Moyamoya disease
Moyamoya disease is a chronic, occlusive cerebrovascular disease, characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid artery and an abnormal vascular network at the base of the brain.
Moyamoya vessels are a distinctive feature of Moyamoya disease. In response to the reduced blood flow caused by arterial narrowing, the brain attempts to compensate by developing a network of small, fragile, and often disorganized collateral blood vessels. These small blood vessels are known as “Moyamoya vessels.
| Feature | Moyamoya Disease (MMD) | Moyamoya Syndrome (MMS) |
|---|---|---|
| Cause | Idiopathic / primary | Secondary to another condition |
| Laterality | Typically bilateral | Can be unilateral or bilateral |
| Associated conditions | None | Yes (e.g., NF1, Down syndrome, sickle cell, lupus) |
| Management | Surgical revascularization | Surgical + treat underlying cause |
| Diagnostic label | Used when no other cause is found | Used when an associated condition is identified |
| Imaging appearance | “Puff of smoke” vessels on angiography | Same appearance as MMD |
Moyamoya disease and Moyamoya syndrome are related vascular disorders, but they have distinct characteristics:
Moyamoya Disease:
Primary Condition: Moyamoya disease is a primary or idiopathic disorder, meaning it occurs on its own without an underlying cause. Bilateral Stenosis: It is characterized by progressive bilateral stenosis (narrowing) or occlusion of the internal carotid arteries and the arteries that branch from them, leading to reduced blood flow to the brain. Affects Both Hemispheres: Moyamoya disease typically affects both hemispheres of the brain. Genetic Component: There is often a genetic component, and it may run in families. Moyamoya Syndrome:
Secondary to Underlying Conditions: Moyamoya syndrome, on the other hand, is secondary to other underlying conditions or diseases. Associated Conditions: It can be associated with various conditions such as sickle cell disease, neurofibromatosis type 1, Down syndrome, or other genetic or autoimmune disorders. Unilateral or Bilateral: It can involve unilateral or bilateral narrowing of the arteries, and the severity may vary depending on the underlying cause. Occurs as a Secondary Phenomenon: In Moyamoya syndrome, the moyamoya vascular pattern occurs as a secondary phenomenon related to the primary condition. In summary, while both conditions involve the development of a characteristic “moyamoya” vascular pattern in the brain, Moyamoya disease is a primary, idiopathic disorder, while Moyamoya syndrome is secondary to other underlying conditions. The distinction is crucial for proper diagnosis and management. If you suspect moyamoya syndrome or disease, it's important to consult with a healthcare professional for a thorough evaluation and appropriate treatment.
These diagnostic criteria of the moyamoya disease, stated by the Research Committee on Spontaneous Occlusion of the Circle of Willis (moyamoya disease) in Japan, are well established and generally accepted as the definition of this rare entity. On the contrary to the diagnosis of definitive moyamoya disease, there is some confusion in the terminology and understanding of quasi-moyamoya disease; moyamoya disease in association with various disease entities, such as atherosclerosis, autoimmune diseases, Down syndrome, etc. Although clinical management is not affected by these semantic distinctions, terminological confusion may interfere with international collaboration in the clinical investigation of these rare conditions 1).
The perforating arteries in the basal ganglia and thalamus markedly dilate and function as an important collateral circulation, called “moyamoya” vessels. The posterior cerebral artery is also involved in a certain subgroup of patients. Therefore, cerebral hemodynamics is often impaired especially in the frontal lobe, leading to transient ischemic attack (TIa) and cerebral infarction. Furthermore, the dilated, fragile moyamoya vessels often rupture and cause intracranial hemorrhage 2) 3).
Epidemiology
Classification
Suzuki staging
Etiology
Unknown etiology.
A study indicated a higher overall autoimmune disease prevalence in unilateral than in bilateral MMD. Unilateral MMD may be more associated with autoimmune disease than bilateral MMD. Different pathogenetic mechanisms may underlie moyamoya vessel formation in unilateral and bilateral MMD 4).
Risk factors
The p.R4810K mutation in RNF213 gene confers a risk of MMD, but other factors remain largely unknown. Mineharu et al. tested the association of gut microbiota with MMD. Fecal samples were collected from 27 patients with MMD, 7 patients with non-moyamoya intracranial large artery disease (ICAD) and 15 control individuals with other disorders, and 16S rRNA were sequenced. Although there was no difference in alpha diversity or beta diversity between patients with MMD and controls, the cladogram showed Streptococcaceae was enriched in patient samples. The relative abundance analysis demonstrated that 23 species were differentially abundant between patients with MMD and controls. Among them, increased abundance of Ruminococcus gnavus > 0.003 and decreased abundance of Roseburia inulinivorans < 0.002 were associated with higher risks of MMD (odds ratio 9.6, P = 0.0024; odds ratio 11.1, P = 0.0051). Also, Ruminococcus gnavus was more abundant and Roseburia inulinivorans was less abundant in patients with ICAD than controls (P = 0.046, P = 0.012). The relative abundance of Ruminococcus gnavus or Roseburia inulinivorans was not different between the p.R4810K mutant and wildtype. The data demonstrated that gut microbiota was associated with both MMD and ICAD 5).
Histopathological features
The histopathological features of the middle cerebral artery (MCA) and superficial temporal artery (STA) from moyamoya disease (MMD) and their relationships with gender, age, angiography stage were explored. The causes and the clinical significance of vasculopathy of STA were also discussed. The clinical data and specimens of MCA and STA from 30 MMD patients were collected. Twelve samples of MCA and STA from non-MMD patients served as control group. Histopathological examination was then performed by measuring the thickness of intima and media, and statistical analysis was conducted. The MCA and STA specimens from MMD group had apparently thicker intima and thinner media than those from the control group. There was no significant pathological difference between the hemorrhage group and non-hemorrhage group, and between the males and females in MMD patients. Neither the age nor the digital subtraction angiography (DSA) stage was correlated with the thickness of intima in MCA and STA. MMD is a systemic vascular disease involving both intracranial and extracranial vessels. Preoperative external carotid arteriography, especially super-selective arteriography of the STA, benefits the selection of donor vessel 6).
Pathogenesis
Clinical features
Diagnosis
Hemodynamic parameter
Quantification of the severity of vasculopathy and its impact on parenchymal hemodynamics is a necessary prerequisite for informing management decisions and evaluating intervention response in patients with moyamoya.
Computational fluid dynamics (CFD) analysis on eight patients (5 female, 3 male) with MMD treated by EDAS (encephalo-duro-arterio-synangiosis) between 2011 and 2012. All the eight patients presented with haemorrhage, with subsequent 4-12 month follow-up done using Magnetic Resonance Angiography (MRA) to capture auto-remodelling. Karunanithi et al. calculated percentage change in flow rate and pressure drop indicator (ΡDI) across the Left and Right ICA. Pressure drop indicator (PDI) is defined as the difference of pressure reduction within the carotid arteries, measured at post-op and follow up, using patient specific inflow rates. The measured percentage flow change and pressure reduction showed an increase at follow up for improved patients (characterised by angiography according to the method of Matsushima), who did not develop any complications after surgery. The inverse was observed in patients who were clinically classified as no change and retrogressed (according to the method of Matsushima) cases post-operation. This elucidates the findings of a new parameter that may well play a critical role as an assistive clinical decision making tool in MMD 7).
Differential diagnosis
Moyamoya disease and Moyamoya syndrome are related vascular disorders, but they have distinct characteristics:
Moyamoya Disease:
Primary Condition: Moyamoya disease is a primary or idiopathic disorder, meaning it occurs on its own without an underlying cause. Bilateral Stenosis: It is characterized by progressive bilateral stenosis (narrowing) or occlusion of the internal carotid arteries and the arteries that branch from them, leading to reduced blood flow to the brain. Affects Both Hemispheres: Moyamoya disease typically affects both hemispheres of the brain. Genetic Component: There is often a genetic component, and it may run in families. Moyamoya Syndrome:
Secondary to Underlying Conditions: Moyamoya syndrome, on the other hand, is secondary to other underlying conditions or diseases. Associated Conditions: It can be associated with various conditions such as sickle cell disease, neurofibromatosis type 1, Down syndrome, or other genetic or autoimmune disorders. Unilateral or Bilateral: It can involve unilateral or bilateral narrowing of the arteries, and the severity may vary depending on the underlying cause. Occurs as a Secondary Phenomenon: In Moyamoya syndrome, the moyamoya vascular pattern occurs as a secondary phenomenon related to the primary condition. In summary, while both conditions involve the development of a characteristic “moyamoya” vascular pattern in the brain, Moyamoya disease is a primary, idiopathic disorder, while Moyamoya syndrome is secondary to other underlying conditions. The distinction is crucial for proper diagnosis and management. If you suspect moyamoya syndrome or disease, it's important to consult with a healthcare professional for a thorough evaluation and appropriate treatment.
Treatment
Outcome
Complications
Articles
Artificial intelligence (AI) clustering was used to classify the articles into 5 clusters: (1) pathophysiology (23.5%); (2) clinical background (37.3%); (3) imaging (13.2%); (4) treatment (17.3%); and (5) genetics (8.7%). Many articles in the “clinical background” cluster were published from the 1970s. However, in the “treatment” and “genetics” clusters, the articles were published from the 2010s through 2021. In 2011, it was confirmed that a gene called Ringin protein 213 (RNF213) is a susceptibility gene for moyamoya disease. Since then, tremendous progress in genomic, transcriptomics, and epigenetics (e.g., methylation profiling) has resulted in new concepts for classifying moyamoya disease. The literature survey revealed that the pathogenesis involves aberrations of multiple signaling pathways through genetic mutations and altered gene expression 8).
Retrospective observational studies
Patel et al. used an approach based on the global cerebral atrophy scale to identify patients with severe brain atrophy from a single-surgeon series of patients with moyamoya disease undergoing revascularization from January 2015 to January 2024. Clinical outcomes (modified Rankin Scale [mRS] score, improvement in symptoms and cognitive function) and radiological outcomes (arterial spin labeling [ASL] perfusion) were studied and compared between direct and indirect revascularization groups.
Of 153 patients in the series, 16 (mean age 8.9 years) had severe brain atrophy (cortical atrophy score ≥ 8). The presenting symptoms were recurrent transient ischemic attack in 6 patients (37.5%), major stroke in 7 patients (43.75%), and seizure in 3 patients (18.75%). Fourteen patients underwent surgeries for both hemispheres and 2 patients underwent surgery for 1 hemisphere. Of the 30 hemispheres, 17 (56.7%) were treated with direct revascularization and 13 (43.3%) with indirect revascularization. The mean follow-up duration was 38.8 months. The median mRS score improved from 3 (preoperative) to 1.5 (last follow-up), with 11 patients (68.75%) showing improvement in mRS score. Thirteen patients (81.25%) showed improvement in presenting symptoms. Overall, 12 of 16 patients (75%) showed improvement in cognitive function at the last follow-up. The mean preoperative and follow-up ASL scores improved for the lower-perfusion hemispheres from 7.9 to 8.9 and for the higher-perfusion hemispheres from 9.6 to 10.45, respectively. Differences between preoperative and postoperative ASL scores for both groups were statistically significant. There was no significant difference in clinical and radiological outcomes between the direct and indirect revascularization groups. Clinical outcomes were comparable across patient groups based on the distribution of brain atrophy (unilateral/bilateral, predominant left/right side, predominant vascular territory involved).
Moyamoya patients with severe brain atrophy showed improvement in paroxysmal symptoms, cognitive function, and overall clinical functioning status, as well as radiological perfusion, after undergoing either direct or indirect revascularization. Comparative efficacy of direct and indirect revascularization in these patients needs further investigation 9).
Patel et al. contribute valuable data supporting the feasibility and potential efficacy of surgical intervention in a population often considered poor candidates due to brain atrophy. However, methodological limitations temper the generalizability of the findings. Further high-quality studies are needed to confirm and expand upon these encouraging results.
Case series
Case reports
Q9008
Cerebrovascular Disease (CVD): Right carotid ischemic stroke with residual left hemiparesis and right carotid transient ischemic attack (TIA).
Hyperhomocysteinemia.
Psoriatic Arthropathy treated with Humira
Carpal Tunnel Syndrome.
Right corneal opacity secondary to chemical burn.
Surgical History:
Meniscectomy.
Right inguinal hernia intervention.
Toxic Habits:
Smoking 10 cigarettes a day.
Cardiovascular Risk Factors (CVRF):
Hypertension (HTN).
Current Treatment:
Atorvastatin, Clopidogrel, Adiro, Diazepam, Diliban, Humira.
Angiography and Cranial CT Results:
Angiography: Occlusion of both middle cerebral arteries at the M1 level, suggestive of Moya-Moya disease.
Revascularization Surgery: Right EC-IC ATS-ACM M4 branch bypass.
Cranial CT: Postoperative changes at the right parietotemporal level, permeability of STA-ACM bypass without complications.
Postoperative Recommendations:
Neurological Follow-up:
Evaluate progression and effectiveness of treatment.
Surgery Monitoring:
Assess the function of the STA-ACM bypass. The patient has been discharged with good progress, but close follow-up is required to manage his complex medical conditions.