Moyamoya disease is a rare cerebrovascular disorder, a kind of idiopathic arteriopathy that manifests as progressive stenosis of terminal internal carotid arteries (ICAs) and/or proximal parts of arteries forming the circle of Willis, including the middle (MCA) and anterior (ACA) cerebral arteries, and is accompanied by the development of an abnormal vascular network at the base of the brain [1]. In Russia, no official statistics are available on MMD but the disease is recognized as a possible cause of stroke in young children [2, 3]. MMD was first described in 1957 by two Japanese doctors Takeuch and Shimizu; the name “moyamoya” proposed in 1967 means “a puff of smoke” in Japanese and refers to the angiographic appearance of the abnormal blood vessels at the base of the brain [4, 5]. The highest prevalence of MMD is observed in East Asia (Japan and Korea), reaching ~3.16 cases per 100,000 population, which is 7–10 times higher than in other world regions [6, 7].

The underlying pathogenetic mechanisms of MMD are not fully clear. Common histopathologic findings in the affected vascular wall include fibrocellular intimal thickening, folded and contracted internal elastic lamina, proliferation of smooth muscle cells, and thinning of the media; no signs of inflammation or atherosclerosis are reported [8, 9]. The collateral vessels at the base of the brain traditionally referred to as moyamoya vessels are formed by dilated lenticulostriate, thalamic or choroidal anastomoses [9, 10]. Based on the severity of damage to the main cerebral arteries and the degree of involvement of the collateral vessels, 6 MMD stages are distinguished [11].

Genome-wide linkage analysis and whole-exome sequencing have identified the RNF213 gene on chromosome 17q25 as the main susceptibility gene for MMD in East Asians [12]; later studies have demonstrated the remarkable variation of this gene across different ethnic groups [13]. According to Korean researchers, the 4950G>A polymorphism of the RNF213 gene is implicated in MMD in adults and therefore may be a potential biomarker for this disease [14].

MMD is characterized by bimodal age distribution with incidence peaks at 5–10 years and in the fourth decade of life [1, 7, 9]. Women are affected twice as often as men. The disease has ischemic and hemorrhagic presentations [7, 9, 15]. According to studies conducted in small cohorts of adult European patients with idiopathic MMD, cerebral ischemia is a typical manifestation in this subpopulation [16].

Patients with MMD are at high risk for recurrent vascular accidents: the Kaplan-Meier estimate for the risk of recurrent IS within 5 years after the first episode is 80.95% [17].

Therefore, the importance of timely MMD diagnosis cannot be overestimated. The primary treatment option for this condition is surgery (cerebral revascularization) which aims to reduce the risk of recurrent strokes [2, 6, 18].

This article highlights the role of MMD as a potential cause of IS in adults, requiring timely diagnosis.

Clinical cases

In 2020, 426 patients with a past history of CVA underwent a clinical examination at the Federal Center of Brain Research and Neurotechnologies (Moscow, Russia). Three patients with a history of IS were found to have MMD. One patient with MMD was examined at the outpatient facility. Only 1 patient had been diagnosed with MMD prior to this study; 3 patients had never been diagnosed with MMD before.

Patients

Patient B, 38 years old, suffered a lacunar stroke in 2016 manifesting as sudden dizziness that spontaneously resolved shortly afterwards. The patient was referred to Sklifosovsky Research Institute of Emergency Medicine, where he was diagnosed with stage 3 MMD. The patient had two extracranial-intracranial (EC-IC) bypass surgeries for his condition in 2017 and 2018.

Patient G, 39 years old, had IS in the right MCA territory in February 2020. Following treatment and rehabilitation, the patient was able to walk around his house using a cane and perform some self-care activities. On admission to the Center, the patient was in his late rehabilitation period; his stroke subtype was cryptogenic.

Patient Yu, 51 years old, developed clinical symptoms in September 2017, including sudden facial nerve paresis, difficulty swallowing and slurred speech. The patient was hospitalized to a local medical facility. MRI of the brain revealed multiple lesions in the white matter of both cerebral hemispheres. The lesions were interpreted as demyelinating, which determined the choice of further treatment until September 2019, when the patient underwent a few additional tests. The tests did not confirm multiple sclerosis. On admission to the Center, the official diagnosis was mixed encephalopathy, sequelae of cryptogenic stroke registered in September 2017 and March 2018.

Female patient V, 57 years old, had a lacunar IS in the left MCA when she was 36; at that time the patient developed mild paresis in her right hand, which was interpreted as peripheral neuropathy; the hand restored its function within a week. The patient presented at the Center with complaints of transient loss of consciousness, frequent headaches and dizziness. The sharpened Romberg test revealed mild coordination impairment. The most recent neurological examination had been conducted 10 years prior. MRI findings of that time had been interpreted as variant anatomy of cerebral arteries.

At the Center, the examination protocol was the same for all patients and included MRI and MSCT of the brain and intracranial arteries, cerebral MSCT perfusion imaging, and color duplex ultrasonography of extra- and intracranial brachiocephalic arteries (BCA). MRI scans were performed on a 3T Discovery 370 MR scanner (GE; USA). The following sequences were obtained: Т1-WI, Т2-WI, isotropic 3D FLAIR pulse sequence (slice thickness: 1 mm), diffusion-weighted images (DWI), susceptibility weighted angiography sequence (SWAN), and time-of-flight angiography (3D-TOF) of intracranial arteries. Brain MSCT and MSCT perfusion imaging were performed using a 128-slice Optima scanner (GE; USA). Contrast enhancement was achieved with iopromide (370 mg iodine/ml). High-resolution duplex ultrasonography of BCA was performed using a Philips Epiq 7G scanner (Philips; USA).

Brain MRI findings

All patients had signs of a past cerebral infarction and gliotic foci in the hemispheric white matter, in the border zone between MCA and ACA. One patient (patient G) had signs of a past infarction in the deep perforating branches of the right MCA (fig. 1). Patient Yu had areas of hemorrhagic transformation (petechiae). No intracranial hemorrhages were detected in either patient. The obtained T2-weighted images showed a network of small blood vessels in the proximal MCA territory on both sides both MCA trunks were not detectable at this level (fig. 2).

Unenhanced MR angiography demonstrated significant narrowing/occlusion of terminal ICA and proximal MCA segments. ACAs were intact in patients B and G, but their diameter was small in one of these patients. Proximal ACAs were affected in patients Yu and V (fig. 3). Posterior cerebral arteries (PCAs) and posterior communicating arteries (PCcoms) were dilated in all 4 patients.

Findings of multislice computed tomography of the brain

The CT-angiography of intracranial arteries revealed an abnormal vascular network (fig. 4; arrows) in place of М1 MCA trunks and the enhancement of lenticulostriate arteries in the basal ganglia area, corresponding to different stages of MMD. The abnormal vascular network was well defined on the images of patients B and V, which was interpreted as stage 3 of the disease, and not so well developed in patients Yu and G, who had more pronounced neurological deficit and larger (both in number and size) post-infarction lesions, which was interpreted as later MMD stages characterized by the regression of moyamoya vessels at the base of the brain. Distal MCA and ACA were visible, their diameter being normal in some patients.

Signs of cerebral hypoperfusion in the MCA and ACA territories and increased posterior cerebral perfusion were observed in 3 of 4 patients (fig. 5). The fourth patient (Patient B) had previously received an EC-IC bypass on both sides, so a reduction in cerebral perfusion in the border zones between MCA and ACA and between MCA and PCA was not so pronounced in this patient.

Findings of duplex ultrasonography of brachiocephalic arteries

Duplex ultrasonography did not detect any significant changes in extracranial BCAs; their diameters and velocity characteristics fell within the reference range (in most patients, these parameters approximated the lower limit). Diameters of vertebral arteries (VAs) varied significantly, blood flow in VAs was either normal or slightly increased.

Transcranial scans revealed stenosis of both terminal IСАs in patients Yu and V, inferred from the local hemodynamic changes (fig. 6H, I). Single and multiple differently directed intertwining flows were detected in the M1 segments of MCA in the color Doppler mode. Spectral Doppler demonstrated that their velocities were low and peripheral resistance was either moderate or significantly reduced, which is typical for collateral blood flow (fig. 6A–G). Besides, all patients had high-velocity blood flow in PCcoms directed toward the vertebrobasilar system (VBS) and increased blood flow in PCAs and their branches. Three to four PCA segments were visualized (fig. 7). Blood flow was compensatorily increased in the distal VA (V4) and the basilar artery (BA) in patients B and V; such compensation was not observed in patients G and Yu.

Discussion

Vascular changes typical for MMD can be detected by different imaging techniques. The T2-weighted images of all 4 patients showed abnormal vascular networks at the base of the brain in place of large M1-segments of MCA. MR-angiography conducted without a contrast agent revealed occlusion of distal (supraclinoid) ICA and proximal parts of МCА; in 2 patients, ACA was also affected. However, the abnormal vascular network had a puff of smoke appearance on MR angiograms in only one case. MSCT angiography allowed us to visualize lenticulostriate arteries in the basal ganglia and abnormal blood vessels at the brain base in greater detail, confirming MMD in all 4 patients.

Duplex ultrasonography of extracranial BCA detected no pronounced specific changes in ICA or VA. A reduced ICA diameter, which is a diagnostic criterion [1], was not detected in any of 4 patients. This might have been due to the degree of occlusion, which is not typical for other types of ICA damage. In MMD, the supraclinoid segments of ICA are occluded upstream of the PCcom divergence site; they are represented by communicating segments of ICA and their bifurcations. This is key in the redistribution of the cerebral blood flow from ICA via PCcom in VBS and then via PCA and its branches through cortical and leptomeningeal anastomoses back to MCA and ACA. Thus, signs of distal ICA occlusion in patients with MMD [1] can be seen on ultrasound scans in the absence of PCcom.

On intracranial scans, the abnormal vascular network at the base of the brain was visible if it was well developed. Otherwise, no signal was captured from the proximal MCA. Yet the M2segment of MCA could be located, showing a relatively normal blood flow and thus raising a possibility of wrong interpretation. Velocity characteristics of blood flow in MCA branches and the distal segments of their trunks varied significantly but peripheral vascular resistance was reduced in all 4 patients, indicating collateralization.

Bilateral ICA occlusions co-occurred with small areas of past infarctions and gliotic lesions in the border zone between MCA and ACA. The inconsistency between the large arteries occlusions and the size of infarctions suggested an old history of a pathological process leading to the formation of these occlusions and sufficient collateral compensation. Cerebral infarctions occurring in the setting of MMD can be categorized as hemodynamic, associated with a reduction in blood flow due to low arterial blood pressure. Another possible cause of cerebral infractions in MMD is regression of collateral vessels, leading to circulatory decompensation. In our patients, perfusion deficit (CBF) with prolonged Tmax was inferred from CT perfusion imaging data in the border zones between MCA and АCA (deep and subcortical white matter of frontal lobes). Hyperperfusion was observed in 3 patients except for the patient with an EC-IC bypass. In patient V, the collateral vascular network was very well developed.

Conclusion

Our findings suggest that MMD can be diagnosed based on the known diagnostic criteria and using different imaging techniques: MRI, MSCT and duplex ultrasonography of brachiocephalic arteries. Diagnostic errors may be due to the unavailability of angiography for neuroimaging or the lack of awareness about MMD as a possible cause of IS in adults.