MMD is a chronic cerebrovascular disease presenting with ischemic and/or hemorrhagic manifestations. The pathogenesis of this disease remains unclear, so the currently available treatments have an unfavorable curative effect (29). Pathological changes in the vascular wall have been implicated in MMD pathogenesis, namely fibrocystic proliferation of the vascular intima, significant smooth muscle cell proliferation, and extracellular matrix deposition without phospholipid deposition in the intima and inner elastic layer. These changes are different to those which occur in atherosclerosis (20, 32). In addition, Ezura et al. suggested that the disease was related to immune complex-mediated injury (6). Hoshimaru et al. studied studied superficial temporal artery sections and dura mater samples from MMD patients and found increased basic fibroblast growth factor (bFGF) expression in endothelial cells, smooth muscle cells, and the dura mater (10). Similarly, Takahashi et al. demonstrated significantly increased bFGF levels in the cerebrospinal fluid of MMD patients (33). Consequently, bFGF was suggested to promote the proliferation of vascular endothelial cells and smooth muscle cells, resulting in stenosis and occlusion of the ICA and abnormal proliferation of blood vessels in the base of the brain.
In our series, CT showed lower sensitivity and higher specificity than MRI for diagnosing cerebral hemorrhage. Therefore, MRI has a higher ability to detect cases than CT, and patients will rarely be missed, while CT has a higher ability to exclude non-cases than MRI, and almost no non-patients will be misjudged as patients. In other words, MRI demonstrated a lower ‘missed-diagnosis’ rate and higher ‘misdiagnosis’ rate than CT. On the contrary, in patients with cerebral infarction, CT demonstrated a lower ‘missed-diagnosis’ rate and higher ‘misdiagnosis’ rate than MRI. However, the Youden index, which reflects the overall ability of diagnostic tests to identify patients and non-patients, showed no statistical differences between CT and MRI, regardless of the type of MMD. In addition, MMD-related cerebral hemorrhage often exhibited bleeding into the ventricles; aneurysms and arteriovenous malformations are almost always associated with SAH; whereas hypertension often caused ICH. Indeed, we observed that most hemorrhages were in or around the ventricles such that 29.5% of the patients in our series exhibited intraventricular hemorrhage. Similarly, the frontal lobe and paraventricular area were the most common sites of MMD-induced cerebral infarction, and multiple areas of cerebral infarction were frequently observed.
All patients in our series were diagnosed by DSA. DSA can clearly show the degree of stenosis or occlusion of the vessels and abnormal neovascularization at the base of the brain, and can also accurately evaluate the pattern and hemodynamics of the compensatory blood supply. We also observed a pattern between the symptoms and imaging findings of MMD. The patients with hemorrhagic symptoms were generally older than those with ischemic symptoms, and showed abundant neovascularization in the base of the brain and ample anastomosis of intracranial and extracranial vessels. Some of the compensatory vessels were tortuous, dilated, and even cystoid. In contrast, the patients with ischemic symptoms were generally younger, and exhibited relatively sparse neovascularization in the base of the brain and poorer collateral circulation. These patients also exhibited a significantly prolonged cerebral circulation time. Variations in clinical symptoms and imaging findings have been suggested to closely correlate with MMD stage. In the early stage, cerebral infarction may occur if neovascularization is not established in time to increase the blood flow to the ischemic area. The most common symptoms at this stage are motor and sensory impairments. Once neovascularization is established, the patient experiences a period of blood flow compensation. However, due to the thinness and poor elasticity of the walls of the proliferated vessels, these vessels gradually dilate, distort, and even form aneurysms in response to the continuous pressure exerted by blood, resulting in eventual rupture and bleeding. The most common symptoms at this stage are headache, motor dysfunction, epilepsy, and even unconsciousness.
Recently, CTA and MRA have gained attention with respect to MMD diagnosis. CTA is a convenient, time-saving, and non-invasive technique with good sensitivity and specificity. Importantly, CTA can be performed quickly, which is particularly valuable in pediatric and emergent MMD cases (30). Additionally, CTA can be used to guide surgical treatment, as it allows the relationship between the abnormal blood vessels or aneurysms and the skull to be visualized. Specifically, 4D CTA showed strong consistency and correlation with DSA with respect to vascular stenosis score, but remains insufficient for evaluating the collateral circulation (34). MRA is nonradiative, and the sensitivity and specificity of 3.0T MRA in diagnosing MMD were reported to be 69.2% and 93.3%, respectively (5). However, compared to DSA, MRA has a tendency to over-diagnose, and often overestimates the degree of vascular stenosis. On the other hand, during the early stages of vascularization or in cases of mild vascular network abnormalities, MRA may fail to diagnose MMD. In addition, the ability of MRA to display collateral circulation and secondary micro-aneurysms is poor. 3.0T TOF MRA, a non-contrast technique, has been proven to be at least equal to CTA for the assessment of internal-external carotid bypass and superior to CTA in the evaluation of the intracranial segment (2). Nevertheless, neither MRA nor CTA were effective at identifying small perforating vessels or early moyamoya vessels. Therefore, different imaging techniques are suited to different situations in line with their advantages and disadvantages (19).
CTP is a sensitive functional imaging technique which can be used to study the cerebral microcirculation, facilitating the evaluation of cerebral perfusion changes in MMD patients before and after surgery (25). Although CBF has been reported to be more strongly correlated with the patency of the bypass artery (3), both CBF and TTP have been demonstrated to be quite sensitive to the presence of altered brain perfusion early after indirect revascularization (4). In line with a previous study (36), using CTP, we showed that adult patients with ischemic MMD exhibited reduced cerebral perfusion compared to patients with hemorrhagic MMD.
Currently, the incidence of intracranial aneurysms in MMD patients is known to range from 3.4 to 14.8%, which is significantly higher than that in the general population (1–3%) (38). The complex pathogenesis of aneurysms development in MMD may involve multiple factors including hemodynamic disorders and pathological vessel architecture, both of which are known to increase the risk of aneurysm formation (38). Intracranial aneurysms primarily occur in hemorrhagic MMD, and are associated with a high rate of rupture. The rupture of these aneurysms occurs due to the presence of weak and pathological moyamoya vessels (15). Occlusion of the ICA system may result in hemodynamic changes within the circle of Willis by increasing the blood flow in the basilar artery (BA) and PCA. This leads to the development of turbulence in the posterior circulation, which increases the risk of aneurysm formation and subsequent rupture. Several authors have suggested that spontaneous occlusion of the MCA may also lead to the focal moyamoya phenomenon and aneurysmal hemorrhages such as cerebral parenchymal hemorrhage, ventricular hemorrhage, and SAH (28). In decreasing order of frequency, the most common locations of aneurysms in MMD patients are the distal anterior choroidal artery (AchA), distal posterior choroidal artery (PchA), AcoA, and BA (22). MMD involving aneurysms can be divided into two types according to the location of the aneurysms: MMD with aneurysms involving the circle of Willis and MMD with peripheral aneurysms involving the moyamoya vessels, which are often located around the ventricles and close to the distal end of the perforating artery, AchA, and PchA (8).
Bypass is the main surgical method used to treat MMD, and involves surgical reconstruction of the collateral circulation to increase cortical perfusion. In 1967, Yasargil performed the first successful STA-MCA anastomosis to treat cerebral ischemia in Switzerland. Since then, STA-MCA bypass has been widely used in the treatment of MMD (9). Indeed, collateral vessels, including an intracerebral vascular anastomosis system, corticopial-meningeal vascular anastomosis system, circle of Willis communication system, dural vascular network, and extracranial vascular network, can spontaneously form in MMD patients. However, due to the presence of the meninges, cerebrospinal fluid, and skull, effective collateral circulation cannot be established. The dural and extracranial vascular networks, which comprise many collateral vessels, are unable to be anastomosed to the surface of the brain. However, this can be solved by indirect bypass procedures including encephalo-duro-arterio-synangiosis (EDAS), encephalo-myo-synangiosis (EMS), encephalo-duro-arterio-myo-synangiosis (EDAMS). Multiple burr-hole surgery, which are simple, effective, and particularly suitable for anterior circulation ischemia. It has also been suggested that direct and indirect bypass should be combined (21).
In patients with ischemic MMD, direct, indirect, or combined bypass can alleviate ischemic symptoms such as transient ischemic attack (TIA) and reversible neurological deficit (RIND), improve the intellectual capacity of pediatric patients, and effectively prevent the occurrence of future cerebral ischemia (24, 40, 41). Direct bypass was previously suggested to prevent rebleeding as it can reduce the number and expansion of abnormal branches and the blood flow in the AchA and PcoA (13). This prevents the formation of micro-aneurysms due to abnormal hemodynamics, which are thought to be precursors of hemorrhage or rebleeding (14). In children, indirect bypass is a more effective treatment as the anastomotic vessels are narrow, vulnerable to restenosis, and cannot tolerate direct bypass. The integrity of the STA should be preserved for as long as possible, so that anastomosis can still be performed if necessary. Direct or combined bypass may be more beneficial in adult MMD patients.
This was a single-center study, which may have affected the reliability of the results. Therefore, larger-scale, multi-center studies are warranted. Additionally, this study mainly focused on the multi-model imaging and treatment of MMD. However, we did not evaluate the long-term therapeutic effects or follow-up results. This was beyond the scope of this study, and further research is therefore required.