What is Moyamoya disease, including its typical presentation, diagnostic workup, and recommended treatment options?

Moyamoya Disease: Definition, Diagnosis, and Management

What is Moyamoya Disease?

Moyamoya disease is a progressive cerebrovascular arteriopathy characterized by stenosis or occlusion of the terminal internal carotid arteries and their proximal branches, with compensatory development of fragile collateral vessels at the skull base that appear as a "puff of smoke" on angiography. 1 The disease affects approximately 1 in 1 million children in the United States but accounts for 6% of all childhood strokes. 1 In adults, the incidence is 0.57 per 100,000 people per year, with highest prevalence in Asian populations, particularly Japanese. 1

The arteriopathy can present as isolated moyamoya disease (bilateral or unilateral involvement without other causes) or moyamoya syndrome when associated with identifiable conditions including autoimmune diseases, Down syndrome, neurofibromatosis type 1, sickle cell disease, prior cranial radiation, meningitis, or brain tumors. 1, 2 Notably, atherosclerosis and hyperthyroidism were removed from the list of associated conditions in the 2021 Japanese criteria revision. 1, 2

Clinical Presentation

Pediatric Presentation

Children predominantly present with recurrent ischemic strokes or transient ischemic attacks involving the carotid circulation, with infarctions in superficial, deep, or watershed territories. 3 Ischemic symptoms are characteristically triggered by hyperventilation, crying, coughing, straining, or fever due to vasoconstriction in already compromised vessels. 3 A pathognomonic electroencephalographic finding is the "rebuild-up" phenomenon—slowing of background rhythm after cessation of hyperventilation. 3

Adult Presentation

Adults in Western countries more commonly present with recurrent ischemia, though hemorrhagic events (intracerebral, intraventricular, or subarachnoid hemorrhage) occur from rupture of fragile collateral vessels or pseudo-aneurysms. 3, 4 The disease shows two age peaks: one at 5 years and another around 40 years. 4

Additional Clinical Features

• Headaches occur in >50% of patients, typically with migraine-like features (often with aura) or tension-type characteristics 3
• Neurocognitive impairment results from chronic cerebral hypoperfusion 3
• Seizures may occur as part of the clinical spectrum 3
• Movement disorders can develop secondarily 3

Diagnostic Workup

Gold Standard: Digital Subtraction Angiography

Digital subtraction angiography (DSA) remains the definitive diagnostic test, demonstrating stenosis or occlusion of the terminal intracranial internal carotid artery and characteristic moyamoya collateral vessels. 2 Both unilateral and bilateral involvement satisfy diagnostic criteria according to the 2015 Japanese revision, which eliminated the former "definite" versus "probable" distinction. 2 The Suzuki classification describes six progressive angiographic stages, though it has limited practical value for single time-point assessment. 1, 2

Non-Invasive MRI/MRA Criteria

MRI/MRA performed on ≥1.5 Tesla scanners can replace DSA only when all three of the following are present: 2

1. Stenosis/occlusion of the terminal ICA
2. Reduced outer diameter of the terminal ICA and horizontal MCA on heavy T2-weighted images
3. At least two flow-voids in the basal ganglia or periventricular white matter representing abnormal collateral networks

Critical caveat: MRA fails to visualize moyamoya vessels in approximately 17% of cases and is less reliable for detecting occlusion of smaller distal vessels. 2 When vessels are not clearly seen, DSA should be performed. 2

Pathognomonic MRI Findings

The combination of markedly diminished flow-voids in the ICA, MCA, and ACA together with markedly prominent basal-ganglia/thalamic collateral flow-voids is virtually diagnostic and can eliminate the need for invasive angiography in typical presentations. 2

Hemodynamic Assessment

The European Stroke Organisation recommends that all patients undergo hemodynamic assessment to inform therapeutic decision-making. 5 Recommended modalities include: 2, 3, 5

• Arterial spin-labeling MRI
• CT perfusion
• Acetazolamide-challenged SPECT
• PET imaging

These techniques detect regional perfusion instability and cerebrovascular reserve capacity, which are critical predictors of stroke risk and surgical candidacy. 2, 3 The "Ivy sign" (linear high signal following sulci on FLAIR imaging) indicates slow cortical perfusion. 2 However, these perfusion techniques remain poorly validated and their use varies by institution. 2, 5

Additional Imaging

• Diffusion-weighted MRI best detects acute cerebral infarcts 2
• Transcranial Doppler ultrasonography is useful for longitudinal monitoring of cerebral blood-flow velocities 2, 3
• CT scan alone is inadequate for diagnosis but can identify complications such as hemorrhage 2

Exclusion of Secondary Causes

Clinicians must rule out secondary causes to differentiate moyamoya disease from syndrome: 2

• Autoimmune disorders (SLE, antiphospholipid syndrome, polyarteritis nodosa, Sjögren syndrome)
• Prior cranial radiation (2-4.3% develop moyamoya; up to 60% in neurofibromatosis type 1 patients receiving radiation)
• Genetic syndromes (Down syndrome, neurofibromatosis type 1)
• Infections (leptospirosis, HIV)
• Sickle cell disease
• Meningitis and brain tumors

Genetic Testing

Genetic testing is not required for diagnosis but may be offered for familial counseling. 2 The RNF213 R4810K variant is a major founder variant for East Asians. 1 Patients with Noonan-like phenotypes should be screened for PTPN11 and CBL mutations; those with neurofibromatosis type 1 features should undergo NF1 gene testing. 2

Treatment Recommendations

Surgical Revascularization: The Definitive Treatment

All patients with ongoing ischemic symptoms and/or evidence of compromised cerebral perfusion should undergo revascularization surgery (Class I, Level B recommendation). 3 Even clinically asymptomatic patients demonstrating radiographic or functional evidence of impaired cerebral perfusion should be considered surgical candidates. 3 Surgery markedly reduces stroke risk: preoperative stroke rate of 67% drops to 4.3% at 5-year follow-up after revascularization. 3

Surgical Technique Selection

For hemorrhagic moyamoya, direct bypass (superficial temporal artery to middle cerebral artery) is the most appropriate intervention, reducing rebleeding from 7.6%/year to 2.7%/year (P=0.04). 3 The Japan Adult Moyamoya trial established this as the standard. 3

For pediatric patients, indirect revascularization techniques (pial synangiosis, encephaloduroarteriosynangiosis, multiple burr holes) are preferred due to small vessel size making direct bypass technically difficult. 3 Indirect bypass relies on angiogenic proliferation over days to weeks. 3

Combined direct and indirect revascularization approaches have shown superior results, with 96% probability of remaining stroke-free over 5 years. 3

Perioperative Management: Critical to Prevent Complications

The perioperative stroke risk is 4-10%, requiring meticulous management: 3

Hemodynamic optimization:

• Provide intravenous fluids at 1.5 times normal maintenance rate for 48-72 hours postoperatively 3
• Maintain systolic blood pressure at or above preoperative baseline 3
• Maintain euvolemia to mild hypervolemia to avoid hypotension and decreased cerebral perfusion 3

Respiratory management:

• Maintain strict normocapnia with end-tidal CO₂ 35-45 mmHg—hypocapnia causes vasoconstriction and ischemia 3
• Minimize triggers of hyperventilation using perioperative sedation and painless wound dressing techniques 3

Avoid: systemic hypotension, hypovolemia, hyperthermia, and hypocarbia 3

Cerebral hyperperfusion syndrome occurs in 16.5% overall (3.8% in pediatric patients, 19.9% in adults) and requires vigilant monitoring. 3

Medical Management

Antiplatelet Therapy

Aspirin may be considered in individuals after revascularization surgery or in asymptomatic individuals for whom surgery is not anticipated (Class IIb recommendation). 3 Aspirin is most commonly used at 81 mg daily in children with weight-based dosing. 3 The evidence for antiplatelet therapy is mixed and practice varies globally, with more common use in Western countries than Asia where hemorrhagic presentation is more prevalent. 3

Cilostazol (a vasodilator) may improve survival, cerebral blood flow, and cognition compared to other antiplatelet drugs, though this requires further validation. 3

Anticoagulation: Contraindicated

Anticoagulants like warfarin are NOT recommended for most patients due to hemorrhage risk and difficulty maintaining therapeutic levels, particularly in children (Class III recommendation). 3

Risk Factor Management

• Diabetes is an independent predictor of recurrent ischemic stroke and requires aggressive management 3
• Hypertension and dyslipidemia are risk factors for cerebrovascular events in asymptomatic moyamoya 3
• Atorvastatin may improve collateral circulation post-revascularization 3

Acute Management

• Maintain euvolemia to mild hypervolemia 3
• Maintain normocapnia with end-tidal CO₂ 35-45 mmHg 3
• Avoid systemic hypotension, hypovolemia, hyperthermia, and hypocarbia 3

Long-Term Surveillance

Serial follow-up is necessary given 5% annual risk of cerebrovascular events in asymptomatic patients and 20% disease progression rate. 3 Transcranial Doppler may be useful in evaluation and follow-up (Class IIb recommendation). 3 Techniques to measure cerebral perfusion and blood flow reserve may assist in ongoing evaluation. 3

Common Diagnostic Pitfalls

• Do not dismiss unilateral disease: 20-27% of patients with unilateral moyamoya later develop bilateral involvement, and unilateral cases meet diagnostic criteria 2
• Do not rely on MRA alone when moyamoya vessels are not clearly visualized, as MRA misses vessels in ~17% of cases 2
• Do not mistake normal flow-voids for pathology: the key finding is diminished flow-voids in major vessels combined with prominent collateral flow-voids in basal ganglia/thalamus 2
• CT alone is insufficient for diagnosis 2
• Screen first-degree relatives and high-risk groups (neurofibromatosis type 1, Down syndrome, sickle cell disease) 2

Natural History and Prognosis

Without treatment, patients face: 3

• Recurrent ischemic strokes with annual risk around 5% in asymptomatic patients
• Disease progression in 20% over mean follow-up of 6 years
• Posterior circulation involvement associated with worse clinical presentation and higher recurrent hemorrhages