4e). There was a remarkable improvement in the perfusion in the left MCA territory according to the SPECT study three days after surgery (Fig. 4f). She did not have any further stroke during the follow-up period of 38 months.
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Fig. 1 Bar graph showing modified rankin scale (mRS) distribution in the preoperative and postoperative follow-up periods. mRS scores in the preoperative period were significantly higher in patients with PCi than in patients without PCi (median 1 [IQR 0–2.25] vs 0 [IQR 0–0], p=0.0004, Mann–Whitney U-test). In the postoperative follow-up period, likewise, mRS scores were significantly higher in patients with PCi than in patients
without PCi (median 1 [IQR 0–2] vs 0 [IQR 0–1], p=0.04, Mann– Whitney U-test). There were no significant differences between the preoperative and postoperative follow-up periods in patients with PCi (p=0.3, paired t-test) or in patients without PCi (p=0.2, paired t-test). The broken horizontal line indicates the 50th percentile of patients
Discussion
relation between PCi and clinical outcomes in adult patients with MMD. Our data showed that the patients with PCi at initial onset had significantly worse outcomes compared with those without PCi. According to Suzuki’s grading system, PCi was involved in Stage 4 [22]. It has been reported that there was a significant positive correlation between Suzuki’s grade and the number of infarctions [14]. This is probably because there are significant interactions between ICAs and PCAs, and a decrease in the leptomeningeal collaterals from the PCA to the anterior circulation could cause severe cerebral ischemia [4, 14]. Given the significant correlation between PCi and cerebral infarction in this study, neurological deficit due to cerebral infarction is supposed to be a leading cause of the poor outcomes in patients with PCi. Only the progression of steno-occlusive ICA lesions does not affect the CBF, because PCAs can compensate in order to maintain the CBF [24]. Once steno-occlusive PCA lesions appear along with the progression of ICA lesions, the CBF of the total hemisphere ipsilateral to the PCA lesions is significantly reduced [24]. Especially, the medial frontal lobe is usually supplied by PCA as a collateral pathway in MMD. It has been reported that long-standing hemodynamic ischemia in the medial frontal lobe could lead to cognitive dysfunction in adult patients with MMD [17]. Cognitive dysfunction due to the medial frontal lobe ischemia may be related to the higher mRS scores in patients with PCi. Taking the significant correlation between PCi at initial onset and poor outcomes into consideration, it is thought to be important to detect PCi before the symptoms occur in the
Impact of PCi on clinical outcomes in adult patients with MMD The prevalence of PCi in MMD was reported to be 27 % in pediatric cases and 33 % in adult cases [4]. PCi is thus relatively common in MMD, yet its pathophysiology is assessed mainly from a radiological point of view [3, 4, 9, 12, 14–16, 23, 24]. This paper is the first to evaluate the
Fig. 2 Kaplan-Meier survival curve showing cumulative event-free rate. The five-year Kaplan-Meier risk of surgical morbidity and any ipsilateral stroke was 14.3 % in the 14 surgically treated hemispheres with PCi versus 14.9 % in the 27 surgically treated hemispheres without PCi (p= 0.96)
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Preventive effect of revascularization surgery on recurrent stroke
Fig. 3 Kaplan-Meier survival curve showing cumulative event-free rate. The five-year Kaplan-Meier risk limited to any ipsilateral stroke was 0 % in the 14 surgically treated hemispheres with PCi versus 3.7 % in the 27 surgically treated hemispheres without PCi
clinical setting. Recently, the opportunity to identify asymptomatic patients with MMD has increased due to advancements in noninvasive diagnostic modalities such as MR examination [8]. Serial follow-up using MR examination is needed to achieve the early identification of PCi in asymptomatic patients with MMD. Moreover, it has been reported that RNF213 is a susceptibility gene [10] and that one of the variants of the RNF213 gene could be a good biomarker for predicting PCi [13]. This genetic screening method could help assess the risk of developing PCi for asymptomatic patients with MMD.
Fig. 4 An illustrative case with PCi. An MRI revealed a left frontal lobe infarction (A). Left common carotid angiography (B) showed occlusion of the terminal portion of the left ICA (black arrow) and development of moyamoya vessels, and right vertebral angiography (C) demonstrated severe stenosis in the P4 segment of the left PCA (black arrow). A good collateral flow through the bypass graft (open circle) was observed on left internal carotid angiography after the surgery (D). Preoperative SPECT at rest showed decreased perfusion in the left MCA territory (E). A SPECT at rest performed three days after surgery revealed the remarkable improvement in the perfusion in the left MCA territory (F)
Revascularization surgery has been reported to be an effective means of preventing recurrent ischemic events in ischemictype adult patients with MMD [2, 21]. Our investigation distinguished the MMD patients with PCi from those without PCi and revealed that the revascularization surgeries for the MCA territory maintained the mRS scores equally well in patients with and without PCi. Hallemeier et al. revealed that the five-year risk of recurrent ipsilateral stroke was 65 % in medically treated symptomatic hemispheres [2]. The Kaplan– Meier analysis in this study demonstrated that the five-year risk of recurrent ipsilateral stroke was very low in patients both with and without PCi if surgical morbidity could be avoided. This indicates that the preventive effect of the revascularization surgery on recurrent stroke is remarkably high in patients both with and without PCi. Our investigation demonstrated that only 2 (6 %) of 32 patients with and without PCi and 2 (17 %) of 12 patients with PCi had PCA territory infarction at initial presentation. There was no posterior circulation revascularization as first-line or additional treatment in this study. Miyamoto et al. [12] reported that revascularization in the MCA territory as a standard surgical procedure for MMD indirectly improved CBF in the PCA distribution by decreasing the vascular steal of the collateral vessels supplying the anterior circulation. They considered this phenomenon to be an indirect redistribution effect of revascularization in the MCA territory on the posterior circulation. The revascularization surgery in the MCA territory in patients with PCi
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could have a preventive effect not only on anterior circulation but also on posterior circulation through this mechanism. As surgical morbidity in patients with PCi was similar to that in patients without PCi and the prevalence of PCA territory infarction was low at initial presentation in this cohort, revascularization in the MCA territory should be employed as a first-line treatment for patients with PCi. On the other hand, the fact remains that some MMD patients are refractory to revascularization surgery for the MCA territory [5, 11, 19]. Almost every case in previous reports has been reported to need a second operation for the MCA territory after indirect revascularization surgery for the MCA territory. The mechanism of this refractory response is poorly understood, and its relation to PCi in MMD is unclear. These findings underline the importance of periodic and careful observation in patients with MMD who undergo revascularization surgery. Study limitations There are certain limitations to this study that should be noted. First, this study had a retrospective nature and limited sample size, and incorporated data from only one institute. Second, we employed mRS score as an index of clinical outcomes in MMD patients. Starke et al. [21] pointed out that mRS score does not measure higher cortical function and emphasized the importance of neuropsychological testing in patients with MMD. Third, this study demonstrates the preventive effect of revascularization surgery against recurrent stroke in adult MMD patients with and without PCi, but the effect of revascularization surgery on asymptomatic MMD patients is unknown. In the future, a prospective study is warranted to evaluate the effect of revascularization surgery on asymptomatic MMD patients with PCi who are at risk of becoming symptomatic.
Conclusions PCi at initial onset had an adverse impact on clinical outcomes in adult MMD patients. Revascularization surgery in the MCA territory in patients with PCi was effective at preserving the preoperative clinical outcome and preventing recurrent ischemic stroke. It will be an important issue to identify PCi in asymptomatic patients with MMD in order to prevent the patients from suffering severe ischemic damage.
Conflicts of interest None.
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