Ivy sign in moyamoya disease

doi:10.21203/rs.3.rs-2118338/v1

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Ivy sign in moyamoya disease

https://doi.org/10.21203/rs.3.rs-2118338/v1

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Background: Moyamoya disease can not be found commonly as a rare type compared to other vascular diseases, such as intracranial aneurysms. However, it can not be ignored for its high fatality and disability rate. In addition, the exact pathogenesis study of this disease is still on the way. The ivy sign is always observed in moyamoya disease (MMD), but the clinical importance of this sign in MMD isn't known. The main purpose of this research was to specifically investigate the clinical significance.

Methods: The patients with moyamoya disease were hospitalized from January 2016 to 2020, it’s a retrospective cohort study to gather the baseline clinical and imaging study. The study was approved by the Institutional Review Board and Ethics Committee of West China Hospital, Sichuan University (No. 2018-219), Informed consent was obtained from all individual participants included in the study，all experiments were performed in accordance with relevant guidelines and regulations. In the analysis, univariate and multivariate logistic regression was utilized to testify whether ivy sign was independently associated with MMD characteristics, including cerebrovascular morphology, cerebral hemodynamics, cerebrovascular events, and postoperative collateral formation (PCF).

Results: 156 patients were included with 312 hemispheres (Table 1). As for the result of multivariate logistic regression analysis, we could discover a fact that ivy sign was tightly connected to the Suzuki stage ≥IV(OR,1.386;95%CI,1.055-1.822;p=0.019（Table2）), rCBF(cerebral blood flow) decreased type (OR,2.330;95%CI,1.733-3.133;p=0.000（Table3）), age acted as a protective factor for rCBF(OR, 0.966; 95%CI,0.946-0.986;p=0.001, the elder was more likely associated with decreased rCBF. ivy sign also played a significant role in Ischemic cerebrovascular events(OR,5.653;95%CI,3.092-10.336; p=0.003(Table5)), their remarkable connection could be seen in the study. We could also find that ivy was closely connected to good postoperative collateral formation (PCF)( OR,2.830;95%CI,1.329-6.027; p=0.007(Table4), we couldn't ignore that age was associated with good PCF as well(OR, 0.933;95%CI, 0.882-0.987; p=0.015).

Discussion: We could be more aware of the connection between ivy signs and moyamoya disease from this study, to implement diagnosis, treatment, and prognosis more efficiently.

Biological sciences/Neuroscience

Health sciences/Neurology

ivy sign

moyamoya disease

postoperative collateral formation

cerebral blood flow

As we all know, MMD is characterized by progressive stenosis or occlusion of the terminal internal cerebral artery and its branches, with the formation of a vascular network at the base of the brain^1–5, accompanied by abnormal cerebrovascular morphology and cerebral hemodynamics, As the disease progresses, transient ischemic attacks and hemorrhagic strokes occur. Clinically, the disease is characterized by recurrent cephalgia, epileptic seizures, cognitive decline, movement disorders, and spastic paresis^1,6. We can diagnose MMD with cerebral angiography and perfusion imaging⁷. Ivy sign is defined as the continuous linear or punctate high intensity along the cortical sulci and subarachnoid space on magnetic resonance images (MRI) in MMD patients⁸. It refers to a diffuse leptomeningeal enhancement found on postcontrast MR images or unenhanced fluid-attenuated inversion recovery (FLAIR) images(Fig. 1) ^{1–4, 8,9}, which mostly indicates a negative relationship with cerebral vascular reserve (CVR), collateral formation, and a positive relationship with severity of ischemia^{1,2,4,5,8−11}. However, no studies comprehensively investigate the relationship between ivy signs and MMD. Owe to this study, a realization of ivy sign and MMD will be strengthened

2.1 Data Availability

The datasets used and analyzed during the current study available from the corresponding author on reasonable request.

2.2 Patients

From January 2016 to January 2020 156 patients were diagnosed with MMD at our institution according to the criteria in 2012⁷. The study was approved by the Institutional Review Board and Ethics Committee of West China Hospital, Sichuan University (No. 2018 − 219), Informed consent was obtained from all individual participants included in the study, all experiments were performed in accordance with relevant guidelines and regulations. All digital subtraction angiography (DSA) and/or MR angiography imaging were screened and then included in this study. Exclusion criteria were: 1)patients without MRI and/or perfusion images(CTP);2)images were performed in the acute phase;3)patients can not be judged which hemisphere was with intracranial hemorrhage;

4)other situations can interfere with the manifestation of images.

Imaging scans

MRI was performed by a 3.0-T scanner (Skyra, Siemens Medical System, Erlangen, Germany), including four sequences: T2 weighted imaging (section thickness, 5 mm; section gap, 1.5 mm; repetition time 4250 milliseconds; and echo time 98 milliseconds), fluid attenuation inversion recovery (FLAIR) (section thickness, 5 mm; section gap, 1.5 mm; repetition time 5000 milliseconds; echo time 85 milliseconds).

2.3 Imaging analysis

MRI analysis

Ivy sign is a special imaging manifestation in MMD and is defined as the continuous linear or punctate hyperintensities on FLAIR imaging along the cortical sulci and subarachnoid space⁸ Because Ivy sign is associated with pathological changes in cerebral small vessels and reflects the development of compensatory collaterals^1,2,8,11. The ivy sign grade of each hemisphere was defined as follows: 0 (absence), 1 (less than half of the cortical surface), and 2 (more than half of the cortical surface). Ivy sign severity was classified as mild (grade 0–1) or severe (grade 2)^8,12. Two neuroradiologists reviewed the ivy sign independently without knowledge of the clinical information or DSA/CTP findings. If there was inconsistency with the images, it would be resolved by discussion.

Cerebral Morphology Assessment

Conventionally, we utilized Suzuki's angiographic stage ¹²to stand for the situation of cerebral morphology. Based on the literature, Suzuki's angiographic stage was graded into 6 stages,≥4 stages represent severe disease.

Cerebral Hemodynamics Assessment

Regional cerebral blood flow (rCBF) was equal to cerebral hemodynamics for MMD patients. Decreased rCBF indicates hemodynamic dysfunction. the bilateral cerebral cortex and basal ganglia territories were set as regions of interest and ischemic areas. They were compared with normal areas.

All these CTP examinations in our institution were completed on the 128-row dual-source CT system (Somatom Definition FLASH, Siemens Healthcare, Forchheim, Germany). We pick an adaptive 4D spiral imaging range of 100 mm, above the base of the skull and parallel to the AC-PC line. CTP was initiated 5 seconds after injection of 40 mL Ultravist 370 (370 mg I/mL) at a flow rate of 5 mL/s into the antecubital vein using a power injector. The acquisition parameters were as follows: 70 kVp, 150 mAs,0.28 s/rotation, 5 mm slice thickness, 512×512 image matrix size, 1.5 seconds sampling time per volume, and 31 acquisitions in total. Then the parameter of CBF was obtained through post-processing at commercial workstations (Syngo MMWP [VE40A], Siemens Healthcare).

Postoperative Collateral Formation Assessment

The prevalent surgical treatment of MMD was revascularization directly or indirectly. The patients in this assessment underwent superficial temporal artery (STA) -middle cerebral artery (MCA) bypass surgeries. Patients who had the experience of surgery were advised to return to the hospital to reinspect with DSA. It aimed at estimating the collateral formation with the Matsushima scale^12,13 (Fig. 2):Level A, more than 2/3 of the MCA distribution; Level B, between 2/3 and 1/3 of the MCA distribution; and Level C, slight or none. According to the literature, Level A and B were defined as "Good" PCF and Level C was defined as "Poor" PCF¹⁴.

2.4 Statistical Analysis

The univariate and multivariate logistic regression models were used to determine whether the ivy sign was independently associated with the four MMD characteristics. Baseline characteristics were taken as confounding factors. We measure with odd ratios (ORs) and 95% confidence intervals (CIs), and the significance level was set at P < 0.05. The tool we used to calculate was IBM SPSS statistical software.

Ivy sign showed a significant positive correlation with MMD, especially ischemic events.

156 patients were included in the research with 312 hemispheres. 114(36.5%) hemispheres were at ≤ 3 stage, 198(63.5%)hemispheres were ≥ 4 stage. Decreased rCBF was 157(50.3%). 149 symptomatic stroke hemispheres were included in this study. Hemorrhagic events were 44(40.4%) and ischemic events were 105(70.5%). Finally, 81 patients with 86 hemispheres underwent bypass surgery.25(29.1%)was with poor PCF and 61(70.9%) was with good PCF(Table 1).Multivariate logistic regression analysis indicated that the ivy sign (OR,1.386;95%CI,1.055–1.822; p = 0.019(Table 2)) was associated with the Suzuki stage ≥ IV. Baseline characteristics were found no significant association with Cerebrovascular Morphology. Ivy sign(OR,2.330;95%CI,1.733–3.133;p = 0.000(Table 3))was also associate with rCBF decreased type. age was a protective factor for decreased rCBF. In accordance with expectation, the ivy sign(OR,5.653;95%CI,3.092–10.336; p = 0.003(Table 5)) was significantly correlated to severe ischemic events. Ultimately, the ivy sign (OR,2.830;95%CI,1.329–6.027; p = 0.007(Table 4))was associated with good PCF too, age was still associated with PCF, as a protective factor. All other confounding factors were of no significant correlation with MMD.

Table 1

Clinical and Imaging Characteristics of the MMD Study Cohort
Characteristics	Total (156)
Baseline clinical characteristics
Age, ^a years	44.0 (30.0–51.0)
Sex, female	97 (62.2%)
Hypertension	55 (35.3%)
Diabetes mellitus	15 (9.6%)
Hyperlipidemia	20 (12.8%)
Tobacco abuse	31 (19.9%)
Alcohol abuse	24 (15.4%)
Clinical manifestation
Hemorrhagic MMD	44(40.4%)
Ischemic MMD	105(70.5%)
Imaging characteristics
Suzuki stage
I-III	114 (36.5%)
IV-VI	198(63.5%)
Decreased rCBF	157 (50.3%)
Ivy sign ^a (3 grades based on areas)	2.0 (0.0–2.0)
Mild (grade 0–1)	134(42.9%)
Severe (grade 2)	178 (57.1%)

Table 2

Logistic regression analysis exploring Associations of Ivy sign and Cerebrovascular Morphology in MMD
Characteristics	Suzuki stage (312)		P value		OR (95% CI)
	I-III (114)	IV-VI (198)	Uni	Multi
Baseline clinical characteristics
Age, ^a years	41.0(29.0–51.0)	45.0(30.8–51.0)	0.279	0.183	1.014(0.994–1.034)
Sex, female	74(64.9%)	120(60.6%)	0.450	0.560	0.833(0.449–1.543)
Hypertension	39(34.2%)	71(35.9%)	0.769	0.749	0.917(0.537–1.563)
Diabetes mellitus	9(7.9%)	21(10.6%)	0.436	0.484	1.373(0.565–3.337)
Hyperlipidemia	17(14.9%)	31(15.7%)	0.403	0.172	0.599(0.287–1.250)
Tobacco abuse	19(16.7%)	43(21.7%)	0.283	0.551	1.286(0.562–2.942)
Alcohol abuse	17(14.9%)	31(15.7%)	0.861	0.537	0.763(0.323–1.802)
Imaging characteristics
Ivy sign ^a (3 grades based on areas)	1.0(0–2.0)	2.0(0.75-2.0)	0.026	0.019	1.386(1.055–1.822)

Table 3

Logistic regression analysis exploring Associations of Ivy sign and Cerebral Hemodynamics in MMD
Characteristics	rCBF (312)		P value		OR (95% CI)
	Normal (155)	Decreased (157)	Uni	Multi
Baseline clinical characteristics
Age, ^a years	45(33.0–54.0)	42.0(24.0–49.0)	0.011	0.001	0.966(0.946–0.986)
Sex, female	101 (65.2%)	93 (59.2%)	0.281	0.860	0.943(0.490–1.814)
Hypertension	50(32.3%)	60 (38.2%)	0.271	0.194	1.444(0.830–2.514)
Diabetes mellitus	12(7.7%)	18 (11.5%)	0.267	0.190	1.834(0.740–4.543)
Hyperlipidemia	16 (10.3%)	24 (15.3%)	0.192	0.188	1.705(0.770–3.772)
Tobacco abuse	24 (15.5%)	38 (24.2%)	0.055	0.325	1.529(0.657–3.560)
Alcohol abuse	19 (12.3%)	29(18.5%)	0.131	0.443	1.408(0.587–3.382)
Imaging characteristics
Ivy sign ^a (3 grades based on areas)	1.0(0–2.0)	2.0(1.5-2.0)	< 0.001	< 0.001	2.330(1.733–3.133)

Table 4

Logistic regression analysis exploring Associations of Ivy sign and postoperative collateral formation in MMD
Characteristics	PCF (86)		P value		OR (95% CI)
	Poor (25)	Good (61)	Uni	Multi
Baseline clinical characteristics
Age, ^a years	49(42.5–55)	35(22–48)	0.001	0.015	0.933(0.882–0.987)
Sex, female	17 (68.0%)	34(55.7%)	0.296	0.063	0.135(0.016–1.116)
Hypertension	12 (48.0%)	18 (29.5%)	0.106	0.325	0.542(0.160–1.836)
Diabetes mellitus	3 (12.0%)	6(9.8%)	0.766	0.277	3.364(0.378–29.926)
Hyperlipidemia	4 (16.0%)	7 (11.5%)	0.570	0.645	0.653(0.106–4.020)
Tobacco abuse	5 (20.0%)	13 (21.3%)	0.892	0.577	2.072(0.161–26.722)
Alcohol abuse	6 (24.0%)	7 (11.5%)	0.149	0.038	0.054(0.003–0.853)
Imaging characteristics
Ivy sign ^a (3 grades based on areas)	1.0(0–2.0)	2.0(2.0–2.0)	0.001	0.007	2.830(1.329–6.027)

Table 5

Logistic regression analysis exploring Associations of Ivy sign and cerebrovascular events in MMD
Characteristics	Cerebrovascular events (149)		P value		OR (95% CI)
	Hemorrhagic (44)	Ischemic (105)	Uni	Multi
Baseline clinical characteristics
Age, ^a years	41(23.3–48)	45(30.5–51)	0.137	0.148	1.029(0.990–1.070)
Sex, female	28 (63.6%)	64 (61.0%)	0.759	0.964	1.026(0.340–3.092)
Hypertension	11(25%)	44 (41.9%)	0.159	0.815	0.885(0.317–2.466)
Diabetes mellitus	2 (4.5%)	15 (14.3%)	0.106	0.200	3.613(0.506–25.806)
Hyperlipidemia	3 (6.8%)	14(13.3%)	0.072	0.266	4.259(0.332–54.655)
Tobacco abuse	6 (13.6%)	27 (25.7%)	0.111	0.307	2.417(0.444–13.159)
Alcohol abuse	1 (2.3%)	18 (17.1%)	0.214	0.604	1.652(0.248-11.000)
Imaging characteristics
Ivy sign ^a (3 grades based on areas)	0.5(0–2.0)	2.0(2.0–2.0)	< 0.001	< 0.001	5.653(3.092–10.336)

MMD was characterized by progressive stenosis or occlusion of the terminal internal cerebral artery and its branches accompanied by abnormal cerebrovascular morphology and cerebral hemodynamics^1–5, which can lead to cerebral ischemia, intracranial hemorrhage, secondary epilepsy, cognitive impairment, and other symptom⁶. The surgical treatment of this disease was to prevent ischemic and hemorrhagic events, which were two main outcomings of MMD⁷. Patients returned to the hospital with an evaluation of DSA to identify PCF. As for MMD patients, cerebrovascular morphology 、cerebral hemodynamics、cerebrovascular events, and PCF were essential to the diagnosis、treatment, and prognosis of MMD, but the relationship between ivy signs and MMD was unclear. In this study, we find the fact that the ivy sign was significantly associated with MMD at 4 items. It's helpful for us to evaluate MMD by ivy sign more accurately.

Ivy sign is a special imaging manifestation of MMD on contrast-enhanced T1 weighted and FLAIR imaging ^{1–4, 8,9}, Janina Gburek-Augustat¹ reported that the ivy Sign was a linear signal increase along the cortical sulci of the brain surface. Maeda, M⁹ also proposed that ivy sign referred to diffuse leptomeningeal enhancement found on postcontrast MR images of patients with moyamoya disease. The reason why ivy sign arose could be explained as follows: Fujiwara, H³ reported that ivy sign arose from slow and stagnant flow in engorged pial vessels, via leptomeningeal anastomosis and thickening of the leptomeninges due to congestion. the prevalence of ivy signs in MMD ranged from 30.3–100%¹⁵. Although the mechanism of the ivy sign is uncertain, as the literature indicates: Seo. K. D⁵ pointed out that ivy signs indicated a negative relationship with cerebral vascular reserve (CVR)and a positive relationship with the severity of ischemia. In this research,83 patients with moyamoya disease were accompanied by ivy signs overall. 46 patients suffered cerebral infarction and transient ischemic attacks. Gburek Augusta t, J¹ agreed with this theory and pointed out that the expression of the ivy sign correlated negatively with the cerebral vascular reserve. Unluckily, three patients in this case with ivy signs were mistaken and identified as other diseases at first. Yu, J⁸ concluded that MMD patients with ivy signs showed significant ischemic symptoms such as frequent transient ischemic attacks (TIAs) and completed stroke.

in our research, the prevalence of ivy sign was 73.1%, not only ischemic events but also decreased rCBF, good PCF, and Suzuki stage ≥ IV were tightly associated with ivy sign. With ivy signs, we could evaluate the severity of the disease and prognosis postoperatively more accurately.

LIMITATIONS:

Limitation still exists in this study. Firstly, the data only manifest the focal area, which can not perfectly represent an overall situation. next, SPECT-CT and 4D-flow MRI were not considered as a choice to evaluate blood flow due to economics and convenience. In the end, intraventricular hemorrhage which was difficult to judge the side exactly was excluded from the study, this may lead to bias.

The ivy sign was independently associated with four MMD characteristics, including cerebrovascular morphology, cerebral hemodynamics, cerebrovascular events, and PCF. It identifies ivy signs' clinical significance. This study did strengthen our realization of the ivy sign.

Author Contributions Conceptualization: Y.L., H.S., Y.L.; Methodology: Y.L., H.S., Y.L., J.T.; Formal analysis and investigation: W.L., J.T., A.X., C.X.; Writing-original draft preparation: Y.L. Writing-review and editing: W.L., Y.L.; Funding acquisition: Y.L.; Supervision: Y.L., H.S.

Funding Information Funding This study was supported by funding from the National Key

R&D Program of China (No. 2018YFA0108603); 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. 2018HXFH007); Clinical Research Innovation Project, West China Hospital, Sichuan University (No. 2019HXCX07); 1·3·5 Project for Disciplines of Excellence⁃Clinical Research Incubation Project, West China Hospital, Sichuan University (No. 2021HXFH014); Science and Technology Department of Sichuan Province (No. 2020YFS0223); and 1·3·5 Project for Disciplines of Excellence, West China Hospital, Sichuan University (No. 2018HXFH010).

Conflict of Interest The authors declare that they have no conflicts of interest..

Gburek-Augustat, J., Sorge, I. & Merkenschlager, A. The "Ivy-Sign" in Moyamoya Disease-From MRI Pattern to Diagnosis. Neuropediatrics 51, 241-244, doi:10.1055/s-0040-1708546 (2020).
Sivrioglu, A. K., Saglam, M., Yildiz, B., Anagnostakou, V. & Kizilkilic, O. Ivy Sign in Moyamoya Disease. Eurasian J Med 48, 58-61 (2016).
Fujiwara, H., Momoshima, S. & Kuribayashi, S. Leptomeningeal high signal intensity (ivy sign) on fluid-attenuated inversion-recovery (FLAIR) MR images in moyamoya disease. Eur J Radiol 55, 224-230, doi:10.1016/j.ejrad.2004.11.009 (2005).
Kaku, Y. et al. The leptomeningeal ivy sign on fluid-attenuated inversion recovery images in moyamoya disease: positron emission tomography study. Cerebrovasc Dis 36, 19-25, doi:10.1159/000351143 (2013).
Seo, K. D. et al. Ivy Sign on Fluid-Attenuated Inversion Recovery Images in Moyamoya Disease: Correlation with Clinical Severity and Old Brain Lesions. Yonsei Med J 56, 1322-1327 (2015).
Miyamoto, S. et al. Effects of extracranial-intracranial bypass for patients with hemorrhagic moyamoya disease: results of the Japan Adult Moyamoya Trial. Stroke 45, 1415-1421, doi:10.1161/strokeaha.113.004386 (2014).
Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 52, 245-266, doi:10.2176/nmc.52.245 (2012).
Yu, J., Du, Q., Xie, H., Chen, J. & Chen, J. What and why: the current situation and future prospects of "ivy sign" in moyamoya disease. Ther Adv Chronic Dis 11, 2040622320960004 (2020).
Maeda, M. & Tsuchida, C. "Ivy sign" on fluid-attenuated inversion-recovery images in childhood moyamoya disease. AJNR Am J Neuroradiol 20, 1836-1838 (1999).
El Beltagi, A. H., El-Sheikh, A., El-Saif, R. & Norbash, A. Ivy sign in mildly symptomatic β-thalassemia intermedia, with development of moyamoya disease. The neuroradiology journal 27, 23-28 (2014).
Ohta, T., Tanaka, H. & Kuroiwa, T. Diffuse leptomeningeal enhancement, "ivy sign," in magnetic resonance images of moyamoya disease in childhood: case report. Neurosurgery 37, 1009-1012, doi:10.1227/00006123-199511000-00024 (1995).
Wang, L. X. et al. Ivy Sign in Moyamoya Disease: A Comparative Study of the FLAIR Vascular Hyperintensity Sign Against Contrast-Enhanced MRI. AJNR Am J Neuroradiol 42, 694-700 (2021).
Matsushima, T. et al. Surgical treatment of moyamoya disease in pediatric patients--comparison between the results of indirect and direct revascularization procedures. Neurosurgery 31, 401-405, doi:10.1227/00006123-199209000-00003 (1992).
Ge, P. et al. Angiographic Outcomes of Direct and Combined Bypass Surgery in Moyamoya Disease. Front Neurol 10, 1267 (2019).
Komatsu, K. et al. Reversibility of White Matter Hyperintensity by Revascularization Surgery in Moyamoya Disease

No competing interests reported.

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Ivy sign in moyamoya disease

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Abstract

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1. Introduction

2. Methods

2.1 Data Availability

2.2 Patients

2.3 Imaging analysis

2.4 Statistical Analysis

3. Results

4. Discussion

5. Conclusions

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