Moyamoya Disease: Symptoms, Types, Causes and Treatment

Moyamoya disease (MMD) is a rare and complex cerebrovascular disorder that affects both children and adults, often leading to strokes and other significant neurological symptoms. Named after the Japanese word for "puff of smoke"—a reference to the appearance of abnormal blood vessels on brain imaging—MMD remains a topic of active research and clinical interest worldwide. Understanding its symptoms, types, causes, and treatment options is essential for early detection and effective management. In this comprehensive guide, we break down the critical facets of Moyamoya disease, drawing on the latest research to inform patients, families, and clinicians.

Symptoms of Moyamoya Disease

Moyamoya disease often presents with a diverse array of neurological symptoms, which can vary considerably between children, adolescents, and adults. Early recognition is crucial, as timely intervention can reduce the risk of permanent deficits and improve outcomes.

Symptom	Age Group	Common Presentation	Source(s)
Limb Weakness	Children/Teens	Sudden hemiplegia, transient attacks	2 3 5
Headache	All	Isolated or with other symptoms	2 3 7
Speech Issues	Children/Teens	Difficulty in speech, aphasia	2 5
Seizures	Children/Teens	Convulsions, epilepsy	2 3 4
Hemorrhage	Adults	Intracranial bleeding, sudden onset	1 6 18
Asymptomatic	All	Incidental diagnosis	3

Table 1: Key Symptoms

Age-Dependent Presentation

• Children: Typically present with ischemic symptoms such as transient ischemic attacks (TIAs), strokes, limb weakness, and speech difficulties. Seizures and involuntary movements are also common in this age group. Headaches may be the only symptom in some cases, and a significant number of children present with multiple neurological deficits at onset 1 2 3 5.
• Adolescents: Cluster analyses highlight limb weakness as the most frequent symptom, followed by headaches, speech problems, convulsions, dizziness, and nausea/vomiting. Some may be entirely asymptomatic or present with isolated seizures 2.
• Adults: More likely to present with hemorrhagic stroke, often accompanied by intracerebral and intraventricular hemorrhage. Ischemic events and headaches are also reported, but bleeding is a more common initial event in adults than in children 1 6 18.

Symptom Clusters and Variability

Recent studies using cluster analyses in adolescents have identified distinct groupings of symptoms:

• Cluster 1: Limb weakness dominates, often signaling a vascular event.
• Cluster 2: Asymptomatic or convulsions only.
• Cluster 3: Speech difficulty and facial paralysis.
• Cluster 4: Dizziness and sensory disturbances (pins and needles).
• Cluster 5: Headaches and nausea/vomiting 2.

Other Manifestations

• Intellectual decline and behavioral issues are not uncommon, especially in children with recurrent events.
• Movement disorders, such as involuntary movements or tremors, may arise due to collateral vessel proliferation within the basal ganglia 2 3 9.
• Epilepsy may develop, particularly in those with early-onset disease or underlying syndromic associations 3 4.

Types of Moyamoya Disease

Moyamoya disease is classified based on its clinical presentation, underlying causes, and association with other conditions. This classification helps guide diagnostic and therapeutic strategies.

Type	Key Features	Population	Source(s)
Ischemic	Strokes, TIAs, mainly in children	Pediatric	1 3 6
Hemorrhagic	Intracranial bleeding, adults	Adults	1 6 18
Epileptic	Seizures, convulsions	Children/Teens	6 3 4
Other	Movement, cognitive changes	All	3 6 9
Moyamoya Syndrome	Secondary to other disorders	Syndromic cases	4 9 10

Table 2: Types of Moyamoya Disease

Primary Moyamoya Disease (MMD)

• Definition: A primary, idiopathic condition characterized by progressive bilateral stenosis or occlusion of the terminal internal carotid arteries and the development of abnormal collateral vessels at the base of the brain 1 6 9.
• Subtypes:
  • Ischemic Type: Most common in children, presents with TIAs and strokes.
  • Hemorrhagic Type: Predominant in adults, manifests as intracranial bleeding.
  • Epileptic Type: Characterized by recurrent seizures.
  • Other Type: Includes cognitive, psychiatric, or movement disorders 6.

Moyamoya Syndrome (MMS)

• Definition: Moyamoya angiopathy occurring secondary to other conditions, such as Down syndrome, sickle cell anemia, neurofibromatosis, or after cranial irradiation 4 9 10.
• Distinction: MMS shares the radiological features of MMD but arises from a known underlying cause, whereas MMD is idiopathic 9 10. MMS can also be associated with chromosomal abnormalities (e.g., trisomy 13), mitochondrial diseases, and autoimmune disorders 4 8 10.

Clinical and Radiological Classification

• Suzuki Stages: Based on angiographic progression from mild narrowing to complete occlusion and disappearance of the moyamoya vessels.
• Berlin Moyamoya Grading: Uses MRI and hemodynamic assessments to stratify disease severity and surgical risk, now favored over traditional angiographic staging for clinical management 18.

Causes of Moyamoya Disease

While the exact cause of Moyamoya disease remains elusive, current research highlights a multifactorial etiology involving genetic, environmental, and possibly immunological factors.

Cause	Description	Population/Evidence	Source(s)
Genetic	RNF213 gene variants	East Asians, familial	1 11 12 13 14
Secondary	Syndromic/underlying disease	MMS: Down’s, Sickle Cell	4 9 10 12
Immunological	Immune/inflammatory triggers	Infection, autoimmune	8 14
Multifactorial	Hemodynamics, vessel biology	Complex interplay	10 13 14

Table 3: Causes and Risk Factors

Genetic Susceptibility

• RNF213 Gene: The strongest known genetic risk factor, especially in East Asian populations. The p.R4810K variant is found in a significant percentage of Asian patients and is associated with earlier onset, more severe ischemic events, and familial clustering 1 11 12 13 14.
• Other Genes: Rare variants in other genes have been identified but are less common and may contribute to disease in non-Asian populations 11 12.
• Familial Cases: Family history is present in 9–15% of Asian patients, suggesting a heritable component 14.

Secondary or Syndromic Causes (Moyamoya Syndrome)

• Associated Conditions: Down syndrome, sickle cell anemia, neurofibromatosis, cranial irradiation, chromosomal abnormalities, and mitochondrial diseases can all lead to moyamoya-like vascular changes (MMS) 4 9 10 12.
• Phenotypic Variability: These cases often present earlier and may have more complex clinical courses due to the underlying disorder 4.

Immune and Environmental Factors

• Immune Triggers: Recent research suggests a "second hit" (such as infection or autoimmune activation) may be necessary for disease expression in genetically susceptible individuals 8.
• Inflammatory Markers: Elevated cytokines and growth factors in blood and cerebrospinal fluid support the role of abnormal angiogenesis and inflammation in MMD pathogenesis 13 14.

Mechanobiological and Hemodynamic Factors

• Vessel Wall Biology: Abnormalities in endothelial and smooth muscle cells, as well as molecular mediators of angiogenesis, contribute to progressive vessel narrowing and new vessel formation 10 13 14.
• Anatomical Predilection: The disease preferentially affects the terminal internal carotid arteries due to unique hemodynamic and biomechanical stresses at this vascular junction 10.

Treatment of Moyamoya Disease

Timely and appropriate treatment is essential to reduce the risk of stroke and improve long-term outcomes in Moyamoya disease. Management strategies are tailored to disease severity, age, and clinical presentation.

Treatment	Approach	Patient Group	Source(s)
Direct Bypass	STA-MCA anastomosis	Adults, severe cases	6 15 16 17 18
Indirect Bypass	EDAS, pial synangiosis	Children, some adults	6 15 16 18
Combined/Other	Hybrid procedures	Complex cases	6 15 17
Medical Therapy	Aspirin, supportive care	Mild/asymptomatic	3 7 15
Aneurysm Tx	Revascularization, clipping	With aneurysms	17
Monitoring	Imaging, follow-up	All	1 18

Table 4: Treatment Approaches

Surgical Revascularization

• Direct Bypass: Involves connecting a scalp artery (usually the superficial temporal artery) directly to a brain artery (middle cerebral artery, MCA) to immediately improve blood flow. Used mainly in adults and selected pediatric cases 6 15 16 18.
• Indirect Bypass: Techniques such as encephaloduroarteriosynangiosis (EDAS) place vascularized tissue near the brain surface to promote gradual new vessel growth. This is the mainstay in children and has proven effective in many adults 6 15 16 18.
  • Modified EDAS (mEDAS) is a newer, less strenuous indirect technique with favorable outcomes for symptomatic adults 16.
• Combined Procedures: In complex or refractory cases, both direct and indirect methods may be used together 6 15 17.

Medical Management

• Aspirin: Used to reduce the risk of ischemic events, especially in children and those awaiting surgery. Not sufficient to halt disease progression 3 7 15.
• Supportive Care: Includes control of risk factors and symptomatic management of neurological deficits.

Treatment of Associated Aneurysms

• Endovascular or Surgical Clipping: Depending on aneurysm location and size, revascularization is often combined with direct aneurysm treatment to reduce rupture risk 17.

Monitoring and Follow-up

• Imaging: Regular MRI/MRA or angiography is needed to assess disease progression and post-surgical collateral formation 1 18.
• Functional Assessment: Ongoing neurological and cognitive testing helps track outcomes.

Outcomes and Complications

• Effectiveness: Surgical revascularization is highly effective in preventing further ischemic strokes and, according to recent trials, may also reduce hemorrhagic stroke risk 15.
• Complications: Peri-operative risks include stroke, hyperperfusion syndrome, and wound problems, but these are manageable with expert care 15 16.
• Prognosis: Early diagnosis and intervention are linked to better outcomes. Delays can result in permanent disability or cognitive decline, especially in children 3 18.

Conclusion

Moyamoya disease is a rare but serious condition that requires prompt recognition and expert management. Here are the key takeaways:

• Symptoms are highly variable, with children experiencing ischemic events and adults more prone to hemorrhagic strokes. Limb weakness, headaches, and speech difficulties are common signs.
• Types of Moyamoya disease include ischemic, hemorrhagic, epileptic, and syndromic forms, with distinct presentations across age groups.
• Causes are multifactorial, involving genetic predisposition (especially RNF213 mutations), secondary syndromic associations, immune triggers, and complex vessel biology.
• Treatment is centered on surgical revascularization (direct or indirect bypass), with medical therapy playing a supportive role. Outcomes are best when diagnosis and intervention are early.

Staying vigilant for subtle neurological symptoms and understanding the nuances of Moyamoya disease can make a life-changing difference for affected patients and families.