- Email: [email protected]
Factors Associated with Moyamoya Syndrome in a Kentucky Regional Population
Factors Associated with Moyamoya Syndrome in a Kentucky Regional Population Catherine Y. Wang, MD,* Stephen L. Grupke, MD,* Jill Roberts, Jessica Lee, MD,† and Justin F. Fraser, MD*,†,‡,§
PhD,§ ‖ ,
Objectives: Our study aimed to report both new and previously identified conditions associated with moyamoya syndrome in a Western population and to present our outcomes after surgical treatment with indirect bypass. Methods: We performed a retrospective chart review of patients evaluated at our institution from June 2011 to June 2015 who were diagnosed with moyamoya. Data collected include patient demographics, presenting manifestations, vessels involved, comorbid conditions, abnormal laboratory values, treatments administered, and clinical outcomes. Results: Thirty-one patients with moyamoya were enrolled (11 male and 20 female), with 84% Caucasian and 16% African-American. The most common comorbidity was hypertension in 61% of the patients. Coexisting autoimmune conditions were present in 26%, with another 13% having coexisting prothrombotic disorders. Diabetes mellitus was not found to correlate with the Suzuki grade of disease at presentation (P = .30). When noninvasive imaging was performed before the cerebral angiogram, the computed tomography angiography had a false-negative rate of 59%, and magnetic resonance angiography had a false-negative rate of 33%. Twenty-one patients underwent surgical intervention, 2 underwent intracranial stenting, and 19 underwent indirect bypass with encephaloduroarteriosynangiosis. At an average 28-month follow-up, all 15 patients who had an angiogram after intervention showed evidence of neovascularization. Conclusions: Autoimmune and prothrombotic disorders were found to be comorbid in patients with moyamoya at much higher rates than expected in the general population. Diabetes mellitus was not significantly correlated with Suzuki grade. Angiogram remains an important diagnostic modality when noninvasive imaging is negative for vasculopathy. We demonstrate excellent evidence of revascularization within 1 year with intracranial stenting and indirect bypass. Key Words: Angiography—artery—stenosis— stroke—moyamoya—bypass. © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurosurgery; †Department of Neurology; ‡Department of Radiology; §Department of Neuroscience; and ‖Sanders Brown Center on Aging, University of Kentucky, Lexington, Kentucky. Received July 13, 2017; revision received September 24, 2017; accepted October 12, 2017. Author contributions: Catherine Wang: data collection and analysis of patient demographics, comorbid disorders, and treatment outcomes; Stephen Grupke: Suzuki grading of pre- and post-treatment angiograms; Jessica Lee and Justin Fraser: provision of patient data for study and overall study design; Catherine Wang, Jill Roberts, and Justin Fraser: writing of the manuscript. All authors read and edited the text. Grant support: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Data sharing: Not applicable. Address correspondence to Catherine Y. Wang, MD, Justin F. Fraser, MD, Department of Neurosurgery, University of Kentucky, 800 Rose Street, MS 101A, Lexington KY 40536. E-mail: [email protected], [email protected]. 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.10.016
Journal of Stroke and Cerebrovascular Diseases, Vol. 27, No. 3 (March), 2018: pp 793–800
793
C.Y. WANG ET AL.
794
Introduction Moyamoya disease is a progressive occlusive disease of the cerebral vasculature, with particular involvement of the vessels of the circle of Willis.1 Over time, abnormal collateral networks develop to bypass these stenotic vessels. Although first described as a bilateral phenomenon affecting East Asians,2 similar angiographic features of moyamoya disease are evident in patients with other medical conditions, such as autoimmune or congenital disorders.3-6 In these instances, the terms “moyamoya syndrome” or “moyamoya vasculopathy” are often used. Medical management of the disease usually consists of managing complications, such as controlling hypertension and modifying stroke risk factors, as well as antiplatelet therapy. Surgical revascularization techniques can restore cerebral blood flow through forms of direct or indirect bypass.7 Numerous associated conditions have been reported in the literature in reference to moyamoya syndrome, but most occur as case reports.8 Few publications have analyzed the prevalence of such conditions or have given a comprehensive overview of associated conditions within a regional population.9 Even fewer studies have focused on moyamoya within a Caucasian population, which has different epidemiological and clinical features. The aim of the present study was 2-fold: first, to report both new and previously identified conditions in patients with moyamoya syndrome within a Kentucky regional population treated at the University of Kentucky Medical Center and to compare this to what has been reported in the literature; second, we report clinical and angiographic outcomes in our cohort of patients undergoing surgical intervention. The identification of these coexisting conditions will hopefully serve to allow better conceptualization of the pathophysiology involved in moyamoya syndrome, as well as a more timely and accurate diagnosis of moyamoya syndrome.
Methods Patient Population We performed a retrospective chart review of all patients with the International Classification of Diseases, Ninth Revision (ICD-9), and the subsequent International Classification of Diseases, 10th Revision (ICD-10), diagnoses of moyamoya disease who were evaluated at the University of Kentucky Medical Center between June 1, 2011, and June 1, 2015. All were patients under treatment by one of the investigators. Thirtysix total patients were initially identified, but 5 patients were subsequently excluded due to age younger than 18 years or having incomplete hospital records necessary for analysis. Records of all inpatient stroke admissions
between 2011 and 2015 were also obtained for epidemiological comparison.
Data Collection Epidemiological information about patient demographics was obtained, including age at diagnosis, gender, presenting manifestation, and vessels involved. Baseline stroke risk factors, including hypertension, hyperlipidemia, obesity, diabetes, smoking, coronary artery disease, and peripheral vascular disease, were collected. In addition, moyamoya syndrome risk factors, in particular, comorbid autoimmune and prothrombotic disorders, were assessed. Treatments administered were classified as either medical only (antiplatelet or anticoagulation therapy), surgical (indirect bypass or stenting), or both. Patient angiograms were reviewed retrospectively by an independent investigator (S.G.) who had not performed the procedures for Suzuki grade and for angiographic success of bypass procedures. In addition, results of noninvasive imaging modalities like computed tomography angiography (CTA) and magnetic resonance angiography (MRA) before the diagnostic angiogram were reviewed. The results were determined to be diagnostic of moyamoya if the term “moyamoya” was included as part of the radiology report; otherwise, they were considered nondiagnostic for moyamoya. Data storage and analysis were performed using REDCap (Research Electronic Data Capture), a secure online application for building clinical databases hosted at the University of Kentucky. Subsequent statistical analyses were performed using Microsoft Excel. The protocol used obtained institutional review board approval.
Statistical Analysis Although the majority of the present study was descriptive, statistical analysis was performed to compare the severity of moyamoya disease at the time of diagnosis between patients with and without diabetes, as well as between patients with and without autoimmune disease, as measured by Suzuki grade on angiogram. Because disease burden most likely had laterality, the left and right sides of intracranial arteries were graded separately, and comparisons were performed using both the higher Suzuki grade and the total Suzuki grade for each patient. An unpaired, 1-tailed Student t-test was used to compare the severity of the disease in patients without diabetes with that of patients with diabetes. In addition, a 1-tailed Student t-test was also used to determine whether a higher glycosylated hemoglobin at diagnosis in diabetics correlated with more severe disease just among diabetic patients. We also compared the Suzuki grade of patients with autoimmune disease with that of patients without autoimmune disease to investigate whether those with comorbid autoimmune disease had a more severe moyamoya presentation.
FACTORS ASSOCIATED WITH MOYAMOYA SYNDROME
795
Diabetes or Autoimmune Disorder and Severity of Moyamoya Disease
Results Patient Characteristics From 2011 to 2015, 31 cases of moyamoya met the inclusion criteria (11 male and 20 female). Of these cases, 26 presented initially as ischemic stroke, 2 as hemorrhagic stroke, and 3 with transient ischemic attack or syncope. Patient demographics, as well as preprocedural information, are shown in Table 1. All patients underwent initial medical management with antiplatelet therapy, with some also undergoing additional dual antiplatelet or anticoagulation treatment, as well as 21 patients undergoing further surgical intervention.
Comorbidities Associated with Moyamoya Syndrome In addition to classic stroke risk factors, 26% of the patients were found to have a coexisting autoimmune condition, and another 13% had a coexisting prothrombotic disorder. The breakdown of prevalence of specific conditions is listed in Table 2.
Out of the 31 patients enrolled in the present study, 11 had concurrent diabetes mellitus. The presence of diabetes was found not to be significantly correlated with severity of intracranial stenosis at diagnosis determined by Suzuki grading of vessels, either when using only the side of the brain with the higher Suzuki grade (P = .37) or when using the total Suzuki grade for each patient (P = .30). Likewise, the severity of diabetes (using surrogate marker of glycosylated hemoglobin) at the time of the initial angiogram for moyamoya diagnosis was not found to be correlated with more severe stenosis when comparing the side with the higher Suzuki grade (P = .17) or when comparing the total Suzuki grade (.43). Out of the 31 patients enrolled in the present study, 8 had concurrent autoimmune disease. The severity of intracranial stenosis at diagnosis was not found to be significantly correlated with whether patients had an autoimmune condition, either when using the side of the
Table 1. Patient demographics, disease manifestation, and treatment administered for 31 patients with moyamoya syndrome Age at diagnosis 12-72 (median age 40) Gender 65% female, 35% male Ethnicity 84% Caucasian, 16% African-American Initial presentation 84% ischemic 6% hemorrhagic 10% other (TIA, syncope) Vessels involved 58% bilateral, 42% unilateral 68% ICA, 71% MCA, 23% ACA (>45% multivessel) Comorbidities Known stroke risk factors 61% Hypertension 52% Obesity 39% Hyperlipidemia 39% Smoking 35% Diabetes 19% CAD or PVD
Other 26% Autoimmune disorders 13% Prothrombotic disorders 6% Genetic disorders
Treatment type Anticoagulation 100% treated medically 6% Warfarin Antiplatelets 48% Aspirin only 45% Aspirin + clopidogrel 3% Clopidogrel only 3% Aspirin or dipyridamole 68% underwent additional surgical treatment in addition to medical therapy 61% indirect bypass (EDAS) 7% intracranial stent Abbreviations: ACA, anterior cerebral artery; CAD, coronary artery disease; EDAS, encephaloduroarteriosynangiosis; ICA, internal carotid artery; MCA, middle cerebral artery; PVD, peripheral vascular disease; TIA, transient ischemic attack.
C.Y. WANG ET AL.
796
Table 2. Comorbidities associated with moyamoya syndrome Comorbidity
n
Percent
Diabetes Type 1 Type 2 Autoimmune Rheumatoid arthritis Hypothyroidism Lupus Psoriasis PGA type 1 Autoimmune hepatitis Addison disease ITP Crohn disease Multiple sclerosis Celiac sprue Dermatitis herpetiformis Prothrombotic Protein C deficiency Protein S deficiency Hgb G trait Factor V Leiden Prothrombin G20210A
11 1 10 8 3 3 2 2 1 1 1 1 1 1 1 1 4 2 2 1 1 1
35
26
13
Abbreviations: Hgb, hemoglobin; ITP, idiopathic thrombocytopenic purpura; PGA type 1, polyglandular autoimmune syndrome type 1.
brain with the higher Suzuki grade (P = .16) or when using the total Suzuki grade for each patient (P = .09).
False-Negative Diagnostic Rate of Noninvasive Imaging Of the 31 patients with moyamoya, 26 underwent noninvasive imaging by CTA or MRA before the diagnostic angiogram. The false-negative rate of CTA for the diagnosis of moyamoya was 59%, and the false-negative rate of MRA was 33%.
Surgical Treatment with Follow-Up Ten patients deemed poor candidates for surgical intervention were treated medically with antiplatelets, with or without anticoagulation. The remaining 21 patients underwent additional surgical intervention, with 2 undergoing intracranial stenting and 19 undergoing indirect bypass. We prefer encephaloduroarteriosynangiosis (EDAS) in general because of shorter anesthesia times and less pial dissection. In cases of bilateral disease evident at presentation, bilateral EDAS was performed. In such cases, each side is performed separately with reprepping or redraping in between. The EDAS is typically performed using the posterior branch of the superficial temporal artery and using microscopic dissection of the arachnoid planes. We typically do not perform intracranial stenting as a treat-
ment for moyamoya. In the 2 cases noted, we performed angioplasty and stenting in 2 patients with focal unilateral internal carotid artery or M1 stenosis with stroke risk factors. At the time of treatment, angiograms were more suggestive of intracranial atherosclerotic disease. However, after stenting, on follow-up imaging, the moyamoya became more radiographically evident. Angiograms for followup after surgical intervention were performed at 1 year post treatment, with 100% of the patients showing evidence of revascularization at follow-up, as shown in Figure 1. A case example of a patient approximately 30 years of age with moyamoya and coexisting systemic lupus erythematosus is shown in Figure 2, with the angiogram showing left-sided moyamoya preoperatively, as well as a postbypass angiogram of the same patient at 1 year post procedure, with visible collateral circulation.
Discussion We present in this study a comprehensive overview of comorbid conditions seen in patients with moyamoya. The reported incidence of moyamoya in Japan is .35 per 100,000.10 In the United States, the incidence is closer to .086 per 100,000.11 At our institution, we saw 31 cases of moyamoya syndrome within a 4-year period, treated by the investigators who include a vascular neurologist and a cerebrovascular neurosurgeon, between whom all cases of moyamoya were managed at our institution. All of our patients were thought to have moyamoya syndrome as opposed to the disease, given their age at presentation and the lack of a family history of moyamoya. During this same time, we had 6683 overall stroke admissions and 4984 ischemic stroke admissions. The patients with moyamoya therefore represent .58% of the ischemic stroke patients. The incidence of moyamoya in our study is difficult to estimate, given the study was performed at a tertiary care center with a wide referral base; however, the incidence can be estimated to be ~.70 per 100,000 if the population of Kentucky is used as an estimate for the population we treated. This is nearly 10 times the expected incidence of moyamoya in the American population as noted previously. Although our estimate is limited by which patients presented only to our institution, such an error would, if anything, result in an underestimation of the true incidence. Our results showed some consistent trends with previously reported studies of moyamoya in the United States, with a majority of the patients being female (65%)5,12 and the main presenting manifestation being ischemic rather than hemorrhagic symptoms in the adult population. Noninvasive imaging by CTA or MRA was performed before diagnostic angiogram in 26 of our 31 patients. The false-negative rate for the diagnosis of moyamoya by CTA was determined to be 59%, and the false-negative rate by MRA was 33%. Other reports in
FACTORS ASSOCIATED WITH MOYAMOYA SYNDROME
797
Figure 1. Surgical treatment with follow-up for intracranial stenting and indirect bypass. Twenty-one out of 31 patients underwent surgical intervention, either with intracranial stent or EDAS. One hundred percent of the patients with angiogram at follow-up after surgery showed evidence of revascularization. Abbreviation: EDAS, encephaloduroarteriosynangiosis.
the literature have suggested good correspondence between MRA and CTA and conventional cerebral angiogram, although MRA was found to underestimate moyamoya vessels and to overestimate the amount of stenosis.13-15
Figure 2. Case of a patient with systemic lupus erythematosus. (A) Anteroposterior view and (B) lateral view of left common carotid artery injection showing left internal carotid artery moyamoya preop. (C) Oblique view and (D) lateral view of the left external carotid artery injection in the same patient at 1 year postop, showing collaterals from MMA and STA. Abbreviations: MMA, middle meningeal artery; STA, superficial temporal artery.
However, these studies have mostly studied pediatric cases of moyamoya in the Asian population, and have used additional imaging sequences beyond the ones typically employed for routine evaluation for stroke. In contrast,
798
our results provide support for the role of angiography in the definitive diagnosis of moyamoya, as many cases may still be missed using traditional noninvasive imaging methods. Thus, stroke occurring in young patients with consistent risk factors should be considered for cerebral angiography to rule out moyamoya. The effect that diabetes mellitus has on moyamoya has been under ongoing investigation, with recent literature suggesting that patients with type 2 diabetes may achieve better collateral circulation and clinical outcomes following EDAS.16 Of the 31 patients in our study, 10 had a concurrent diagnosis of type 2 diabetes and 1 had type 1diabetes. This finding represents a significantly higher prevalence than that in the general population (3.2% versus .4% for type 1 diabetes and 32.2% versus 9.7% for type 2 diabetes).17,18 However, we found no association between the presence of diabetes as a comorbid condition and the severity of moyamoya disease at the time of diagnosis (P = .37). In addition, among diabetic patients, we also found no association between the degree of glycemic control and the severity of moyamoya disease (P = .17). This finding is consistent with the results of a previous study that found no association between the presence of diabetes and pretreatment Suzuki grade in patients with moyamoya.16 Also in our cohort of patients, we did not find a significant association between the severity of moyamoya disease and the presence of a coexisting autoimmune disorder (P = .16). Our population of patients with moyamoya is unique from many studies published in the literature as it consists of 84% Caucasians and 16% African-Americans, which is more representative of the population we have treated. As expected, we found a high prevalence of comorbidities known to be stroke risk factors, including hypertension, hyperlipidemia, diabetes, smoking, and peripheral atherosclerotic disease. In addition, we also found a surprisingly high prevalence of autoimmune and prothrombotic disorders, many of which have previously individually been reported to be seen with moyamoya syndrome as case reports. As it is being increasingly recognized, this finding may suggest an underlying autoimmune component or predisposition to moyamoya syndrome.4-6 In addition to autoimmune and prothrombotic disorders, we also found 1 patient with coarctation of the aorta, which has been reported with moyamoya,19-21 but no other cases of congenital syndromes reported in the literature. In our population, the presence of “traditional” atherosclerotic stroke risk factors (smoking, hypertension, hyperlipidemia, and diabetes) can confound the diagnosis and treatment of moyamoya. Early moyamoya could be confused with intracranial atherosclerotic disease, and these risk factors can also contribute to poor wound healing after bypass surgery. As such, the combination of moyamoya syndrome with these traditional stroke risk factors complicates both diagnosis and management.
C.Y. WANG ET AL.
When comparing our results with another recent study investigating the properties of moyamoya in a predominantly white population, we see some consistent trends.5 Bower et al reported an ethnic composition that was 85% white, with 22% out of a cohort of 94 patients with moyamoya having a coexisting autoimmune disease, with the highest associations being type 1 diabetes mellitus and thyroid disease. In comparison, our population was 84% white, with a 26% rate of coexisting autoimmune disease. We did not find as high a rate of coexisting type 1 diabetes or thyroid disease, which may be a result of our smaller sample size. However, we do report a slightly different composition of autoimmune disorders, with a similar overall prevalence that is much higher than expected (26% compared with 3.2% in the general population). As such, our findings add to those reported by Bower et al in generating a need for further study of moyamoya in this population. Furthermore, our data, combined with those by Bower et al, support a need for a larger epidemiological evaluation of acquired moyamoya syndrome in association with autoimmune and coagulopathy disorders. In addition, we demonstrated a gender predominance in women, suggesting that, although the female gender tends to be neuroprotective for other stroke diseases, it may be a risk factor for moyamoya syndrome. This finding is consistent with epidemiological studies showing a higher incidence of stroke among young women than men.22 Currently, the method of bypass for the treatment of adult moyamoya still varies between institutions. Although many centers advocate direct bypass or a combination of direct and indirect bypass in adults, EDAS is our most commonly used method of surgical revascularization. In our hands, EDAS involves a faster total case time, resulting in shorter anesthesia times. Specifically, we typically perform a unilateral EDAS within 90 minutes; this provides an opportunity to treat bilateral disease with bilateral EDAS in approximately 3 hours. Of the 21 patients undergoing surgical intervention, all 15 who had an angiogram at 1 year of follow-up demonstrated evidence of vessel collateralization. Our average follow-up period for patients undergoing surgical intervention was 28 months. With this mean clinical and radiographic follow-up, we have had success with indirect bypass. Out of the 21 patients, 15 were found to have developed no additional symptoms of stroke or complications from surgery during the last follow-up. Of the other treated patients, one developed subsequent transient ischemic attacks and eventually underwent EDAS of the contralateral hemisphere due to disease progression, one developed new hemorrhagic stroke with new neurologic deficits, two had complications of scalp neuropathy, and two were lost to follow-up. Thus, in our hands, we have had no new permanent ischemic events in patients who have undergone EDAS. These results are consistent with other studies that have found positive
FACTORS ASSOCIATED WITH MOYAMOYA SYNDROME
799
long-term outcomes after EDAS treatment in adult moyamoya.23,24 In relation to treatment, intracranial stenting is not a typically performed procedure for diagnosed moyamoya. However, as noted in the Results, many of our patients also had concomitant traditional atherosclerotic risk factors. In the 2 cases noted, focal unilateral stenosis was initially diagnosed as intracranial atherosclerotic disease and was treated; the moyamoya findings were not evident until follow-up. A major limitation to the study is inherent to the relative rarity of moyamoya disease, leading to the small sample size as well as the predominant reliance on retrospective data. Because the study was a retrospective review, our only reliable outcome measure after surgical intervention was the angiographic evidence of revascularization, whereas future studies with longer followup periods would allow assessment of long-term clinical and functional outcomes. Another limitation in our ability to better understand this disease is the lack of a representative animal model for moyamoya syndrome. Although the mechanisms of action for many of the comorbidities associated with moyamoya syndrome are known, the etiology of the vasculopathy that occurs in moyamoya is not clear. Recently, a genome-wide association study was performed with Japanese patients with moyamoya, and the ring finger protein (RNF) 213 gene was found to have a strong association with the disease .25 Studies are now using transgenic mouse models to examine the effects of the gene.26,27 However, this genetic link does not account for patients with moyamoya syndrome. Therefore, there is a need for the development of an animal model with an existing comorbidity. This will further our understanding of the mechanisms that underlie moyamoya syndrome and aid in the development of a potential therapeutic target.
2. Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease: disease showing abnormal net-like vessels in base of brain. Arch Neurol 1969;20:288-299. 3. Bonduel M, Hepner M, Sciuccati G, et al. Prothrombotic disorders in children with moyamoya syndrome. Stroke 2001;32:1786-1792. 4. Chen J, Liu Y, Zhou L, et al. Prevalence of autoimmune disease in moyamoya disease patients in Western Chinese population. J Neurol Sci 2015;351:184-186. 5. Bower R, Mallory G, Nwojo M, et al. Moyamoya disease in a primarily white, Midwestern US population: increased prevalence of autoimmune disease. Stroke 2013;44:19971999. 6. Chen J, Liu Y, Zhou L, et al. Increased prevalence of autoimmune disease in patients with unilateral compared with bilateral moyamoya disease. J Neurosurg 2016;124:1215-1220. 7. Starke R, Komotar R, Connolly E. Optimal surgical treatment for moyamoya disease in adults: direct versus indirect bypass. Neurosurg Focus 2009;26. 8. Lee D, Liebeskind D. Characterization of inpatient moyamoya in the United States. Front Neurol 2011;2:19882004. 9. Cho B, Tominaga T. Moyamoya disease update. New York, NY: Springer, 2010. 10. Wakai K, Akiko T, Kiyonobu I, et al. Epidemiological features of moyamoya disease in Japan: findings from a nationwide survey. Clin Neurol Neurosurg 1997;99. 11. Uchino K, Johnston S, Becker K, et al. Moyamoya disease in Washington state and California. Neurology 2005;65:956-958. 12. Starke R, Crowley R, Maltenfort M, et al. Moyamoya disorder in the United States. Neurosurgery 2012;71:93-99. 13. Saeki N, Silva M, Kubota M, et al. Comparative performance of magnetic resonance angiography and conventional angiography in moyamoya disease. J Clin Neurosci 2000;7:112-115. 14. Yamada I, Suzuki S, Matsushima Y. Moyamoya disease: comparison of assessment with MR angiography and MR imaging versus conventional angiography. Radiology 1995;196:211-218. 15. Hasuo K, Yasumori K, Yoshida K, et al. Magnetic resonance imaging compared with computed tomography and angiography in moyamoya disease. Acta Radiol 1990;31:191-195. 16. Ren B, Zhang Z, Liu W, et al. Surgical outcomes following encephaloduroarteriosynangiosis in adult moyamoya disease associated with Type 2 diabetes. J Neurosurg 2016;125:308-314. 17. National Diabetes Information Clearinghouse (NDIC), a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). National Diabetes Statistics 2011. Available at: http://www.diabetes.niddk.nih.gov/dm/pubs/ statistics/. 18. Department for Medicaid Services, Department for Public Health, Office of Health Policy, Cabinet for Health and Family Services, Department of Employee Insurance, and Personnel Cabinet. 2015 Kentucky Diabetes Report. 2015. Available at: http://chfs.ky.gov/NR/rdonlyres/7D367886 -671C-435E-BCF4-B2A740438699/0/2015DiabetesReport Final.pdf. 19. Lutterman J, Scott M, Nass R, et al. Moyamoya syndrome associated with congenital heart disease. Pediatrics 1998;101:57-60. 20. Christiaens F, Van den Broeck L, Christophe C, et al. Moyamoya disease (moyamoya syndrome) and
Conclusions The pathogenesis of moyamoya syndrome remains unclear. Our study in a predominantly Caucasian population of patients with moyamoya reveals multiple coexisting autoimmune and prothrombotic disorders, at a rate higher than would be expected in the general population. Our experience with intracranial stenting and indirect bypass demonstrates excellent evidence of revascularization within 1 year of treatment. Acknowledgments: We thank Margie Campbell, Stroke Program Coordinator, for providing data for stroke admission rates for our hospital, and Mary Faulkner for help in preparing the institutional review board submission for this study.
References 1. Burke G, Burke A, Sherma A, et al. Moyamoya disease: a summary. Neurosurg Focus 2009;26.
C.Y. WANG ET AL.
800
21. 22.
23.
24.
coarctation of the aorta. Neuropediatrics 2000;31:4748. Zheng Y, Xie C, Gong F. Moyamoya disease associated with aortic coarctation. World J Pediatr 2014;10:374. Reeves M, Bushnell C, Howard G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 2008;7:915-926. Han D, Nam D, Oh C. Moyamoya disease in adults: characteristics of clinical presentation and outcome after encephalo-duro-arterio-synangiosis. Clin Neurol Neurosurg 1997;99. Starke R, Komotar R, Hickman Z, et al. Clinical features, surgical treatment, and long-term outcome in adult
patients with moyamoya disease. J Neurosurg 2009;111:936-942. 25. Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first moyamoya disease gene. J Hum Genet 2011;56:34-40. 26. Sonobe S, Fujimura M, Niizuma K, et al. Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. Neuroreport 2014;25:14421446. 27. Sato-Maeda M, Fujimura M, Kanoke A, et al. Transient middle cerebral artery occlusion in mice induces neuronal expression of RNF213, a susceptibility gene for moyamoya disease. Brain Res 2016;1630:50-55.
PhD,§ ‖ ,
Objectives: Our study aimed to report both new and previously identified conditions associated with moyamoya syndrome in a Western population and to present our outcomes after surgical treatment with indirect bypass. Methods: We performed a retrospective chart review of patients evaluated at our institution from June 2011 to June 2015 who were diagnosed with moyamoya. Data collected include patient demographics, presenting manifestations, vessels involved, comorbid conditions, abnormal laboratory values, treatments administered, and clinical outcomes. Results: Thirty-one patients with moyamoya were enrolled (11 male and 20 female), with 84% Caucasian and 16% African-American. The most common comorbidity was hypertension in 61% of the patients. Coexisting autoimmune conditions were present in 26%, with another 13% having coexisting prothrombotic disorders. Diabetes mellitus was not found to correlate with the Suzuki grade of disease at presentation (P = .30). When noninvasive imaging was performed before the cerebral angiogram, the computed tomography angiography had a false-negative rate of 59%, and magnetic resonance angiography had a false-negative rate of 33%. Twenty-one patients underwent surgical intervention, 2 underwent intracranial stenting, and 19 underwent indirect bypass with encephaloduroarteriosynangiosis. At an average 28-month follow-up, all 15 patients who had an angiogram after intervention showed evidence of neovascularization. Conclusions: Autoimmune and prothrombotic disorders were found to be comorbid in patients with moyamoya at much higher rates than expected in the general population. Diabetes mellitus was not significantly correlated with Suzuki grade. Angiogram remains an important diagnostic modality when noninvasive imaging is negative for vasculopathy. We demonstrate excellent evidence of revascularization within 1 year with intracranial stenting and indirect bypass. Key Words: Angiography—artery—stenosis— stroke—moyamoya—bypass. © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved.
From the *Department of Neurosurgery; †Department of Neurology; ‡Department of Radiology; §Department of Neuroscience; and ‖Sanders Brown Center on Aging, University of Kentucky, Lexington, Kentucky. Received July 13, 2017; revision received September 24, 2017; accepted October 12, 2017. Author contributions: Catherine Wang: data collection and analysis of patient demographics, comorbid disorders, and treatment outcomes; Stephen Grupke: Suzuki grading of pre- and post-treatment angiograms; Jessica Lee and Justin Fraser: provision of patient data for study and overall study design; Catherine Wang, Jill Roberts, and Justin Fraser: writing of the manuscript. All authors read and edited the text. Grant support: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. Data sharing: Not applicable. Address correspondence to Catherine Y. Wang, MD, Justin F. Fraser, MD, Department of Neurosurgery, University of Kentucky, 800 Rose Street, MS 101A, Lexington KY 40536. E-mail: [email protected], [email protected]. 1052-3057/$ - see front matter © 2018 National Stroke Association. Published by Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jstrokecerebrovasdis.2017.10.016
Journal of Stroke and Cerebrovascular Diseases, Vol. 27, No. 3 (March), 2018: pp 793–800
793
C.Y. WANG ET AL.
794
Introduction Moyamoya disease is a progressive occlusive disease of the cerebral vasculature, with particular involvement of the vessels of the circle of Willis.1 Over time, abnormal collateral networks develop to bypass these stenotic vessels. Although first described as a bilateral phenomenon affecting East Asians,2 similar angiographic features of moyamoya disease are evident in patients with other medical conditions, such as autoimmune or congenital disorders.3-6 In these instances, the terms “moyamoya syndrome” or “moyamoya vasculopathy” are often used. Medical management of the disease usually consists of managing complications, such as controlling hypertension and modifying stroke risk factors, as well as antiplatelet therapy. Surgical revascularization techniques can restore cerebral blood flow through forms of direct or indirect bypass.7 Numerous associated conditions have been reported in the literature in reference to moyamoya syndrome, but most occur as case reports.8 Few publications have analyzed the prevalence of such conditions or have given a comprehensive overview of associated conditions within a regional population.9 Even fewer studies have focused on moyamoya within a Caucasian population, which has different epidemiological and clinical features. The aim of the present study was 2-fold: first, to report both new and previously identified conditions in patients with moyamoya syndrome within a Kentucky regional population treated at the University of Kentucky Medical Center and to compare this to what has been reported in the literature; second, we report clinical and angiographic outcomes in our cohort of patients undergoing surgical intervention. The identification of these coexisting conditions will hopefully serve to allow better conceptualization of the pathophysiology involved in moyamoya syndrome, as well as a more timely and accurate diagnosis of moyamoya syndrome.
Methods Patient Population We performed a retrospective chart review of all patients with the International Classification of Diseases, Ninth Revision (ICD-9), and the subsequent International Classification of Diseases, 10th Revision (ICD-10), diagnoses of moyamoya disease who were evaluated at the University of Kentucky Medical Center between June 1, 2011, and June 1, 2015. All were patients under treatment by one of the investigators. Thirtysix total patients were initially identified, but 5 patients were subsequently excluded due to age younger than 18 years or having incomplete hospital records necessary for analysis. Records of all inpatient stroke admissions
between 2011 and 2015 were also obtained for epidemiological comparison.
Data Collection Epidemiological information about patient demographics was obtained, including age at diagnosis, gender, presenting manifestation, and vessels involved. Baseline stroke risk factors, including hypertension, hyperlipidemia, obesity, diabetes, smoking, coronary artery disease, and peripheral vascular disease, were collected. In addition, moyamoya syndrome risk factors, in particular, comorbid autoimmune and prothrombotic disorders, were assessed. Treatments administered were classified as either medical only (antiplatelet or anticoagulation therapy), surgical (indirect bypass or stenting), or both. Patient angiograms were reviewed retrospectively by an independent investigator (S.G.) who had not performed the procedures for Suzuki grade and for angiographic success of bypass procedures. In addition, results of noninvasive imaging modalities like computed tomography angiography (CTA) and magnetic resonance angiography (MRA) before the diagnostic angiogram were reviewed. The results were determined to be diagnostic of moyamoya if the term “moyamoya” was included as part of the radiology report; otherwise, they were considered nondiagnostic for moyamoya. Data storage and analysis were performed using REDCap (Research Electronic Data Capture), a secure online application for building clinical databases hosted at the University of Kentucky. Subsequent statistical analyses were performed using Microsoft Excel. The protocol used obtained institutional review board approval.
Statistical Analysis Although the majority of the present study was descriptive, statistical analysis was performed to compare the severity of moyamoya disease at the time of diagnosis between patients with and without diabetes, as well as between patients with and without autoimmune disease, as measured by Suzuki grade on angiogram. Because disease burden most likely had laterality, the left and right sides of intracranial arteries were graded separately, and comparisons were performed using both the higher Suzuki grade and the total Suzuki grade for each patient. An unpaired, 1-tailed Student t-test was used to compare the severity of the disease in patients without diabetes with that of patients with diabetes. In addition, a 1-tailed Student t-test was also used to determine whether a higher glycosylated hemoglobin at diagnosis in diabetics correlated with more severe disease just among diabetic patients. We also compared the Suzuki grade of patients with autoimmune disease with that of patients without autoimmune disease to investigate whether those with comorbid autoimmune disease had a more severe moyamoya presentation.
FACTORS ASSOCIATED WITH MOYAMOYA SYNDROME
795
Diabetes or Autoimmune Disorder and Severity of Moyamoya Disease
Results Patient Characteristics From 2011 to 2015, 31 cases of moyamoya met the inclusion criteria (11 male and 20 female). Of these cases, 26 presented initially as ischemic stroke, 2 as hemorrhagic stroke, and 3 with transient ischemic attack or syncope. Patient demographics, as well as preprocedural information, are shown in Table 1. All patients underwent initial medical management with antiplatelet therapy, with some also undergoing additional dual antiplatelet or anticoagulation treatment, as well as 21 patients undergoing further surgical intervention.
Comorbidities Associated with Moyamoya Syndrome In addition to classic stroke risk factors, 26% of the patients were found to have a coexisting autoimmune condition, and another 13% had a coexisting prothrombotic disorder. The breakdown of prevalence of specific conditions is listed in Table 2.
Out of the 31 patients enrolled in the present study, 11 had concurrent diabetes mellitus. The presence of diabetes was found not to be significantly correlated with severity of intracranial stenosis at diagnosis determined by Suzuki grading of vessels, either when using only the side of the brain with the higher Suzuki grade (P = .37) or when using the total Suzuki grade for each patient (P = .30). Likewise, the severity of diabetes (using surrogate marker of glycosylated hemoglobin) at the time of the initial angiogram for moyamoya diagnosis was not found to be correlated with more severe stenosis when comparing the side with the higher Suzuki grade (P = .17) or when comparing the total Suzuki grade (.43). Out of the 31 patients enrolled in the present study, 8 had concurrent autoimmune disease. The severity of intracranial stenosis at diagnosis was not found to be significantly correlated with whether patients had an autoimmune condition, either when using the side of the
Table 1. Patient demographics, disease manifestation, and treatment administered for 31 patients with moyamoya syndrome Age at diagnosis 12-72 (median age 40) Gender 65% female, 35% male Ethnicity 84% Caucasian, 16% African-American Initial presentation 84% ischemic 6% hemorrhagic 10% other (TIA, syncope) Vessels involved 58% bilateral, 42% unilateral 68% ICA, 71% MCA, 23% ACA (>45% multivessel) Comorbidities Known stroke risk factors 61% Hypertension 52% Obesity 39% Hyperlipidemia 39% Smoking 35% Diabetes 19% CAD or PVD
Other 26% Autoimmune disorders 13% Prothrombotic disorders 6% Genetic disorders
Treatment type Anticoagulation 100% treated medically 6% Warfarin Antiplatelets 48% Aspirin only 45% Aspirin + clopidogrel 3% Clopidogrel only 3% Aspirin or dipyridamole 68% underwent additional surgical treatment in addition to medical therapy 61% indirect bypass (EDAS) 7% intracranial stent Abbreviations: ACA, anterior cerebral artery; CAD, coronary artery disease; EDAS, encephaloduroarteriosynangiosis; ICA, internal carotid artery; MCA, middle cerebral artery; PVD, peripheral vascular disease; TIA, transient ischemic attack.
C.Y. WANG ET AL.
796
Table 2. Comorbidities associated with moyamoya syndrome Comorbidity
n
Percent
Diabetes Type 1 Type 2 Autoimmune Rheumatoid arthritis Hypothyroidism Lupus Psoriasis PGA type 1 Autoimmune hepatitis Addison disease ITP Crohn disease Multiple sclerosis Celiac sprue Dermatitis herpetiformis Prothrombotic Protein C deficiency Protein S deficiency Hgb G trait Factor V Leiden Prothrombin G20210A
11 1 10 8 3 3 2 2 1 1 1 1 1 1 1 1 4 2 2 1 1 1
35
26
13
Abbreviations: Hgb, hemoglobin; ITP, idiopathic thrombocytopenic purpura; PGA type 1, polyglandular autoimmune syndrome type 1.
brain with the higher Suzuki grade (P = .16) or when using the total Suzuki grade for each patient (P = .09).
False-Negative Diagnostic Rate of Noninvasive Imaging Of the 31 patients with moyamoya, 26 underwent noninvasive imaging by CTA or MRA before the diagnostic angiogram. The false-negative rate of CTA for the diagnosis of moyamoya was 59%, and the false-negative rate of MRA was 33%.
Surgical Treatment with Follow-Up Ten patients deemed poor candidates for surgical intervention were treated medically with antiplatelets, with or without anticoagulation. The remaining 21 patients underwent additional surgical intervention, with 2 undergoing intracranial stenting and 19 undergoing indirect bypass. We prefer encephaloduroarteriosynangiosis (EDAS) in general because of shorter anesthesia times and less pial dissection. In cases of bilateral disease evident at presentation, bilateral EDAS was performed. In such cases, each side is performed separately with reprepping or redraping in between. The EDAS is typically performed using the posterior branch of the superficial temporal artery and using microscopic dissection of the arachnoid planes. We typically do not perform intracranial stenting as a treat-
ment for moyamoya. In the 2 cases noted, we performed angioplasty and stenting in 2 patients with focal unilateral internal carotid artery or M1 stenosis with stroke risk factors. At the time of treatment, angiograms were more suggestive of intracranial atherosclerotic disease. However, after stenting, on follow-up imaging, the moyamoya became more radiographically evident. Angiograms for followup after surgical intervention were performed at 1 year post treatment, with 100% of the patients showing evidence of revascularization at follow-up, as shown in Figure 1. A case example of a patient approximately 30 years of age with moyamoya and coexisting systemic lupus erythematosus is shown in Figure 2, with the angiogram showing left-sided moyamoya preoperatively, as well as a postbypass angiogram of the same patient at 1 year post procedure, with visible collateral circulation.
Discussion We present in this study a comprehensive overview of comorbid conditions seen in patients with moyamoya. The reported incidence of moyamoya in Japan is .35 per 100,000.10 In the United States, the incidence is closer to .086 per 100,000.11 At our institution, we saw 31 cases of moyamoya syndrome within a 4-year period, treated by the investigators who include a vascular neurologist and a cerebrovascular neurosurgeon, between whom all cases of moyamoya were managed at our institution. All of our patients were thought to have moyamoya syndrome as opposed to the disease, given their age at presentation and the lack of a family history of moyamoya. During this same time, we had 6683 overall stroke admissions and 4984 ischemic stroke admissions. The patients with moyamoya therefore represent .58% of the ischemic stroke patients. The incidence of moyamoya in our study is difficult to estimate, given the study was performed at a tertiary care center with a wide referral base; however, the incidence can be estimated to be ~.70 per 100,000 if the population of Kentucky is used as an estimate for the population we treated. This is nearly 10 times the expected incidence of moyamoya in the American population as noted previously. Although our estimate is limited by which patients presented only to our institution, such an error would, if anything, result in an underestimation of the true incidence. Our results showed some consistent trends with previously reported studies of moyamoya in the United States, with a majority of the patients being female (65%)5,12 and the main presenting manifestation being ischemic rather than hemorrhagic symptoms in the adult population. Noninvasive imaging by CTA or MRA was performed before diagnostic angiogram in 26 of our 31 patients. The false-negative rate for the diagnosis of moyamoya by CTA was determined to be 59%, and the false-negative rate by MRA was 33%. Other reports in
FACTORS ASSOCIATED WITH MOYAMOYA SYNDROME
797
Figure 1. Surgical treatment with follow-up for intracranial stenting and indirect bypass. Twenty-one out of 31 patients underwent surgical intervention, either with intracranial stent or EDAS. One hundred percent of the patients with angiogram at follow-up after surgery showed evidence of revascularization. Abbreviation: EDAS, encephaloduroarteriosynangiosis.
the literature have suggested good correspondence between MRA and CTA and conventional cerebral angiogram, although MRA was found to underestimate moyamoya vessels and to overestimate the amount of stenosis.13-15
Figure 2. Case of a patient with systemic lupus erythematosus. (A) Anteroposterior view and (B) lateral view of left common carotid artery injection showing left internal carotid artery moyamoya preop. (C) Oblique view and (D) lateral view of the left external carotid artery injection in the same patient at 1 year postop, showing collaterals from MMA and STA. Abbreviations: MMA, middle meningeal artery; STA, superficial temporal artery.
However, these studies have mostly studied pediatric cases of moyamoya in the Asian population, and have used additional imaging sequences beyond the ones typically employed for routine evaluation for stroke. In contrast,
798
our results provide support for the role of angiography in the definitive diagnosis of moyamoya, as many cases may still be missed using traditional noninvasive imaging methods. Thus, stroke occurring in young patients with consistent risk factors should be considered for cerebral angiography to rule out moyamoya. The effect that diabetes mellitus has on moyamoya has been under ongoing investigation, with recent literature suggesting that patients with type 2 diabetes may achieve better collateral circulation and clinical outcomes following EDAS.16 Of the 31 patients in our study, 10 had a concurrent diagnosis of type 2 diabetes and 1 had type 1diabetes. This finding represents a significantly higher prevalence than that in the general population (3.2% versus .4% for type 1 diabetes and 32.2% versus 9.7% for type 2 diabetes).17,18 However, we found no association between the presence of diabetes as a comorbid condition and the severity of moyamoya disease at the time of diagnosis (P = .37). In addition, among diabetic patients, we also found no association between the degree of glycemic control and the severity of moyamoya disease (P = .17). This finding is consistent with the results of a previous study that found no association between the presence of diabetes and pretreatment Suzuki grade in patients with moyamoya.16 Also in our cohort of patients, we did not find a significant association between the severity of moyamoya disease and the presence of a coexisting autoimmune disorder (P = .16). Our population of patients with moyamoya is unique from many studies published in the literature as it consists of 84% Caucasians and 16% African-Americans, which is more representative of the population we have treated. As expected, we found a high prevalence of comorbidities known to be stroke risk factors, including hypertension, hyperlipidemia, diabetes, smoking, and peripheral atherosclerotic disease. In addition, we also found a surprisingly high prevalence of autoimmune and prothrombotic disorders, many of which have previously individually been reported to be seen with moyamoya syndrome as case reports. As it is being increasingly recognized, this finding may suggest an underlying autoimmune component or predisposition to moyamoya syndrome.4-6 In addition to autoimmune and prothrombotic disorders, we also found 1 patient with coarctation of the aorta, which has been reported with moyamoya,19-21 but no other cases of congenital syndromes reported in the literature. In our population, the presence of “traditional” atherosclerotic stroke risk factors (smoking, hypertension, hyperlipidemia, and diabetes) can confound the diagnosis and treatment of moyamoya. Early moyamoya could be confused with intracranial atherosclerotic disease, and these risk factors can also contribute to poor wound healing after bypass surgery. As such, the combination of moyamoya syndrome with these traditional stroke risk factors complicates both diagnosis and management.
C.Y. WANG ET AL.
When comparing our results with another recent study investigating the properties of moyamoya in a predominantly white population, we see some consistent trends.5 Bower et al reported an ethnic composition that was 85% white, with 22% out of a cohort of 94 patients with moyamoya having a coexisting autoimmune disease, with the highest associations being type 1 diabetes mellitus and thyroid disease. In comparison, our population was 84% white, with a 26% rate of coexisting autoimmune disease. We did not find as high a rate of coexisting type 1 diabetes or thyroid disease, which may be a result of our smaller sample size. However, we do report a slightly different composition of autoimmune disorders, with a similar overall prevalence that is much higher than expected (26% compared with 3.2% in the general population). As such, our findings add to those reported by Bower et al in generating a need for further study of moyamoya in this population. Furthermore, our data, combined with those by Bower et al, support a need for a larger epidemiological evaluation of acquired moyamoya syndrome in association with autoimmune and coagulopathy disorders. In addition, we demonstrated a gender predominance in women, suggesting that, although the female gender tends to be neuroprotective for other stroke diseases, it may be a risk factor for moyamoya syndrome. This finding is consistent with epidemiological studies showing a higher incidence of stroke among young women than men.22 Currently, the method of bypass for the treatment of adult moyamoya still varies between institutions. Although many centers advocate direct bypass or a combination of direct and indirect bypass in adults, EDAS is our most commonly used method of surgical revascularization. In our hands, EDAS involves a faster total case time, resulting in shorter anesthesia times. Specifically, we typically perform a unilateral EDAS within 90 minutes; this provides an opportunity to treat bilateral disease with bilateral EDAS in approximately 3 hours. Of the 21 patients undergoing surgical intervention, all 15 who had an angiogram at 1 year of follow-up demonstrated evidence of vessel collateralization. Our average follow-up period for patients undergoing surgical intervention was 28 months. With this mean clinical and radiographic follow-up, we have had success with indirect bypass. Out of the 21 patients, 15 were found to have developed no additional symptoms of stroke or complications from surgery during the last follow-up. Of the other treated patients, one developed subsequent transient ischemic attacks and eventually underwent EDAS of the contralateral hemisphere due to disease progression, one developed new hemorrhagic stroke with new neurologic deficits, two had complications of scalp neuropathy, and two were lost to follow-up. Thus, in our hands, we have had no new permanent ischemic events in patients who have undergone EDAS. These results are consistent with other studies that have found positive
FACTORS ASSOCIATED WITH MOYAMOYA SYNDROME
799
long-term outcomes after EDAS treatment in adult moyamoya.23,24 In relation to treatment, intracranial stenting is not a typically performed procedure for diagnosed moyamoya. However, as noted in the Results, many of our patients also had concomitant traditional atherosclerotic risk factors. In the 2 cases noted, focal unilateral stenosis was initially diagnosed as intracranial atherosclerotic disease and was treated; the moyamoya findings were not evident until follow-up. A major limitation to the study is inherent to the relative rarity of moyamoya disease, leading to the small sample size as well as the predominant reliance on retrospective data. Because the study was a retrospective review, our only reliable outcome measure after surgical intervention was the angiographic evidence of revascularization, whereas future studies with longer followup periods would allow assessment of long-term clinical and functional outcomes. Another limitation in our ability to better understand this disease is the lack of a representative animal model for moyamoya syndrome. Although the mechanisms of action for many of the comorbidities associated with moyamoya syndrome are known, the etiology of the vasculopathy that occurs in moyamoya is not clear. Recently, a genome-wide association study was performed with Japanese patients with moyamoya, and the ring finger protein (RNF) 213 gene was found to have a strong association with the disease .25 Studies are now using transgenic mouse models to examine the effects of the gene.26,27 However, this genetic link does not account for patients with moyamoya syndrome. Therefore, there is a need for the development of an animal model with an existing comorbidity. This will further our understanding of the mechanisms that underlie moyamoya syndrome and aid in the development of a potential therapeutic target.
2. Suzuki J, Takaku A. Cerebrovascular “moyamoya” disease: disease showing abnormal net-like vessels in base of brain. Arch Neurol 1969;20:288-299. 3. Bonduel M, Hepner M, Sciuccati G, et al. Prothrombotic disorders in children with moyamoya syndrome. Stroke 2001;32:1786-1792. 4. Chen J, Liu Y, Zhou L, et al. Prevalence of autoimmune disease in moyamoya disease patients in Western Chinese population. J Neurol Sci 2015;351:184-186. 5. Bower R, Mallory G, Nwojo M, et al. Moyamoya disease in a primarily white, Midwestern US population: increased prevalence of autoimmune disease. Stroke 2013;44:19971999. 6. Chen J, Liu Y, Zhou L, et al. Increased prevalence of autoimmune disease in patients with unilateral compared with bilateral moyamoya disease. J Neurosurg 2016;124:1215-1220. 7. Starke R, Komotar R, Connolly E. Optimal surgical treatment for moyamoya disease in adults: direct versus indirect bypass. Neurosurg Focus 2009;26. 8. Lee D, Liebeskind D. Characterization of inpatient moyamoya in the United States. Front Neurol 2011;2:19882004. 9. Cho B, Tominaga T. Moyamoya disease update. New York, NY: Springer, 2010. 10. Wakai K, Akiko T, Kiyonobu I, et al. Epidemiological features of moyamoya disease in Japan: findings from a nationwide survey. Clin Neurol Neurosurg 1997;99. 11. Uchino K, Johnston S, Becker K, et al. Moyamoya disease in Washington state and California. Neurology 2005;65:956-958. 12. Starke R, Crowley R, Maltenfort M, et al. Moyamoya disorder in the United States. Neurosurgery 2012;71:93-99. 13. Saeki N, Silva M, Kubota M, et al. Comparative performance of magnetic resonance angiography and conventional angiography in moyamoya disease. J Clin Neurosci 2000;7:112-115. 14. Yamada I, Suzuki S, Matsushima Y. Moyamoya disease: comparison of assessment with MR angiography and MR imaging versus conventional angiography. Radiology 1995;196:211-218. 15. Hasuo K, Yasumori K, Yoshida K, et al. Magnetic resonance imaging compared with computed tomography and angiography in moyamoya disease. Acta Radiol 1990;31:191-195. 16. Ren B, Zhang Z, Liu W, et al. Surgical outcomes following encephaloduroarteriosynangiosis in adult moyamoya disease associated with Type 2 diabetes. J Neurosurg 2016;125:308-314. 17. National Diabetes Information Clearinghouse (NDIC), a service of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH). National Diabetes Statistics 2011. Available at: http://www.diabetes.niddk.nih.gov/dm/pubs/ statistics/. 18. Department for Medicaid Services, Department for Public Health, Office of Health Policy, Cabinet for Health and Family Services, Department of Employee Insurance, and Personnel Cabinet. 2015 Kentucky Diabetes Report. 2015. Available at: http://chfs.ky.gov/NR/rdonlyres/7D367886 -671C-435E-BCF4-B2A740438699/0/2015DiabetesReport Final.pdf. 19. Lutterman J, Scott M, Nass R, et al. Moyamoya syndrome associated with congenital heart disease. Pediatrics 1998;101:57-60. 20. Christiaens F, Van den Broeck L, Christophe C, et al. Moyamoya disease (moyamoya syndrome) and
Conclusions The pathogenesis of moyamoya syndrome remains unclear. Our study in a predominantly Caucasian population of patients with moyamoya reveals multiple coexisting autoimmune and prothrombotic disorders, at a rate higher than would be expected in the general population. Our experience with intracranial stenting and indirect bypass demonstrates excellent evidence of revascularization within 1 year of treatment. Acknowledgments: We thank Margie Campbell, Stroke Program Coordinator, for providing data for stroke admission rates for our hospital, and Mary Faulkner for help in preparing the institutional review board submission for this study.
References 1. Burke G, Burke A, Sherma A, et al. Moyamoya disease: a summary. Neurosurg Focus 2009;26.
C.Y. WANG ET AL.
800
21. 22.
23.
24.
coarctation of the aorta. Neuropediatrics 2000;31:4748. Zheng Y, Xie C, Gong F. Moyamoya disease associated with aortic coarctation. World J Pediatr 2014;10:374. Reeves M, Bushnell C, Howard G, et al. Sex differences in stroke: epidemiology, clinical presentation, medical care, and outcomes. Lancet Neurol 2008;7:915-926. Han D, Nam D, Oh C. Moyamoya disease in adults: characteristics of clinical presentation and outcome after encephalo-duro-arterio-synangiosis. Clin Neurol Neurosurg 1997;99. Starke R, Komotar R, Hickman Z, et al. Clinical features, surgical treatment, and long-term outcome in adult
patients with moyamoya disease. J Neurosurg 2009;111:936-942. 25. Kamada F, Aoki Y, Narisawa A, et al. A genome-wide association study identifies RNF213 as the first moyamoya disease gene. J Hum Genet 2011;56:34-40. 26. Sonobe S, Fujimura M, Niizuma K, et al. Increased vascular MMP-9 in mice lacking RNF213: moyamoya disease susceptibility gene. Neuroreport 2014;25:14421446. 27. Sato-Maeda M, Fujimura M, Kanoke A, et al. Transient middle cerebral artery occlusion in mice induces neuronal expression of RNF213, a susceptibility gene for moyamoya disease. Brain Res 2016;1630:50-55.