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Zeferino Demartini Jr.1,2,3,a, Bernardo C.A. Teixeira1,2,b, Gelson Luis Koppe2,3,c, Luana A. Maranha Gatto3,d,
Alex Roman4,e, Renato Puppi Munhoz5,f
1. Complexo Hospital de Clínicas – Universidade Federal do Paraná (UFPR), Curitiba, PR, Brazil. 2. Complexo Hospital Pequeno Príncipe,
Curitiba. PR, Brazil. 3. Hospital Universitário Cajuru – Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba, PR, Brazil. 4. Cleveland
Clinic, Abu-Dhabi, United Arab Emirates. 5. Toronto Western Hospital, Division of Neurology, University of Toronto, Toronto, Canada.
Correspondence: Dr. Zeferino Demartini Jr. Complexo Hospital de Clínicas – UFPR, Departamento de Neurocirurgia. Rua General Carneiro, 181,
8º andar, Alto da Glória. Curitiba, PR, Brazil, 80060-900. Email: demartiniz@gmail.com.
a. https://orcid.org/0000-0002-0683-5418; b. https://orcid.org/0000-0003-4769-6562; c. https://orcid.org/0000-0002-3127-6881;
d. https://orcid.org/0000-0002-1940-2689; e. https://orcid.org/0000-0003-0890-3688; f. https://orcid.org/0000-0002-4783-4067.
Received 11 January 2021. Accepted after revision 25 March 2021.
Abstract Moyamoya disease is a chronic occlusive cerebrovascular disease that is non-inflammatory and non-atherosclerotic. It is character-
ized by endothelial hyperplasia and fibrosis of the intracranial portion of the carotid artery and its proximal branches, leading to
progressive stenosis and occlusion, often clinically manifesting as ischemic or hemorrhagic stroke with high rates of morbidity and
mortality. On cerebral angiography, the formation of collateral vessels has the appearance of a puff of smoke (moyamoya in Japa-
nese), which became more conspicuous with the refinement of modern imaging techniques. When there is associated disease, it is
known as moyamoya syndrome. Treatments are currently limited, although surgical revascularization may prevent ischemic events
and preserve quality of life. In this review, we summarize recent advances in moyamoya disease, covering aspects of epidemiology,
etiology, presentation, imaging, and treatment strategies.
Keywords: Moyamoya disease; Cerebrovascular disorders; Intracranial arterial diseases; Cerebral arterial diseases; Cerebral revas-
cularization.
Resumo A doença de moyamoya, ou doença cerebrovascular oclusiva crônica, é uma afecção não inflamatória e não aterosclerótica, ca-
racterizada por hiperplasia endotelial e fibrose dos segmentos intracranianos das artérias carótidas internas e da porção proximal
de seus ramos. Isso provoca estenose progressiva e oclusão, frequentemente manifestada clinicamente como isquemia cerebral
ou hemorragia intracraniana, com alta morbimortalidade. A formação compensatória de vasos colaterais produz, na angiografia
encefálica, um aspecto de nuvem de fumaça (moyamoya, em japonês). Quando existe doença subjacente que possa estar relacio-
nada, a doença recebe o nome de síndrome de moyamoya. Embora a incidência esteja aumentando graças aos novos métodos
diagnósticos, as estratégias terapêuticas ainda são limitadas. O diagnóstico precoce permite cirurgias de revascularização cerebral
que podem evitar novos acidentes vasculares e melhorar a qualidade de vida. Nesta revisão são apresentados os avanços recentes
sobre a doença de moyamoya, citando aspectos de epidemiologia, etiologia, apresentação, exames diagnósticos e tratamento.
Unitermos: Doença de moyamoya; Transtornos cerebrovasculares; Acidente vascular cerebral; Doenças arteriais intracranianas;
Doenças arteriais cerebrais; Revascularização cerebral.
the anterior, posterolateral, and posteromedial choroidal growth factor, transforming growth factor beta 1, basic fi-
arteries), although transcranial and transdural collaterals broblast growth factor, and hepatocyte growth factor(5,15).
are also commonly seen in the external carotid arteries, It has also been suggested that mitochondrial abnormali-
the ophthalmic artery, and the meningeal artery(6). As the ties and CD34-positive cells, as well as mRNA and protein
disease progresses, the volume of blood flow through the expression of elastin, play a role in the occurrence and de-
collateral channels increases, which may lead to exces- velopment of MMD(5,15).
sive hemodynamic stress, causing rupture and intracranial A genetic contribution is suspected on the basis of the
hemorrhage(7). familial cases observed and the aforementioned strong link
Patients with a vasculopathy similar to MMD in the with ethnicity(5). In East Asian populations, the ring fin-
setting of another (underlying) disease are classified as ger protein 213 on 17q25.3 is considered to be a suscep-
having moyamoya syndrome(9). Such underlying diseases tibility gene for MMD(16), ring finger protein 213 variant
include Down syndrome, cranial irradiation, sickle cell p.R4810K being strongly associated with familial MMD
disease, neurofibromatosis type 1, and thyroid disease, in Japan, China and Korea(17). In addition, autoimmune
as well as, less frequently, systemic lupus erythematous, responses have been implicated as the underlying mecha-
Turner syndrome, and Noonan syndrome(6). In Western nism of MMD(5). Plasma inflammatory factors, including
countries, moyamoya syndrome occurs in less than 20% of interleukin-1 beta, monocyte chemoattractant protein-1,
diagnosed cases of MMD, whereas it accounts for 34–60% and stromal cell-derived factor-1 alpha, have been found
of cases of moyamoya-like vasculopathy in children(10). to be elevated in patients with MMD, suggesting immune-
Although the pathogenesis of MMD is still not fully mediated inflammation as a contributing factor in this
understood and the available treatments are rather lim- equation(18). Furthermore, the role of immunological and
ited, producing unfavorable outcomes, there have been inflammatory mediators in the pathogenesis of MMD in-
recent advances that are promising(5). Here, we review re- cludes abnormal IgG deposition into elastic layers and
cent developments in clinical and imaging findings, as well infiltration by T cells, macrophages, and S100A4-positive
as the treatment options. smooth muscle cells in the intimal layer(19).
From a histological standpoint, the findings of MMD
EPIDEMIOLOGY do not seem to differ between Asians and individuals of
There have been documented cases of MMD all over other ethnicities. Such findings include thickening and
the world, and it is the most common form of pediatric undulation of the internal elastic lamina, as well as fibro-
cerebrovascular disease in East Asian countries(11). The cellular hypertrophy and proliferation of smooth muscle
prevalence and incidence of the disease are higher among cells in the tunica intima, affecting the distal parts of the
Asian individuals, especially those of Japanese, Korean, ICAs and proximal segments of the anterior and middle
or Chinese descent(5,6). In recent decades, the incidence cerebral arteries. Thinning of the tunica media is a late
and prevalence of MMD have increased progressively and finding that tends to be more pronounced among adult
its prevalence among males has come to equal or slightly patients with MMD than among pediatric patients with
surpass that among females(5). The change in prevalence the disease(20). Collateral vessels may show fragmented
is seen as a consequence of better diagnostic accuracy internal elastic lamina and similar thinning of the media
due to modern, noninvasive radiological techniques, with isolated microaneurysms(21).
as well as to increased patient longevity after treatment
with advanced therapeutic strategies(5). Studies have also CLINICAL PRESENTATION
found that there are two main age ranges for the onset of The onset of MMD may occur at any age, from child-
MMD: 5–10 years and 25–49 years(12,13). The prevalence hood to adulthood, the most common symptoms being ce-
of symptomatic MMD in the United States showed a four- rebral ischemia and intracranial hemorrhage. The initial
fold increase between 2005 and 2008, 32 years being the manifestations include transient ischemic attack (TIA),
median age of symptom onset and there being a trend to- ischemic stroke, hemorrhage, headache, seizures, cogni-
ward a predominance of females(14). tive impairment, and movement disorders(5). Although
ischemic and hemorrhagic events are the most common
ETIOLOGY AND HISTOLOGICAL FINDINGS presentations, their frequencies differ between pediat-
Despite many advances, the exact pathophysiological ric and adult patients. In childhood and adolescence,
triggers and precise timeframe of the progression of MMD ischemia is the most common presentation (occurring in
remain unknown, although lines of evidence have indicated 73.9–97.5% of cases), whereas hemorrhage is much less
pathogenic pathways as diverse as those of angiogenesis, common (occurring in only 2.5–8.0%). In adults with
genetics, the immune system, and inflammation(5). The MMD(6,13), there is a higher prevalence of intracranial
pathogenesis of MMD has been associated with several bleeding (19.1–42.3%), with relatively less TIA or cerebral
angiogenesis-related factors, such as endothelial colony- infarction (57.7–70.0%). Variations in age, territory of vas-
forming cells and cytokines, including vascular endothelial cular involvement, stenosis severity, and brain territories
affected account for a wide range of clinical manifestations show hemorrhage in adults and ischemic lesion in chil-
and timeframes(3,5). Typically, the progression of arterial dren (Figure 1), failure to perform specific vascular stud-
stenosis leads to cerebral hypoperfusion, causing multiple ies may result in misdiagnosis(5). The diagnosis of MMD
and recurrent ischemic events(5). Cerebral infarction is a is based on anatomical and functional aspects(5). First-line
common presentation in adults, whereas TIA is more com- imaging examinations include CT angiography and MRI
mon in children and adolescents(22). In pediatric patients angiography to identify anatomical characteristics, such
with MMD, TIA episodes frequently occur during hyper- as steno-occlusive changes and the formation of collateral
ventilation due to crying or are caused by fever or dehy- vessels(5), as well as digital subtraction angiography (DSA),
dration(5). These triggers may induce vasoconstriction or which continues to be the gold standard examination to
an overall decrease in cerebral blood flow (CBF), which is confirm the diagnosis and staging(26). In fact, the definitive
compounded by the fact that cerebral metabolic demand is diagnosis of MMD is still based on the brain DSA findings,
much higher in the first decade of life, decreasing thereaf- which define the dynamic vascular changes and allow the
ter(22). The risk of symptomatic MMD recurrence is 18% disease to be staged with systems such as the Suzuki clas-
in the first year after the initial presentation and increases sification(2,5), as summarized in Table 1. The application
by 5% per year after that, with a 5-year cumulative risk of this technique and classification is also useful for the
of approximately 40%, and lacunar infarcts present better definition of risks. For instance, when the DSA findings of
functional outcomes after revascularization(23). However, ischemic MMD are compared with those of hemorrhagic
ischemic events affecting the posterior circulation, includ- MMD, the latter generally presents with a Suzuki stage
ing the territories of the vertebral artery, basilar artery, and that is more advanced, more intracranial aneurysms, de-
posterior cerebral artery (PCA), may worsen the clinical velopment of fetal-type PCA, and collateral flow including
course and outcomes(5). In adults with MMD, the white ethmoidal and transdural vessels(4). Anterior carotid artery
matter is more susceptible to injury than is the gray mat- occlusion occurs more frequently in patients with intra-
ter, such injury leading to cognitive dysfunction(5). Cere- ventricular or deep intraparenchymal hemorrhage than in
bral hemorrhage is more common in adults with MMD, those with lobar hemorrhage, suggesting that the underly-
often with outcomes worse than those seen in children and ing cause of the elevated risk for these complications in
adolescents(5). Cerebral hemorrhage typically occurs due MMD is major artery occlusion compensated by collateral
to rupture of friable collateral arteries, frequently in intra- vessels(4). A study comparing 7.0-T and 3.0-T MRI in pa-
ventricular and lobar areas, because most of the collateral tients with MMD detected no statistically significant dif-
vessels arise from the choroidal system, which has been as- ferences in ICA diameter, stage, or ivy sign score(27). The
sociated with aneurysms(6). The posterior communicating functional component is assessed using techniques such
arteries can also be a source of bleeding, and the presence as perfusion MRI, single-photon emission CT, positron
of multiple microbleeds predicts the future occurrence of emission tomography, perfusion CT, and xenon-enhanced
more clinically significant hemorrhage(24). perfusion CT, aiming to quantify CBF and cerebrovascular
The concept of unstable MMD, defined as cases of reserve capacity(5,27).
rapid progression or recurrent stroke, represents a more The development of new imaging modalities has im-
clinically challenging condition, most often seen in pa- proved the diagnosis, longitudinal monitoring, and post-
tients under three years of age and in those with an un- operative follow-up of MMD. For instance, dynamic
derlying disorder. Because unstable MMD represents a susceptibility-weighted contrast-enhanced MRI is a safe
potential risk factor for perioperative ischemic complica- and useful technique to show the passage of a gadolinium-
tions, its early recognition may create a valuable window based contrast agent in order to measure brain perfusion
of opportunity for perioperative-focused management and and thus measure cerebrovascular reserve capacity in pa-
surgical risk stratification, thus improving surgical out- tients with MMD(28). Blood oxygen level-dependent func-
comes(7). Movement disorders occur in 3–4% of children tional MRI, typically employed to observe areas of brain
with MMD, occurring even less frequently among adults;
Table 1—Angiographic stages of MMD, as proposed by Suzuki et al.(2).
the most common forms are hemichorea-hemiballismus
or chorea-ballismus, followed by dystonia (segmental, Stage Angiographic findings
generalized, hemidystonia, or acute status dystonicus) 1 Narrowing begins at the ICA bifurcation
and, less frequently, ataxia, myoclonus, and isolated limb- 2 Moyamoya collaterals seen around narrowed vessels
shaking(7). Any of those may occur in combination, and 3 Worsening of collateral vessels
each may manifest as a continuous, paroxysmal, or hyper- 4 Exacerbation of narrowed vessels and initial weakening of the
collaterals
ventilation-induced phenomenon(25).
5 Occlusion of large associated vessels and more pronounced
reduction of surrounding moyamoya changes
DIAGNOSTIC TESTS 6 Disappearance of the moyamoya collaterals and vessels of the
Although initial investigation with computed tomogra- ICA system, which have come to be supplied by the external
carotid artery
phy (CT) and magnetic resonance imaging (MRI) typically
A B C
D E
Figure 1. An 11-year-old girl with a learning disorder who developed right hemichorea. A: MRI angiography showing stenosis of the left ICA (short arrow) and
collateral circulation to the right hemisphere (long arrows). Vessel wall imaging before and after contrast administration (B and C, respectively) showing diffuse
thickening and enhancement at the site of the left ICA stenosis. Selective DSA of the left ICA (D) and right vertebral artery (E) showing carotid stenosis, whereas
collaterals vessels have the moyamoya (“puff of smoke”) aspect.
activation, is also useful in MMD due to its ability to assess illustrated in Figure 2. In addition to brain imaging, diag-
hemodynamic changes(29). In addition, resting-state func- nostic tests for the investigation of associated conditions
tional MRI can detect spontaneous fluctuations of blood are essential in patients with MMD(10).
oxygen level-dependent signals over time in patients with
MMD, suggesting that it is a more sophisticated method TREATMENT
to evaluate the functional organization of the brain(30). Although there is currently no specific therapeutic
Other advanced MRI techniques, such as high-resolution strategy that is effective in preventing or reversing the
MRI and high-resolution vessel wall imaging, may allow background vascular abnormalities in MMD, interven-
early detection of vascular changes, as well as facilitating tions used for stroke prophylaxis have probably changed
the differential diagnosis of various causes of arterial ste- the natural history of the disease(5). Treatments can be
nosis(31). In patients with MMD, high-resolution MRI may classified as conservative or interventional, with the caveat
reveal the absence of a hyperintense juxtaluminal band in that there is as yet no data on long-term treatment com-
T2-weighted sequences, narrowing of the middle cerebral paring conservative and surgical management of MMD(5).
artery, and mild homogeneous concentric wall enhance- The cornerstones of the clinical approach to MMD
ment in the distal ICA, unlike the eccentric wall thicken- are prophylactic and generic symptomatic treatment, such
ing seen in patients with atherosclerotic plaques(31). High- as the use of antiplatelet drugs, anticonvulsant drugs, and
resolution MRI may also identify additional intracranial pain management(5). Treatment with acetylsalicylic acid is
atherosclerotic plaques in the assessment of prognosis in strongly recommended to prevent recurrence of ischemic
adult patients with combined MMD and atherogenic risk attacks, and clopidogrel or another thienopyridine may be
factors(5). Finally, arterial spin-labeling is an MRI perfusion used when acetylsalicylic acid is not tolerated or is ineffec-
technique that does not involve the use of contrast media tive(5). Therefore, pharmacological treatment is directed
and allows qualitative and quantitative analyses of CBF at aggressive prevention of new neurovascular events and
through the use of labeled (tagged) water molecules in the no single-drug regimen is accepted as a gold standard for
arterial blood. It has been shown to identify and determine ischemic or hemorrhagic complications. In addition, rigid
the intensity of collateral flow in patients with MMD, at control of additional risk factors, such as dyslipidemia, hy-
baseline(32) and after revascularization procedures(33), as pertension, and diabetes, is highly recommended(3,5).
A B C
Figure 2. A 46-year-old male presenting with motor deficit and TIAs. A: Diffusion-weighted MRI showing infarcts (arrows) in the territory of right middle cerebral
artery and watershed area. B: Three-dimensional CT angiography showing bilateral stenosis of the terminal carotid arteries (arrows) and reduced opacification
of the middle cerebral arteries. C: Arterial spin-labeling perfusion MRI showing extensive reductions in blood flow in the territories of the anterior and middle
cerebral arteries, with preserved posterior circulation (asterisk).
The main goal of surgical treatment is to minimize results(41). In another meta-analysis of pediatric MMD,
cerebral ischemia by enhancing CBF and decreasing the all revascularization options were found to be effective,
hemodynamic stress that causes cerebral hemorrhage(5). although the incidence of postoperative stroke was 1
Revascularization surgery prevents stroke and secondary episode/190.3 patient-years after direct bypass alone, 1
hemorrhage in patients with MMD, lowering the rate of episode/108.9 patient-years after combined bypass, and 1
recurrence of ischemic attacks and producing clinical episode/61.1 patient-years after indirect bypass alone(42).
outcomes that are significantly more favorable than are The true benefit of revascularization for adults with as-
those achieved with conservative treatment(5,6,10). Sur- ymptomatic MMD remains unknown, and there is as yet
gical revascularization employs external carotid artery no consensus regarding the need for or timing of surgical
branches such as the superficial temporal artery and oc- intervention in such patients(5,6). For patients with MMD
cipital artery as donor arteries, and it can be divided into in an advanced Suzuki stage, indirect revascularization has
direct and indirect types. A few direct bypass techniques been shown to improve in cerebral perfusion, although not
have been tested, including superficial temporal artery- to reduce the risk of stroke recurrence compared with con-
middle cerebral artery anastomosis(34), superficial tem- servative treatment(43). In addition, endovascular oblitera-
poral artery-anterior cerebral artery anastomosis(35), and tion of pseudoaneurysms in collaterals vessels is emerging
occipital artery-PCA anastomosis(36). Direct anastomosis as an option to prevent recurrent bleeding in patients with
leads to an increase in immediate cerebral perfusion and hemorrhagic MMD(6). However, because parent arteries
should therefore be considered the first-line treatment(6). are functional channels, their irrigated territory must be
When that is not possible, indirect methods are useful carefully evaluated during microcatheterization to assess
and technically easier to perform, although they require the risk and benefits of such procedures(6).
more time to adequately restore blood flow(6). The main After surgical intervention, long-term clinical and im-
indirect revascularization technique is synangiosis and aging follow-up is required to ensure the effectiveness of
aims the development of collateral circulation toward the the procedures (Figure 3). Postoperative collateral forma-
brain cortex using connective tissues such as the scalp, tion may be evaluated by cerebral angiography and classi-
muscle, and dura mater(6). Several indirect “onlay” tech- fied in accordance with the Matsushima grading scale(44),
niques have been described: encephalo-duro-arterio- as shown in Table 2.
synangiosis(37); encephalo-myo-synangiosis(38); and en-
cephalo-duro-arterio-myo-synangiosis(39). There are also CONCLUSION
combinations of direct and indirect bypass(34), as well as Advances in diagnostic methods have led to improved
multiple burr hole surgery(40). A meta-analysis showed diagnostic sensitivity and specificity, enabling early treat-
that, in adults with symptomatic MMD, surgery is supe- ment of MMD. A better understanding of the patho-
rior to conservative treatment in terms of preventing fu- physiology and clinical course of the disease, as well as
ture strokes, and direct bypass seems to be more effective of the most effective therapeutic approaches, is critical to
than is indirect bypass, producing favorable long-term achieving better outcomes.
A B
C D
Figure 3. A 22-year-old female with chronic headache, together with incipient seizures and MMD. A: Contrast-enhanced MRI showing chronic right frontotempo-
ral infarct and subacute left parietotemporal infarct, as well as collateral circulation surrounding the middle and anterior cerebral arteries (arrow). B: Dynamic
susceptibility contrast perfusion MRI showing increased time-to-maximum values in both cerebral hemispheres. Axial contrast-enhanced MRI (C) and coronal
CT angiography (D) after right-side encephalo-duro-arterio-synangiosis and left-side bypass between the superficial temporal and middle cerebral arteries (long
arrows) showing moyamoya collaterals (short arrow) and signs of revascularization (asterisks).
Table 2—Postoperative angiographic grading of collaterals from the external 4. Jang DK, Lee KS, Rha HK, et al. Clinical and angiographic features
carotid artery, as proposed by Matsushima et al.(44) . and stroke types in adult moyamoya disease. AJNR Am J Neurora-
diol. 2014;35:1124–31.
Grade Angiographic findings
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synangiosis tions. J Neurosurg. 2015;122:400–7.
8. Bang OY, Fujimura M, Kim SK. The pathophysiology of moyamoya
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