Original Paper Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
Received: December 3, 2012 Accepted: October 14, 2013 Published online: January 16, 2014
Clinical Course of Asymptomatic Adult Moyamoya Disease Kyung-Il Jo Je Young Yeon Seung-Chyul Hong Jong-Soo Kim Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Abstract Background: As regular medical check-ups are becoming more common, the prevalence of asymptomatic moyamoya disease (MMD) is increasing. However, the definition and clinical features are still unclear. The lack of precision has hampered the establishment of guidelines for the management of asymptomatic MMD. The purpose of this study was to define and clarify the clinical characteristics of asymptomatic MMD in adults. Methods: We identified all adults (aged ≥18 years) with MMD who underwent digital subtraction angiography or magnetic resonance angiography at our institution from 1995 through 2010. The authors defined asymptomatic MMD as asymptomatic or nonspecific symptom without any infarction or ischemia on magnetic resonance imaging. In our MMD registry, 40 patients (74 hemispheres) were identified and enrolled in this retrospective cohort study. Their demographic, radiological and clinical findings were evaluated. The log-rank test was used to assess prognostic factors. Pearson’s correlation test and the Mann-Whitney U test were used to identify correlation angiographic staging and age or perfusion status. Results: Overall, 6 patients underwent indirect bypass surgery and 36 received antiplatelet medication. On initial single positron emission
© 2014 S. Karger AG, Basel 1015–9770/14/0372–0094$39.50/0 E-Mail [email protected] www.karger.com/ced
tomography (35 patients, 67 affected hemispheres), basal and acetazolamide stress brain perfusion were decreased in 19 (28.4%) and 22 (32.8%) hemispheres, respectively. Among 70 angiographically evaluated hemispheres, 6 were unilateral MMD; 27 of 64 affected hemispheres (42.2%) had transdural collateral at evaluation. Age (p = 0.309, Pearson’s correlation test) and hemodynamic impairment (p = 0.614, Mann-Whitney U test) did not correlate with angiographic staging. During a median 32-month (range 6–203) clinical follow-up, 3 nonsurgically treated patients had a transient ischemic attack, which was associated with decreased vascular reserve (p < 0.001, log-rank test) and smoking (p = 0.017). Other variables did not show a significant association with clinical progression. During a median 24-month (range 12–108) radiological follow-up, 3 patients displayed angiographic progression and 3 displayed new hemodynamic abnormalities. Radiological progressions were related to hypertension only (p = 0.022). In this case series, there was no case of ischemic or hemorrhagic stroke. Conclusion: The findings suggest that asymptomatic MMD in adults is not a stable disease in our definition. However, stroke rate (0%) was lower than previous reports. Lifestyle modification, stroke risk factor control and/or antiplatelet medication seem to be appropriate initial treatments for patients with normal cerebrovascular reserve. A clear definition of asymptomatic MMD and further clarification of its clinical course are needed to set precise treatment guidelines. © 2014 S. Karger AG, Basel
Jong-Soo Kim, MD, PhD Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine 50 lrwon-dong, Gangnam-gu, Seoul 135-710 (Korea) E-Mail smcnsjs.kim @ gmail.com
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
Key Words Asymptomatic disease · Moyamoya disease · Clinical course · Treatment
Moyamoya disease (MMD) is characterized by progressive stenosis of the terminal portion of the bilateral internal carotid arteries and is associated with an extensive network of cerebral collaterals [1]. Disease progression is not uncommon in adult MMD if untreated [2]. The natural course of MMD is poorly understood but revascularization surgery is believed to be an effective procedure for preventing the progression of clinical symptoms [3, 4]. Although various operation techniques have been developed, perioperative morbidity and mortality rates of 4–17% have been reported [4–6]. Recent advances in angiographic techniques and increased routine health check-ups have raised our awareness of the presence of asymptomatic MMD [7]. Kuroda et al. [8] reported the clinical course of asymptomatic MMD in 2007. They suggested that asymptomatic MMD is not a silent disease, with 3.2% of the annual stroke rate, but that 30% of patients already have a cerebral infarction in that data. It seems incongruous to label MMD as an asymptomatic disease. Asymptomatic MMD has been previously defined as the absence of an ischemic or hemorrhagic episode, although the definition has not been determined precisely. This lack of precision has hampered the establishment of guidelines for the management of asymptomatic MMD. With the aims of rigorously establishing the concept of asymptomatic MMD and clarifying the clinical course, we reviewed the baseline data for asymptomatic MMD, clinical course and outcomes of adult patients with asymptomatic MMD who have been treated at our institution over the past 16 years. Materials and Methods Patient Selection We identified all adults (aged ≥18 years) with MMD who underwent digital subtraction angiography or magnetic resonance angiography (MRA) at our institution from 1995 through 2010. Inclusion criteria were unilateral or bilateral angiographic identification of severe stenosis, occlusion of the distal internal carotid or proximal middle and anterior cerebral arteries with prominent lenticulostriate collaterals [1]. In unilateral disease, Suzuki stage 1 and 2 disease was excluded to minimize diagnostic ambiguities. We defined asymptomatic MMD as patients with moyamoya phenomenon but with the absence of clinical and radiological evidence of stroke. Patients were excluded who experienced any episode suggestive of transient ischemic attack (TIA), cerebral infarction, intracranial bleeding, seizure or involuntary movement caused by MMD. The authors suspected headache or dizziness could be a symptom of cerebral ischemia and
Clinical Course of Asymptomatic Adult Moyamoya Disease
many patients with nonclinical symptoms may not remember they have experienced such symptoms or TIA events. We decided to exclude patients with radiologically defined stroke and/ or ischemia because it would be clearer in analyzing the specific characteristics of asymptomatic MMD. Therefore, patients with nonclinical symptoms (n = 4) or nonspecific symptoms (n = 69) such as headache and/or dizziness with radiological evidence of stroke and/or ischemia were excluded. We defined radiological stroke as multiple (>2) small (3–10 mm) or any large (>10 mm) focal hyperintensities on T2-weighted and fluid-attenuated inversion recovery-weighted images. Multifocal or confluent hyperintensities located in periventricular or subcortical regions were considered as ischemia. Of the 529 patients in our adult MMD registry, 40 (7.6%) fulfilled the above criteria of asymptomatic MMD. Retrospective Chart Review Demographic data, radiological findings, medical and surgical treatment and outcome of patients were precisely analyzed. Magnetic resonance imaging (MRI) and MRA were performed in all patients. Digital subtraction angiography was performed in 35 of 40 patients. Using single photon emission computed tomography (SPECT), cerebral blood flow and cerebrovascular reactivity to acetazolamide were determined in 36 of 40 patients. Ischemic stroke was defined as an acute onset of focal neurological deficit lasting ≥24 h and/or high signal on diffusion-weighted imaging. TIA was defined as an onset of focal neurological deficit lasting 40, p = 0.195), diabetes mellitus (p = 0.539), hypertension (p = 0.281), hyperlipidemia (p = 0.348), history of first-degree stroke or familial disease (p = 0.521), angiographic stage (>3 vs. ≤3, p = 0.390) and posterior cerebral artery involvement (p = 0.376). Hemispheres with inadequate reserve and those without did not show a statistically significant difference (table 3). During a median 24-month (range 12–108) radiological follow-up, 3 patients displayed angiographic progression and 3 displayed new hemodynamic abnormalities (fig. 5); 1 of these 6 showed TIA and others had no symptoms up to the last follow-up. Including these patients, 2 hemispheres with hemodynamic progression were treated with indirect bypass surgery. Univariate analysis using log-rank test showed that only hypertension was associated with radiological progression (p = 0.022). Other variables did not show statistical significance (p > 0.05).
1.0 p < 0.001
0.8
0.6
Perfusion status Normal Inadequate perfusion Inadequate both Inadequate reserve Normal – censored Inadequate perfusion – censored Inadequate both – censored Inadequate reserve – censored
0.4
0.2
0 0
a
50.0
100.0
150.0
Accumulative clinical progression-free survival rate
Accumulative clinical progression-free survival rate
1.0
0.6 Smoking status Non-smoker Current smoker Non-smoker – censored Current smoker – censored
0.4
0.2
0
200.0
Follow-up period (months)
p = 0.017
0.8
0
50.0
b
100.0
150.0
200.0
250.0
Follow-up period (months)
Fig. 4. Actuarial clinical progression-free rate by perfusion status (a) and smoking status (b).
Characteristics
Hemisphere with inadequate vascular reserve (n = 22)
Hemisphere with normal vascular reserve (n = 46)
p value
Female gender Old age (>40 years) Diabetes mellitus Hypertension Hyperlipidemia Smoking Family history of moyamoya disease Advanced Suzuki stage (≥4) Posterior cerebral artery involvement Intracranial aneurysm
13 (59.1%) 17 (77.3%) 4 (18.2%) 7 (31.8%) 5 (22.7%) 1 (4.5%) 4 (8.8%) 13 (59.1%) 3 (13.6%) 3 (13.6%)
30 (65.2%) 34 (73.9%) 2 (4.3%) 15 (32.6%) 4 (8.7%) 3 (6.5%) 2 (4.3%) 16 (34.8%) 9 (19.6%) 2 (4.3%)
0.624 0.765 0.081 0.948 0.253 0.610 0.081 0.071 0.738 0.319
rological deficit and ischemic or hemorrhagic episodes. However, cerebral infarction was detected in 30% of the patients. Considering that cerebral infarction and ischemia can be causes of headache and dizziness, headache with infarction or severe ischemia should be classified as symptomatic MMD [9–11]. If a different treatment strategy can be applied to asymptomatic MMD from symptomatic disease, the definition should be strictly limited. 98
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
We defined asymptomatic MMD as moyamoya phenomenon without ischemic or hemorrhagic episode and with no evidence of radiological infarction. In the current data, 43.1% of the hemispheres already had a transdural collateral and 55.9% showed normal perfusion without any infarction or hemorrhage. These findings may imply that asymptomatic MMD is an adapted condition against vascular pathology. We thought the relative higher percentage of ‘old age’ in asymptomatic Jo/Yeon/Hong/Kim
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
Table 3. Comparison between the hemispheres with and without normal vascular reserve on SPECT
b
c
e
f
g
d
Fig. 5. Radiological progression of asymptomatic moyamoya patients. a Initial conventional angiographic examination of a 51-year-old male patient. Follow-up angiographic examination (b) and MRI (c) at 8 years after initial diagnosis. Follow-up examination demonstrated progressive steno-occlusive change on
angiogram and no identifiable ischemic lesion on MRI. d, e Initial MRA and perfusion image of a 45-year-old patient. Follow-up MRA (f) and perfusion (g) at 4 years after initial diagnosis. Followup imaging showed perfusion abnormality without angiographic change.
MMD may reflect this hypothesis. There was no correlation between angiographic staging and perfusion status or age. Furthermore, there was no correlation between perfusion status and angiographic staging, which may mean that advanced MMD is not always accompanied by cerebral hypoperfusion requiring surgical treatment. In the present study, perfusion abnormality was associated with clinical progression. However, the stroke rate was 0% during the follow-up. Considering that surgical treatment carries a considerable risk of perioperative morbidity (4–17%) [4, 12], it should be performed only in patients with perfusion abnormality in asymptomatic MMD. Also, in this study all of the patients with clinical progression showed hemodynamic abnormality. Therefore, impaired vascular reserve seems to be a more important parameter than resting perfusion in asymptomatic MMD. In this study smoking and hypertension were associated with clinical and radiological progression. Hypertension is a known risk factor of intimal medial thickening [13]. Also, vascular constrictive changes are impor-
tant phenomena reflecting MMD [14]. Therefore, hypertension can lead to angiographic progression and should be managed properly. Smoking is a known risk factor of stroke [15]. Clinical and experimental studies indicated that smoking promotes vasomotor dysfunction, atherogenesis and thrombosis in multiple vascular beds [16]. In this study, MMD risk factors were similar to those of atherosclerotic disease [17]. These risk factors should be managed properly to reduce clinical and/or radiological disease progression. A total of 90% of the patients received antiplatelet medication. None of these patients experienced ischemic or hemorrhagic stroke. There is little evidence for a role of antiplatelet agents in MMD [18]. Clearly, hemodynamic insufficiency is the main cause of ischemic stroke in MMD [19, 20]. Nonetheless, thromboembolism is also suggested as a probable mechanism because histopathological studies showed thrombus formation in the diseased arteries and transcranial Doppler studies showed a microembolic signal in MMD patients [21, 22]. Also, there has been no evidence that antiplatelet agents can increase the intracranial hemorrhage rate of MMD [17].
Clinical Course of Asymptomatic Adult Moyamoya Disease
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
99
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
a
Considering that asymptomatic MMD showed a benign course in this study, we suggest that conservative treatment such as antiplatelet treatment or observation can be alternative options in the treatment of asymptomatic MMD rather than surgical interventions. However, antiplatelet agents evidently have additional hemorrhagic risk in the general population [23]. Efficacy and safety of antiplatelet agents in MMD should be elucidated in a future study. This retrospective cohort study was limited by its retrospective nature. Radiological progression was usually determined by MRA and perfusion MRI, which are useful in MMD diagnosis but which cannot reveal sophisticated angiographic structure compared with conventional angiography [24, 25]. Therefore, the real radiological progression rate could differ from these results. In addition, this relatively inaccurate radiological follow-up study may result in clinical-radiological progression mismatch. The small number of cases was another limitation. Due to this and a missing data problem, we were not able to perform multivariate anal-
ysis, which is needed to draw more reliable results. A prospective large-sized study is required to resolve this problem, but owing to the rarity of the disease and ethical concerns, a prospective large-sized cohort study might be difficult to undertake in asymptomatic MMD. MMD is a progressive disease and surgical treatment could reduce the stroke rate by collateral formation [2, 12, 26]. The results of this study also demonstrate that MMD is not a stable disease, even in asymptomatic patients. Nonetheless, the symptomatic stroke rate was quite low (0%) compared with previous studies (3.2%) [2, 8, 27]. Therefore, conservative treatment including lifestyle modification and/or antiplatelet medication could be suggested for those select patients with uncompromised hemodynamics.
Disclosure Statement The authors have no conflicts of interest to report.
References
100
7 Baba T, Houkin K, Kuroda S: Novel epidemiological features of moyamoya disease. J Neurol Neurosurg Psychiatry 2008; 79: 900– 904. 8 Kuroda S, Hashimoto N, Yoshimoto T, Iwasaki Y: Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 2007;38:1430–1435. 9 Radwan W, El-Sabbagh A, Atweh S, Sawaya R: Ischaemic stroke with headache as its only manifestation. NZ Med J 2012;125:75–77. 10 Hansen AP, Marcussen NS, Klit H, Andersen G, Finnerup NB, Jensen TS: Pain following stroke: a prospective study. Eur J Pain 2012; 16:1128–1136. 11 Okada Y, Kawamata T, Kawashima A, Yamaguchi K, Ono Y, Hori T: The efficacy of superficial temporal artery-middle cerebral artery anastomosis in patients with moyamoya disease complaining of severe headache. J Neurosurg 2012;116:672–679. 12 Han JS, Abou-Hamden A, Mandell DM, Poublanc J, Crawley AP, Fisher JA, Mikulis DJ, Tymianski M: Impact of extracranial-intracranial bypass on cerebrovascular reactivity and clinical outcome in patients with symptomatic moyamoya vasculopathy. Stroke 2011;42:3047–3054. 13 Araki Y, Kumakura H, Kanai H, Kasama S, Sumino H, Ichikawa A, Ito T, Iwasaki T, Takayama Y, Ichikawa S, Fujita K, Nakashima K, Minami K, Kurabayashi M: Prevalence and
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
14
15
16
17
18
risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease. Atherosclerosis 2012;223:473–477. Kaku Y, Morioka M, Ohmori Y, Kawano T, Kai Y, Fukuoka H, Hirai T, Yamashita Y, Kuratsu JI: Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image: is arterial constrictive remodeling a major pathogenesis? Acta Neurochir (Wien) 2012; 154:2151–2157. Gao L, Meschia JF, Judd SE, Muntner P, McClure LA, Howard VJ, Rhodes JD, Cushman M, Safford MM, Soliman EZ, Kleindorfer DO, Howard G: What stroke symptoms tell us: association of risk factors and individual stroke symptoms in the reasons for geographic and racial differences in stroke (REGARDS) study. J Stroke Cerebrovasc Dis 2012;21:411–416. Ambrose JA, Barua RS: The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol 2004; 43: 1731–1737. Turan TN, Derdeyn CP, Fiorella D, Chimowitz MI: Treatment of atherosclerotic intracranial arterial stenosis. Stroke 2009; 40: 2257– 2261. Kraemer M, Berlit P, Diesner F, Khan N: What is the expert’s option on antiplatelet therapy in moyamoya disease? Results of a worldwide survey. Eur J Neurol 2012;19:163– 167.
Jo/Yeon/Hong/Kim
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
1 Suzuki J, Takaku A: Cerebrovascular ‘moyamoya’ disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 1969;20:288–299. 2 Kuroda S, Ishikawa T, Houkin K, Nanba R, Hokari M, Iwasaki Y: Incidence and clinical features of disease progression in adult moyamoya disease. Stroke 2005; 36: 2148– 2153. 3 Imaizumi T, Hayashi K, Saito K, Osawa M, Fukuyama Y: Long-term outcomes of pediatric moyamoya disease monitored to adulthood. Pediatr Neurol 1998; 18: 321– 325. 4 Guzman R, Lee M, Achrol A, Bell-Stephens T, Kelly M, Do HM, Marks MP, Steinberg GK: Clinical outcome after 450 revascularization procedures for moyamoya disease. Clinical article. J Neurosurg 2009; 111: 927– 935. 5 Ishii K, Morishige M, Anan M, Sugita K, Abe E, Kubo T, Fujiki M, Kobayashi H: Superficial temporal artery-to-middle cerebral artery anastomosis with encephalo-duro-myo-synangiosis as a modified operative procedure for moyamoya disease. Acta Neurochir Suppl 2010;107(suppl):95–99. 6 Dusick JR, Gonzalez NR, Martin NA: Clinical and angiographic outcomes from indirect revascularization surgery for moyamoya disease in adults and children: a review of 63 procedures. Neurosurgery 2011; 68: 34–43, discussion 43.
Clinical Course of Asymptomatic Adult Moyamoya Disease
23 Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, Kitagawa Y, Kusuoka H, Nishimaru K, Tsushima M, Koretsune Y, Sawada T, Hamada C: Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, doubleblind, randomised non-inferiority trial. Lancet Neurol 2010;9:959–968. 24 Figueiredo G, Brockmann C, Boll H, Heilmann M, Schambach SJ, Fiebig T, Kramer M, Groden C, Brockmann MA: Comparison of digital subtraction angiography, micro-computed tomography angiography and magnetic resonance angiography in the assessment of the cerebrovascular system in live mice. Clin Neuroradiol 2012;22:21–28.
25 Sawada T, Yamamoto A, Miki Y, Kikuta K, Okada T, Kanagaki M, Kasahara S, Miyamoto S, Takahashi JC, Fukuyama H, Togashi K: Diagnosis of moyamoya disease using 3-T MRI and MRA: value of cisternal moyamoya vessels. Neuroradiology 2012;54:1089–1097. 26 Yeon JY, Shin HJ, Kong DS, Seol HJ, Kim JS, Hong SC, Park K: The prediction of contralateral progression in children and adolescents with unilateral moyamoya disease. Stroke 2011;42:2973–2976. 27 Yamada M, Fujii K, Fukui M: Clinical features and outcomes in patients with asymptomatic moyamoya disease – from the results of a nation-wide questionnaire survey (in Japanese). No Shinkei Geka 2005;33:337–342.
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
101
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
19 Kuroda S, Houkin K: Moyamoya disease: Current concepts and future perspectives. Lancet Neurol 2008;7:1056–1066. 20 Derdeyn CP: Moyamoya disease and moyamoya syndrome. N Engl J Med 2009;361:97, author reply 98. 21 Yamashita M, Oka K, Tanaka K: Histopathology of the brain vascular network in moyamoya disease. Stroke 1983;14:50–58. 22 Horn P, Lanczik O, Vajkoczy P, Daffertshofer M, Bueltmann E, Werner A, Schmiedek P, Hennerici M: Hemodynamic reserve and high-intensity transient signals in moyamoya disease. Cerebrovasc Dis 2005; 19: 141– 146.
Received: December 3, 2012 Accepted: October 14, 2013 Published online: January 16, 2014
Clinical Course of Asymptomatic Adult Moyamoya Disease Kyung-Il Jo Je Young Yeon Seung-Chyul Hong Jong-Soo Kim Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Abstract Background: As regular medical check-ups are becoming more common, the prevalence of asymptomatic moyamoya disease (MMD) is increasing. However, the definition and clinical features are still unclear. The lack of precision has hampered the establishment of guidelines for the management of asymptomatic MMD. The purpose of this study was to define and clarify the clinical characteristics of asymptomatic MMD in adults. Methods: We identified all adults (aged ≥18 years) with MMD who underwent digital subtraction angiography or magnetic resonance angiography at our institution from 1995 through 2010. The authors defined asymptomatic MMD as asymptomatic or nonspecific symptom without any infarction or ischemia on magnetic resonance imaging. In our MMD registry, 40 patients (74 hemispheres) were identified and enrolled in this retrospective cohort study. Their demographic, radiological and clinical findings were evaluated. The log-rank test was used to assess prognostic factors. Pearson’s correlation test and the Mann-Whitney U test were used to identify correlation angiographic staging and age or perfusion status. Results: Overall, 6 patients underwent indirect bypass surgery and 36 received antiplatelet medication. On initial single positron emission
© 2014 S. Karger AG, Basel 1015–9770/14/0372–0094$39.50/0 E-Mail [email protected] www.karger.com/ced
tomography (35 patients, 67 affected hemispheres), basal and acetazolamide stress brain perfusion were decreased in 19 (28.4%) and 22 (32.8%) hemispheres, respectively. Among 70 angiographically evaluated hemispheres, 6 were unilateral MMD; 27 of 64 affected hemispheres (42.2%) had transdural collateral at evaluation. Age (p = 0.309, Pearson’s correlation test) and hemodynamic impairment (p = 0.614, Mann-Whitney U test) did not correlate with angiographic staging. During a median 32-month (range 6–203) clinical follow-up, 3 nonsurgically treated patients had a transient ischemic attack, which was associated with decreased vascular reserve (p < 0.001, log-rank test) and smoking (p = 0.017). Other variables did not show a significant association with clinical progression. During a median 24-month (range 12–108) radiological follow-up, 3 patients displayed angiographic progression and 3 displayed new hemodynamic abnormalities. Radiological progressions were related to hypertension only (p = 0.022). In this case series, there was no case of ischemic or hemorrhagic stroke. Conclusion: The findings suggest that asymptomatic MMD in adults is not a stable disease in our definition. However, stroke rate (0%) was lower than previous reports. Lifestyle modification, stroke risk factor control and/or antiplatelet medication seem to be appropriate initial treatments for patients with normal cerebrovascular reserve. A clear definition of asymptomatic MMD and further clarification of its clinical course are needed to set precise treatment guidelines. © 2014 S. Karger AG, Basel
Jong-Soo Kim, MD, PhD Department of Neurosurgery Samsung Medical Center, Sungkyunkwan University School of Medicine 50 lrwon-dong, Gangnam-gu, Seoul 135-710 (Korea) E-Mail smcnsjs.kim @ gmail.com
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
Key Words Asymptomatic disease · Moyamoya disease · Clinical course · Treatment
Moyamoya disease (MMD) is characterized by progressive stenosis of the terminal portion of the bilateral internal carotid arteries and is associated with an extensive network of cerebral collaterals [1]. Disease progression is not uncommon in adult MMD if untreated [2]. The natural course of MMD is poorly understood but revascularization surgery is believed to be an effective procedure for preventing the progression of clinical symptoms [3, 4]. Although various operation techniques have been developed, perioperative morbidity and mortality rates of 4–17% have been reported [4–6]. Recent advances in angiographic techniques and increased routine health check-ups have raised our awareness of the presence of asymptomatic MMD [7]. Kuroda et al. [8] reported the clinical course of asymptomatic MMD in 2007. They suggested that asymptomatic MMD is not a silent disease, with 3.2% of the annual stroke rate, but that 30% of patients already have a cerebral infarction in that data. It seems incongruous to label MMD as an asymptomatic disease. Asymptomatic MMD has been previously defined as the absence of an ischemic or hemorrhagic episode, although the definition has not been determined precisely. This lack of precision has hampered the establishment of guidelines for the management of asymptomatic MMD. With the aims of rigorously establishing the concept of asymptomatic MMD and clarifying the clinical course, we reviewed the baseline data for asymptomatic MMD, clinical course and outcomes of adult patients with asymptomatic MMD who have been treated at our institution over the past 16 years. Materials and Methods Patient Selection We identified all adults (aged ≥18 years) with MMD who underwent digital subtraction angiography or magnetic resonance angiography (MRA) at our institution from 1995 through 2010. Inclusion criteria were unilateral or bilateral angiographic identification of severe stenosis, occlusion of the distal internal carotid or proximal middle and anterior cerebral arteries with prominent lenticulostriate collaterals [1]. In unilateral disease, Suzuki stage 1 and 2 disease was excluded to minimize diagnostic ambiguities. We defined asymptomatic MMD as patients with moyamoya phenomenon but with the absence of clinical and radiological evidence of stroke. Patients were excluded who experienced any episode suggestive of transient ischemic attack (TIA), cerebral infarction, intracranial bleeding, seizure or involuntary movement caused by MMD. The authors suspected headache or dizziness could be a symptom of cerebral ischemia and
Clinical Course of Asymptomatic Adult Moyamoya Disease
many patients with nonclinical symptoms may not remember they have experienced such symptoms or TIA events. We decided to exclude patients with radiologically defined stroke and/ or ischemia because it would be clearer in analyzing the specific characteristics of asymptomatic MMD. Therefore, patients with nonclinical symptoms (n = 4) or nonspecific symptoms (n = 69) such as headache and/or dizziness with radiological evidence of stroke and/or ischemia were excluded. We defined radiological stroke as multiple (>2) small (3–10 mm) or any large (>10 mm) focal hyperintensities on T2-weighted and fluid-attenuated inversion recovery-weighted images. Multifocal or confluent hyperintensities located in periventricular or subcortical regions were considered as ischemia. Of the 529 patients in our adult MMD registry, 40 (7.6%) fulfilled the above criteria of asymptomatic MMD. Retrospective Chart Review Demographic data, radiological findings, medical and surgical treatment and outcome of patients were precisely analyzed. Magnetic resonance imaging (MRI) and MRA were performed in all patients. Digital subtraction angiography was performed in 35 of 40 patients. Using single photon emission computed tomography (SPECT), cerebral blood flow and cerebrovascular reactivity to acetazolamide were determined in 36 of 40 patients. Ischemic stroke was defined as an acute onset of focal neurological deficit lasting ≥24 h and/or high signal on diffusion-weighted imaging. TIA was defined as an onset of focal neurological deficit lasting 40, p = 0.195), diabetes mellitus (p = 0.539), hypertension (p = 0.281), hyperlipidemia (p = 0.348), history of first-degree stroke or familial disease (p = 0.521), angiographic stage (>3 vs. ≤3, p = 0.390) and posterior cerebral artery involvement (p = 0.376). Hemispheres with inadequate reserve and those without did not show a statistically significant difference (table 3). During a median 24-month (range 12–108) radiological follow-up, 3 patients displayed angiographic progression and 3 displayed new hemodynamic abnormalities (fig. 5); 1 of these 6 showed TIA and others had no symptoms up to the last follow-up. Including these patients, 2 hemispheres with hemodynamic progression were treated with indirect bypass surgery. Univariate analysis using log-rank test showed that only hypertension was associated with radiological progression (p = 0.022). Other variables did not show statistical significance (p > 0.05).
1.0 p < 0.001
0.8
0.6
Perfusion status Normal Inadequate perfusion Inadequate both Inadequate reserve Normal – censored Inadequate perfusion – censored Inadequate both – censored Inadequate reserve – censored
0.4
0.2
0 0
a
50.0
100.0
150.0
Accumulative clinical progression-free survival rate
Accumulative clinical progression-free survival rate
1.0
0.6 Smoking status Non-smoker Current smoker Non-smoker – censored Current smoker – censored
0.4
0.2
0
200.0
Follow-up period (months)
p = 0.017
0.8
0
50.0
b
100.0
150.0
200.0
250.0
Follow-up period (months)
Fig. 4. Actuarial clinical progression-free rate by perfusion status (a) and smoking status (b).
Characteristics
Hemisphere with inadequate vascular reserve (n = 22)
Hemisphere with normal vascular reserve (n = 46)
p value
Female gender Old age (>40 years) Diabetes mellitus Hypertension Hyperlipidemia Smoking Family history of moyamoya disease Advanced Suzuki stage (≥4) Posterior cerebral artery involvement Intracranial aneurysm
13 (59.1%) 17 (77.3%) 4 (18.2%) 7 (31.8%) 5 (22.7%) 1 (4.5%) 4 (8.8%) 13 (59.1%) 3 (13.6%) 3 (13.6%)
30 (65.2%) 34 (73.9%) 2 (4.3%) 15 (32.6%) 4 (8.7%) 3 (6.5%) 2 (4.3%) 16 (34.8%) 9 (19.6%) 2 (4.3%)
0.624 0.765 0.081 0.948 0.253 0.610 0.081 0.071 0.738 0.319
rological deficit and ischemic or hemorrhagic episodes. However, cerebral infarction was detected in 30% of the patients. Considering that cerebral infarction and ischemia can be causes of headache and dizziness, headache with infarction or severe ischemia should be classified as symptomatic MMD [9–11]. If a different treatment strategy can be applied to asymptomatic MMD from symptomatic disease, the definition should be strictly limited. 98
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
We defined asymptomatic MMD as moyamoya phenomenon without ischemic or hemorrhagic episode and with no evidence of radiological infarction. In the current data, 43.1% of the hemispheres already had a transdural collateral and 55.9% showed normal perfusion without any infarction or hemorrhage. These findings may imply that asymptomatic MMD is an adapted condition against vascular pathology. We thought the relative higher percentage of ‘old age’ in asymptomatic Jo/Yeon/Hong/Kim
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
Table 3. Comparison between the hemispheres with and without normal vascular reserve on SPECT
b
c
e
f
g
d
Fig. 5. Radiological progression of asymptomatic moyamoya patients. a Initial conventional angiographic examination of a 51-year-old male patient. Follow-up angiographic examination (b) and MRI (c) at 8 years after initial diagnosis. Follow-up examination demonstrated progressive steno-occlusive change on
angiogram and no identifiable ischemic lesion on MRI. d, e Initial MRA and perfusion image of a 45-year-old patient. Follow-up MRA (f) and perfusion (g) at 4 years after initial diagnosis. Followup imaging showed perfusion abnormality without angiographic change.
MMD may reflect this hypothesis. There was no correlation between angiographic staging and perfusion status or age. Furthermore, there was no correlation between perfusion status and angiographic staging, which may mean that advanced MMD is not always accompanied by cerebral hypoperfusion requiring surgical treatment. In the present study, perfusion abnormality was associated with clinical progression. However, the stroke rate was 0% during the follow-up. Considering that surgical treatment carries a considerable risk of perioperative morbidity (4–17%) [4, 12], it should be performed only in patients with perfusion abnormality in asymptomatic MMD. Also, in this study all of the patients with clinical progression showed hemodynamic abnormality. Therefore, impaired vascular reserve seems to be a more important parameter than resting perfusion in asymptomatic MMD. In this study smoking and hypertension were associated with clinical and radiological progression. Hypertension is a known risk factor of intimal medial thickening [13]. Also, vascular constrictive changes are impor-
tant phenomena reflecting MMD [14]. Therefore, hypertension can lead to angiographic progression and should be managed properly. Smoking is a known risk factor of stroke [15]. Clinical and experimental studies indicated that smoking promotes vasomotor dysfunction, atherogenesis and thrombosis in multiple vascular beds [16]. In this study, MMD risk factors were similar to those of atherosclerotic disease [17]. These risk factors should be managed properly to reduce clinical and/or radiological disease progression. A total of 90% of the patients received antiplatelet medication. None of these patients experienced ischemic or hemorrhagic stroke. There is little evidence for a role of antiplatelet agents in MMD [18]. Clearly, hemodynamic insufficiency is the main cause of ischemic stroke in MMD [19, 20]. Nonetheless, thromboembolism is also suggested as a probable mechanism because histopathological studies showed thrombus formation in the diseased arteries and transcranial Doppler studies showed a microembolic signal in MMD patients [21, 22]. Also, there has been no evidence that antiplatelet agents can increase the intracranial hemorrhage rate of MMD [17].
Clinical Course of Asymptomatic Adult Moyamoya Disease
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
99
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
a
Considering that asymptomatic MMD showed a benign course in this study, we suggest that conservative treatment such as antiplatelet treatment or observation can be alternative options in the treatment of asymptomatic MMD rather than surgical interventions. However, antiplatelet agents evidently have additional hemorrhagic risk in the general population [23]. Efficacy and safety of antiplatelet agents in MMD should be elucidated in a future study. This retrospective cohort study was limited by its retrospective nature. Radiological progression was usually determined by MRA and perfusion MRI, which are useful in MMD diagnosis but which cannot reveal sophisticated angiographic structure compared with conventional angiography [24, 25]. Therefore, the real radiological progression rate could differ from these results. In addition, this relatively inaccurate radiological follow-up study may result in clinical-radiological progression mismatch. The small number of cases was another limitation. Due to this and a missing data problem, we were not able to perform multivariate anal-
ysis, which is needed to draw more reliable results. A prospective large-sized study is required to resolve this problem, but owing to the rarity of the disease and ethical concerns, a prospective large-sized cohort study might be difficult to undertake in asymptomatic MMD. MMD is a progressive disease and surgical treatment could reduce the stroke rate by collateral formation [2, 12, 26]. The results of this study also demonstrate that MMD is not a stable disease, even in asymptomatic patients. Nonetheless, the symptomatic stroke rate was quite low (0%) compared with previous studies (3.2%) [2, 8, 27]. Therefore, conservative treatment including lifestyle modification and/or antiplatelet medication could be suggested for those select patients with uncompromised hemodynamics.
Disclosure Statement The authors have no conflicts of interest to report.
References
100
7 Baba T, Houkin K, Kuroda S: Novel epidemiological features of moyamoya disease. J Neurol Neurosurg Psychiatry 2008; 79: 900– 904. 8 Kuroda S, Hashimoto N, Yoshimoto T, Iwasaki Y: Radiological findings, clinical course, and outcome in asymptomatic moyamoya disease: results of multicenter survey in Japan. Stroke 2007;38:1430–1435. 9 Radwan W, El-Sabbagh A, Atweh S, Sawaya R: Ischaemic stroke with headache as its only manifestation. NZ Med J 2012;125:75–77. 10 Hansen AP, Marcussen NS, Klit H, Andersen G, Finnerup NB, Jensen TS: Pain following stroke: a prospective study. Eur J Pain 2012; 16:1128–1136. 11 Okada Y, Kawamata T, Kawashima A, Yamaguchi K, Ono Y, Hori T: The efficacy of superficial temporal artery-middle cerebral artery anastomosis in patients with moyamoya disease complaining of severe headache. J Neurosurg 2012;116:672–679. 12 Han JS, Abou-Hamden A, Mandell DM, Poublanc J, Crawley AP, Fisher JA, Mikulis DJ, Tymianski M: Impact of extracranial-intracranial bypass on cerebrovascular reactivity and clinical outcome in patients with symptomatic moyamoya vasculopathy. Stroke 2011;42:3047–3054. 13 Araki Y, Kumakura H, Kanai H, Kasama S, Sumino H, Ichikawa A, Ito T, Iwasaki T, Takayama Y, Ichikawa S, Fujita K, Nakashima K, Minami K, Kurabayashi M: Prevalence and
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
14
15
16
17
18
risk factors for cerebral infarction and carotid artery stenosis in peripheral arterial disease. Atherosclerosis 2012;223:473–477. Kaku Y, Morioka M, Ohmori Y, Kawano T, Kai Y, Fukuoka H, Hirai T, Yamashita Y, Kuratsu JI: Outer-diameter narrowing of the internal carotid and middle cerebral arteries in moyamoya disease detected on 3D constructive interference in steady-state MR image: is arterial constrictive remodeling a major pathogenesis? Acta Neurochir (Wien) 2012; 154:2151–2157. Gao L, Meschia JF, Judd SE, Muntner P, McClure LA, Howard VJ, Rhodes JD, Cushman M, Safford MM, Soliman EZ, Kleindorfer DO, Howard G: What stroke symptoms tell us: association of risk factors and individual stroke symptoms in the reasons for geographic and racial differences in stroke (REGARDS) study. J Stroke Cerebrovasc Dis 2012;21:411–416. Ambrose JA, Barua RS: The pathophysiology of cigarette smoking and cardiovascular disease: an update. J Am Coll Cardiol 2004; 43: 1731–1737. Turan TN, Derdeyn CP, Fiorella D, Chimowitz MI: Treatment of atherosclerotic intracranial arterial stenosis. Stroke 2009; 40: 2257– 2261. Kraemer M, Berlit P, Diesner F, Khan N: What is the expert’s option on antiplatelet therapy in moyamoya disease? Results of a worldwide survey. Eur J Neurol 2012;19:163– 167.
Jo/Yeon/Hong/Kim
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
1 Suzuki J, Takaku A: Cerebrovascular ‘moyamoya’ disease. Disease showing abnormal net-like vessels in base of brain. Arch Neurol 1969;20:288–299. 2 Kuroda S, Ishikawa T, Houkin K, Nanba R, Hokari M, Iwasaki Y: Incidence and clinical features of disease progression in adult moyamoya disease. Stroke 2005; 36: 2148– 2153. 3 Imaizumi T, Hayashi K, Saito K, Osawa M, Fukuyama Y: Long-term outcomes of pediatric moyamoya disease monitored to adulthood. Pediatr Neurol 1998; 18: 321– 325. 4 Guzman R, Lee M, Achrol A, Bell-Stephens T, Kelly M, Do HM, Marks MP, Steinberg GK: Clinical outcome after 450 revascularization procedures for moyamoya disease. Clinical article. J Neurosurg 2009; 111: 927– 935. 5 Ishii K, Morishige M, Anan M, Sugita K, Abe E, Kubo T, Fujiki M, Kobayashi H: Superficial temporal artery-to-middle cerebral artery anastomosis with encephalo-duro-myo-synangiosis as a modified operative procedure for moyamoya disease. Acta Neurochir Suppl 2010;107(suppl):95–99. 6 Dusick JR, Gonzalez NR, Martin NA: Clinical and angiographic outcomes from indirect revascularization surgery for moyamoya disease in adults and children: a review of 63 procedures. Neurosurgery 2011; 68: 34–43, discussion 43.
Clinical Course of Asymptomatic Adult Moyamoya Disease
23 Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, Ohashi Y, Tanahashi N, Yamamoto H, Genka C, Kitagawa Y, Kusuoka H, Nishimaru K, Tsushima M, Koretsune Y, Sawada T, Hamada C: Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, doubleblind, randomised non-inferiority trial. Lancet Neurol 2010;9:959–968. 24 Figueiredo G, Brockmann C, Boll H, Heilmann M, Schambach SJ, Fiebig T, Kramer M, Groden C, Brockmann MA: Comparison of digital subtraction angiography, micro-computed tomography angiography and magnetic resonance angiography in the assessment of the cerebrovascular system in live mice. Clin Neuroradiol 2012;22:21–28.
25 Sawada T, Yamamoto A, Miki Y, Kikuta K, Okada T, Kanagaki M, Kasahara S, Miyamoto S, Takahashi JC, Fukuyama H, Togashi K: Diagnosis of moyamoya disease using 3-T MRI and MRA: value of cisternal moyamoya vessels. Neuroradiology 2012;54:1089–1097. 26 Yeon JY, Shin HJ, Kong DS, Seol HJ, Kim JS, Hong SC, Park K: The prediction of contralateral progression in children and adolescents with unilateral moyamoya disease. Stroke 2011;42:2973–2976. 27 Yamada M, Fujii K, Fukui M: Clinical features and outcomes in patients with asymptomatic moyamoya disease – from the results of a nation-wide questionnaire survey (in Japanese). No Shinkei Geka 2005;33:337–342.
Cerebrovasc Dis 2014;37:94–101 DOI: 10.1159/000356350
101
Downloaded by: UCSF Library & CKM 128.218.166.245 - 5/13/2015 8:04:15 PM
19 Kuroda S, Houkin K: Moyamoya disease: Current concepts and future perspectives. Lancet Neurol 2008;7:1056–1066. 20 Derdeyn CP: Moyamoya disease and moyamoya syndrome. N Engl J Med 2009;361:97, author reply 98. 21 Yamashita M, Oka K, Tanaka K: Histopathology of the brain vascular network in moyamoya disease. Stroke 1983;14:50–58. 22 Horn P, Lanczik O, Vajkoczy P, Daffertshofer M, Bueltmann E, Werner A, Schmiedek P, Hennerici M: Hemodynamic reserve and high-intensity transient signals in moyamoya disease. Cerebrovasc Dis 2005; 19: 141– 146.
