What are the diagnostic and treatment approaches for a patient with suspected moyamoya disease?

Moyamoya Disease: Diagnostic and Treatment Approach

Definition and Key Diagnostic Criteria

Moyamoya disease is a progressive cerebrovascular disorder requiring bilateral stenosis or occlusion of the terminal internal carotid arteries with characteristic "puff of smoke" collateral vessels on angiography; however, the 2021 Japanese guidelines now accept unilateral disease given high progression rates to bilateral involvement. 1

• Moyamoya disease (MMD) occurs when no associated comorbidities are present, while moyamoya syndrome (MMS) is diagnosed when associated conditions exist (autoimmune disease, meningitis, brain tumors, Down syndrome, neurofibromatosis type 1, head irradiation, or sickle cell disease) 1
• The disease affects women more than men (2.6:1 ratio in the US), with highest prevalence in Asian populations, particularly Japanese and Korean 1
• Peak incidence occurs bimodally: ages 10-14 years in males and 20-24 years in females 1

Clinical Presentation by Age Group

Children predominantly present with recurrent ischemic strokes or TIAs triggered by hyperventilation, crying, coughing, or fever, while adults in Western countries present more commonly with ischemic events, though hemorrhagic presentation is more frequent in Asian adult populations. 2, 3

• Ischemic symptoms are triggered by vasoconstriction in already compromised vessels during hyperventilation, crying, coughing, straining, or fever 3, 4
• Hemorrhagic strokes occur more frequently in adults than children, particularly in Asian populations 5, 6
• Additional manifestations include headaches (>50% with migraine-like features with aura), seizures, cognitive deficits, and psychiatric symptoms 1, 3
• Characteristic EEG finding: "rebuild-up" phenomenon showing slowing of background rhythm after cessation of hyperventilation 3

Diagnostic Imaging Algorithm

Cerebral digital subtraction angiography (DSA) remains the gold standard for definitive diagnosis, particularly for unilateral lesions or cases complicated by atherosclerosis. 1, 4

Required Angiographic Findings (All Three Must Be Present):

1. Stenosis of the distal ICA bifurcation and proximal ACA/MCA 2, 4
2. Dilated basal collateral arteries creating the "puff of smoke" appearance 2, 4
3. Bilateral abnormalities (though unilateral now accepted per 2021 criteria) 1, 4

Initial Noninvasive Imaging:

• MRI/MRA of the head is the preferred initial noninvasive diagnostic modality, performed together to evaluate both cerebral vasculature and brain parenchyma 1
• T2-weighted FLAIR may show high signal in sulci ("ivy sign") indicating slow flow in affected territories 1
• Susceptibility-weighted imaging (SWI) demonstrates microhemorrhage in up to 52% of patients 1
• CTA (including multiphase CTA) is an alternative to MRA for initial diagnosis and follow-up 1

Perfusion Assessment (Critical for Treatment Planning):

• Perfusion imaging (SPECT, PET, MR perfusion, or CT perfusion) and cerebrovascular reactivity assessment are mandatory for identifying patients with compromised cerebral blood flow reserve 2, 4
• SPECT with acetazolamide challenge assesses perfusion instability and vascular reserve 1
• MR perfusion using arterial spin-labeling (without contrast) or dynamic susceptibility contrast techniques 1
• These studies guide surgical candidacy and assess functional improvement after treatment 1

Medical Management

Antiplatelet Therapy:

• Aspirin may be reasonable for prevention of ischemic events in both surgical and nonsurgical patients with ischemic moyamoya (Class IIb recommendation), though evidence is mixed and practice varies globally 2, 3
• Dosing: 81 mg daily in children, weight-based dosing in adults 3
• Antiplatelet use is more common in Western countries than Asia where hemorrhagic presentation predominates 3
• Anticoagulants like warfarin are NOT recommended due to hemorrhage risk and difficulty maintaining therapeutic levels, particularly in children (Class III recommendation) 2, 3, 4

Hemodynamic Optimization:

• Maintain euvolemia to mild hypervolemia to avoid hypotension and decreased cerebral perfusion 1, 2, 4
• Maintain strict normocapnia with end-tidal CO₂ 35-45 mmHg, as hypocapnia causes vasoconstriction and ischemia 1, 2, 3
• Avoid systemic hypotension, hypovolemia, hyperthermia, and hypocarbia 3
• Avoid mannitol as it can cause hypovolemia and decreased cerebral perfusion pressure 1

Risk Factor Management:

• Diabetes is an independent predictor of recurrent ischemic stroke and requires aggressive management 2, 3
• Hypertension and dyslipidemia are risk factors for cerebrovascular events in asymptomatic moyamoya 3
• Cilostazol (vasodilator) may improve survival, cerebral blood flow, and cognition compared to other antiplatelet drugs, though requires further validation 3
• Atorvastatin may improve collateral circulation post-revascularization 3

Surgical Management

All patients with ongoing ischemic symptoms and/or evidence of compromised cerebral perfusion should undergo revascularization surgery (Class I, Level B recommendation). 2, 3, 4

Surgical Candidacy:

• Even clinically asymptomatic patients with radiographic or functional evidence of impaired cerebral perfusion should be considered surgical candidates 2, 3
• Surgery markedly reduces stroke risk: preoperative stroke rate of 67% drops to 4.3% at 5-year follow-up after revascularization 2, 3
• The key factor in successful outcome is surgeon and institutional experience with moyamoya care 2

Surgical Techniques:

Direct Bypass:

• Superficial temporal artery to middle cerebral artery (STA-MCA) bypass is the most appropriate intervention, particularly for hemorrhagic moyamoya, reducing rebleeding from 7.6%/year to 2.7%/year (P=0.04) 2, 3, 4
• Provides immediate revascularization 7

Indirect Bypass:

• Techniques include pial synangiosis, encephaloduroarteriosynangiosis, and multiple burr holes 3, 7
• Preferred in children due to small vessel size making direct bypass technically difficult 3
• Relies on angiogenic proliferation over days to weeks 3

Combined Approach:

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

Perioperative Management:

Critical Hemodynamic Control:

• Maintain systolic blood pressure at or above preoperative baseline; slight elevation may be beneficial 2, 4
• Provide intravenous fluids at 1.5 times normal maintenance rate for 48-72 hours postoperatively 3
• Maintain strict normocapnia with end-tidal CO₂ 35-45 mmHg 2, 3
• Minimize triggers of hyperventilation using perioperative sedation and painless wound dressing techniques 3

Perioperative Complications:

• Ischemic events occur in 4%-18% of surgical cases 2, 4, 5
• Cerebral hyperperfusion syndrome (CHS) occurs in 16.5% overall (3.8% in pediatric patients, 19.9% in adults) 1, 3
• CHS may be mitigated with strict blood pressure control (typically systolic BP <130), minocycline, or edaravone 1
• Predictive factors for CHS include older age, more severe preoperative hemodynamic impairment, dominant hemisphere surgery, and longer temporary occlusion time 1

Role of Endovascular Treatment:

• Endovascular treatment with stent or angioplasty alone has low success rate (25%) and high complication rates including devastating hemorrhage (7%) without evidence of improvement in natural history 1
• For hemorrhagic moyamoya with identifiable pseudoaneurysms, endovascular management can successfully obliterate aneurysms through distal parent vessel occlusion with ≈80% success rate 1

Long-Term Follow-Up and 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. 2, 3, 4

• Patients with unilateral moyamoya should obtain annual imaging with MRA or CTA to assess for disease progression for at least 3-5 years (Class IIb recommendation) 2
• Transcranial Doppler (TCD) may be useful in evaluation and follow-up (Class IIb recommendation) 3
• Techniques to measure cerebral perfusion and blood flow reserve assist in ongoing evaluation (Class IIb recommendation) 3, 4
• Evaluation of neuropsychological effects, screening for and management of headache and epilepsy are important aspects of chronic care 5

Genetic Considerations

• Up to 12% of patients with moyamoya have a positive family history, suggesting strong genetic component 1
• RNF213 R4810K variant is a major founder variant for East Asians (found in 95% of familial cases and 79% of sporadic cases), while non-R4810K variants increase risk in non-East Asian populations 1
• Screening of first-degree relatives is probably not warranted in the absence of symptoms unless multiple family members are already affected 1