Patient selection
We prospectively enrolled MMD patients at our institution between September 2019 and February 2020. The inclusion criteria for our study were as follows: 1) patients who were diagnosed with MMD according to the MMD guidelines [12]; and 2) patients who received ultrasound and DSA examinations with intervals between the two examinations less than 1 month. The exclusion criteria were as follows: 1) patients who were diagnosed with moyamoya syndrome with identified causes, including autoimmune diseases, meningitis, intracranial tumor, Down syndrome, neurofibromatosis, craniocerebral trauma, and sickle cell anemia, etc. ; [12, 13]; 2) MMD patients with two or more risk factors for atherosclerosis, including hypertension, diabetes, hyperlipidemia, smoking, etc. ; 3) MMD patients who had diseases that affected cardiac output, including hyperthyroidism, severe anemia, congestive heart failure, atrial fibrillation, etc. ; 4) patients who had prior revascularization surgery; and 5) patients with unilateral lesions. Finally, a total of 30 patients were included in our study. Informed consent was obtained from all 30 patients (or their parent or legal guardian in the case of children under 16 years), and the study was approved by the Ethics Committee of Beijing Tiantan Hospital, Capital Medical University.
Angiographic Findings
All 30 patients underwent DSA, including of the bilateral common carotid arteries, internal carotid arteries, vertebral arteries and the late venous phase to evaluate collateral flow. Two independent experienced investigators interpreted the images according to the following diagnostic criteria, they were blinded to the clinical data, and any differences in their results were resolved by consensus.
Suzuki’s vascular criteria [1] [14]
StageⅠ: narrowing of internal carotid artery (ICA) apex; stage Ⅱ: dilatation of the intracerebral main arteries and initiation of the moyamoya; stage Ⅲ, narrowing of the MCA and ACA and intensification of the moyamoya; stage Ⅳ: occlusion of the ICA extending to the junction of the posterior communicating artery and minimization of the moyamoya, resulting in enlargement of the collateral vessels from the external carotid artery; stage Ⅴ: the disappearance of all the main cerebral arteries and further minimization of the moyamoya; and stage Ⅵ: the complete disappearance of the siphon of the ICA, and disappearance of the moyamoya, resulting in cerebral blood flow supply from the external carotid artery and vertebrobasilar artery systems.
Grading score of leptomeningeal system from the PCA territory to the ACA and MCA territory
According to the anatomy extent of pial collateral blood [8], the scores of the leptomeningeal system from the PCA territory to the ACA and MCA territory were the sum of the following three parts, and a score of 0 was assigned if the leptomeningeal anastomoses were absent.
1) Retrograde flow from the parieto-occipital branch of the PCA (pPCA) or posterior pericallosal artery extending to the ACA territory: a score of 1 was assigned if the blood supply extended to the cortical border zone between the ACA and PCA territory; a score of 2 was assigned if the blood supply extended to the central sulcus.
2) A score of 1 was assigned if the anterior temporal branch of the PCA anastomoses to the temporal branch of the MCA.
3) pPCA anastomoses to the MCA: a score of 1 was assigned if the retrograde flow only extended to superficial vessels (M4 segment of MCA); a score of 2 was assigned if the retrograde flow extended into the Sylvian fissure (M3 segment of MCA); and a score of 3 was assigned if the flow extended to the reconstituted vessels at the distal end of the occlusion (M1 or proximal M2 segments of MCA).
Clinical Manifestations
According to clinical manifestation at onset, patients were categorized into the stroke group (including ischemic stroke and hemorrhagic stroke) and the TIA group by an experienced research neurologist. Ischemic stroke was defined as a new symptomatic neurologic deterioration lasting at least 24 hours that was not caused by a nonischemic cause, or a new symptomatic neurological deterioration accompanied by neuroimaging evidence of a new cerebral infarction that was not caused by a nonischemic cause. Hemorrhagic stroke is defined as the acute extravasation of blood into the brain parenchyma. TIA was defined as new neurologic deficit or symptoms lasting less than 24 hours with no evidence of cerebral infarction on neuroimaging [15].
Ultrasound Examination
All subjects underwent ultrasound examination in the ultrasound department of our hospital. All parameters were measured by an experienced sonographer, and the examiner was blinded to the clinical data and radiographic findings.
Carotid Ultrasound
Carotid ultrasound was performed on a color-coded ultrasound system (EPIQ 7, Philips Medical Systems, Bothell, WA) with a 3–9 MHz linear array probe. The patient remained in a supine position with their head remaining dropped back and tilted to the opposite side slightly. The sonographer adjusted the gain, depth, pulse-repetition frequency and wall filter to the appropriate conditions, the size of the doppler sample volume was adjusted to 1/3 − 1/4 of the detected vessel, the doppler angle was adjusted to below 60°, and the EICA was measured on the two-dimensional longitudinal section at 1–2 cm above the carotid bulb. The following parameters were measured: diameter (D), peak systolic velocity (PSV), end-diastolic velocity (EDV), pulsatility index (PI), and resistance index (RI). Then, the sonographer adjusted the doppler sample volume to the entire width of the vessel, when the signal was stable, the time-averaged mean velocity (TAMV) was measured over a minimum of three cardiac cycles, and the flow volume (FV) was calculated as the product of TAMV and the cross-sectional area (A) of the circular vessel according to the formula FV = TAMV × A = TAMV×[(D/2)2×π] [16][17].
Transcranial Color-coded Duplex Sonography
Transcranial color-coded duplex sonography was performed on a color-coded ultrasound system (EPIQ 7, Philips Medical Systems, Bothell, WA) with a 1.5-3.0 MHz phased array probe.
The patient remained in a lateral position, the P2 segment of PCA was examined through a transtemporal window. The sonographer adjusted the gain, pulse-repetition frequency and wall filter to the appropriate conditions, the size of the doppler sample volume was adjusted to 3–5 mm, the depth of insonation for PCA was 60–70 mm, and the doppler angle was adjusted to below 60°, when the signal was stable, the PSV, EDV, PI and RI of PCA were measured.
Statistical Analysis
Continuous variables were described as the means ± standard deviation or median (interquartile range), and categorical variables were described as percentages. The Mann-Whitney U test and Jonckheere-Terpstra test were used for continuous variables. A receiver operating characteristic (ROC) curve analysis was applied to identify the performance of each, and the combination of ultrasound parameters for predicting the clinical manifestations of MMD.
Statistical analyses were performed using SPSS version 24.0 (IBM Corporation, Armonk, NY). All calculated p values were 2-tailed, and a p value < 0.05 was considered statistical significance.