What are the clinical presentation, diagnostic evaluation, and management recommendations for Moyamoya syndrome?

Moyamoya Syndrome

Definition and Pathophysiology

Moyamoya syndrome (MMS) refers to the characteristic vascular pattern of progressive arterial stenosis with compensatory collateral formation that occurs secondary to an identifiable underlying condition, distinguishing it from idiopathic moyamoya disease. 1

• MMS shares the same angiographic appearance as moyamoya disease—progressive occlusion of the terminal internal carotid arteries and proximal branches with development of fragile collateral vessels appearing as a "puff of smoke" on angiography 1
• Associated conditions include autoimmune diseases (SLE, antiphospholipid syndrome, polyarteritis nodosa, Sjögren syndrome), meningitis, brain tumors, Down syndrome, neurofibromatosis type 1, prior cranial radiation, sickle cell disease, and certain infections 1, 2
• Atherosclerosis and hyperthyroidism were specifically excluded from the 2021 Japanese criteria revision as associated conditions 1

Clinical Presentation

Children predominantly present with recurrent ischemic strokes or TIAs, while adults in Western countries more commonly present with ischemia, though hemorrhagic events occur in both populations. 3, 4

Ischemic Manifestations

• Ischemic symptoms are characteristically triggered by hyperventilation, crying, coughing, straining, or fever due to vasoconstriction in already compromised vessels 3, 4
• Infarctions occur in superficial, deep, or watershed territories involving the carotid circulation 3
• Characteristic EEG finding: slowing of background rhythm after cessation of hyperventilation ("rebuild-up" phenomenon) 3

Hemorrhagic Manifestations

• Hemorrhagic events arise from rupture of deep neovascular collaterals or pseudo-aneurysms 2
• Intracerebral, intraventricular, or occasional subarachnoid hemorrhage patterns 2

Additional Clinical Features

• Headaches occur in >50% of patients, typically with migraine-like features (often with aura) or tension-type characteristics 3, 2
• Seizures may occur as part of the clinical spectrum 3
• Neurocognitive impairment results from chronic cerebral hypoperfusion, affecting attention, memory, behavior, and executive functions 5, 2
• Progressive neurological decline can occur in fulminant cases 3

Diagnostic Evaluation

Digital subtraction angiography (DSA) remains the gold standard for diagnosis, though MRI/MRA on ≥1.5T scanners can establish diagnosis when all three specific criteria are met. 2

Angiographic Criteria (Gold Standard)

• DSA must demonstrate: (1) stenosis or occlusion of the terminal intracranial ICA and proximal branches, (2) presence of characteristic moyamoya collateral vessels, and (3) bilateral or unilateral involvement (both satisfy diagnostic criteria per 2015 Japanese revision) 2
• The former distinction between "definite" (bilateral) and "probable" (unilateral) cases was eliminated in 2015 1

MRI/MRA Diagnostic Criteria (Non-invasive Alternative)

• MRI/MRA can replace DSA only when all three findings are present: (1) stenosis/occlusion of terminal ICA, (2) reduced outer diameter of terminal ICA and horizontal MCA on heavy T2-weighted images, and (3) at least two flow-voids in basal ganglia or periventricular white matter representing abnormal collateral networks 2
• Critical limitation: MRA fails to visualize moyamoya vessels in approximately 17% of cases; when vessels are not clearly seen, DSA should be performed 2
• The combination of markedly diminished flow-voids in ICA/MCA/ACA together with markedly prominent basal-ganglia/thalamic collateral flow-voids is virtually diagnostic 2

Hemodynamic Assessment

• The European Stroke Organisation recommends hemodynamic assessment for all patients with moyamoya during diagnostic workup to help in decision-making 1
• Techniques include arterial spin labeling MRI, CT perfusion, acetazolamide-challenged SPECT, or PET 1, 3
• Hemodynamic impairment predicts stroke risk and guides surgical candidacy 1, 2
• These techniques remain poorly validated with heterogeneous use depending on local facilities 1, 2

Exclusion of Secondary Causes

• Must rule out autoimmune disorders, prior cranial radiation (2-4.3% develop moyamoya vasculopathy; up to 60% in neurofibromatosis type 1 patients receiving radiation), genetic syndromes, infections, sickle cell disease, meningitis, and brain tumors 2
• Genetic testing is not required for diagnosis but may be offered for familial counseling; screen for PTPN11 and CBL mutations in Noonan-like phenotypes, NF-1 gene in neurofibromatosis features 2, 5

Management Recommendations

Acute Medical Management

Maintain euvolemia to mild hypervolemia, normocapnia (end-tidal CO₂ 35-45 mmHg), normothermia, and avoid systemic hypotension to preserve cerebral perfusion. 3, 4

• Hypocapnia causes vasoconstriction and ischemia in already compromised vessels 3
• Maintain systolic blood pressure at or above preoperative baseline 3, 4
• Minimize triggers of hyperventilation using perioperative sedation and painless wound dressing techniques 3

Antiplatelet Therapy

Aspirin may be considered for prevention of ischemic events, though evidence is mixed and practice varies globally (Class IIb recommendation). 3, 4

• Aspirin is most commonly used at 81 mg daily in children with weight-based dosing 3
• Cilostazol (a vasodilator) may improve survival, cerebral blood flow, and cognition compared to other antiplatelet drugs, though requires further validation 3
• Anticoagulants like warfarin are NOT recommended due to hemorrhage risk and difficulty maintaining therapeutic levels, particularly in children (Class III recommendation) 3, 4

Surgical Revascularization

All patients with ongoing ischemic symptoms and/or evidence of compromised cerebral perfusion should undergo revascularization surgery (Class I, Level B recommendation). 3, 4

• Even clinically asymptomatic patients with radiographic or functional evidence of impaired cerebral perfusion should be considered surgical candidates 3, 4
• Surgery markedly reduces stroke risk: preoperative stroke rate of 67% drops to 4.3% at 5-year follow-up 3

Direct Bypass

• Superficial temporal artery to middle cerebral artery bypass is the most appropriate intervention, particularly for hemorrhagic moyamoya, reducing rebleeding from 7.6%/year to 2.7%/year (P=0.04) 3, 4
• Provides immediate revascularization 3

Indirect Bypass

• Techniques include pial synangiosis, encephaloduroarteriosynangiosis, and multiple burr holes 3
• Relies on angiogenic proliferation over days to weeks 3
• Preferred in children due to small vessel size making direct bypass technically difficult 3

Combined Approach

• Combined direct and indirect revascularization shows 96% probability of remaining stroke-free over 5 years 3

Perioperative Management

Provide intravenous fluids at 1.5 times normal maintenance rate for 48-72 hours postoperatively for hemodynamic optimization. 3

• Meticulous perioperative management minimizes the 4%-18% risk of perioperative ischemic events 4
• Cerebral hyperperfusion syndrome occurs in 16.5% overall (3.8% in pediatric patients, 19.9% in adults) 3

Risk Factor Management

Aggressively manage diabetes, hypertension, and dyslipidemia as these are independent predictors of recurrent ischemic stroke in moyamoya. 3

• Diabetes is an independent predictor of recurrent ischemic stroke 3
• Atorvastatin may improve collateral circulation post-revascularization 3

Long-Term Surveillance

Serial follow-up is necessary given 5% annual risk of cerebrovascular events in asymptomatic patients and 20% disease progression rate over mean 6-year follow-up. 3, 4

• Transcranial Doppler may be useful for evaluation and follow-up (Class IIb recommendation) 3
• Techniques to measure cerebral perfusion and blood flow reserve may assist in ongoing evaluation (Class IIb recommendation) 3
• Approximately 20-27% of patients with unilateral disease later develop bilateral involvement 2

Common Pitfalls

• Do not dismiss unilateral disease—both unilateral and bilateral involvement satisfy diagnostic criteria, and 20-27% progress from unilateral to bilateral 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 use CT scan alone for diagnosis, though it can identify complications such as hemorrhage and infarcts 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
• Posterior circulation involvement is associated with worse clinical presentation and higher recurrent hemorrhages 3