What are the therapeutic management options for moyamoya disease?

Moyamoya Disease: Etiology, Diagnosis, and Therapeutic Management

Etiology

Moyamoya disease is a chronic progressive cerebrovascular disorder characterized by bilateral stenosis of the terminal internal carotid arteries and proximal anterior and middle cerebral arteries, with compensatory development of fragile collateral vessels that create the characteristic "puff of smoke" appearance on angiography. 1

• The underlying pathophysiology involves irregular internal elastic lamina with luminal narrowing, hyperplasia of the tunica media, and intimal thickening with vacuolar degeneration in smooth muscle cells 1
• The R4810K variant of the RNF213 gene is strongly associated with moyamoya, particularly in East Asian populations, and correlates with severe, early-onset, multisystem vasculopathy 2
• Risk factors include East Asian ancestry, neurofibromatosis type 1, Down syndrome, and sickle cell disease 3, 1
• No known methods exist to arrest the underlying arteriopathy 3

Diagnosis

MR angiography (MRA) has largely supplanted catheter angiography as the primary diagnostic imaging modality, though digital subtraction angiography remains the gold standard for definitive diagnosis. 3, 1

Imaging Findings

• MRI/MRA findings virtually diagnostic of moyamoya include: absence of flow voids in the ICA, MCA, and ACA coupled with abnormally prominent flow voids from basal ganglia and thalamic collateral vessels 3
• Diffusion-weighted imaging (DWI) is best for detecting acute infarcts 3
• Fluid-attenuated inversion recovery (FLAIR) sequences may demonstrate linear high signal following sulcal patterns, representing slow flow in poorly perfused cortical circulation 3

Perfusion Assessment

• Perfusion imaging and cerebrovascular reactivity assessment are critical for treatment planning and identifying high-risk patients 2
• SPECT with acetazolamide challenge, PET, perfusion CT, and MR perfusion can detect inadequate resting perfusion and poor blood flow reserve 3
• These techniques help determine which patients warrant surgical intervention and assess improvement after revascularization 3

Surveillance

• Periodic clinical and radiographic reexaminations are recommended, as 27% of patients with unilateral disease eventually develop bilateral involvement 3
• Disease progression is more likely in younger patients 3

Therapeutic Management

Surgical Revascularization

Revascularization surgery should be offered to all patients with moyamoya who have ongoing ischemic symptoms and/or evidence of compromised cerebral perfusion, barring medical contraindications (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
• The principle of minimizing time between diagnosis and revascularization is supported, though delays may be necessary for experienced staff scheduling or medical contraindications (recent infarction, infection, hemorrhage) 3

Surgical Techniques

For hemorrhagic moyamoya, direct bypass (superficial temporal artery to middle cerebral artery) is the most appropriate intervention based on the Japan Adult Moyamoya trial, which demonstrated reduction in rebleeding from 7.6%/year to 2.7%/year (P=0.04). 3

Pediatric Patients

• Indirect revascularization techniques (pial synangiosis, encephaloduroarteriosynangiosis, multiple burr holes) are preferred in children due to small vessel size making direct bypass technically difficult 3
• Indirect techniques are used in approximately 75% of pediatric cases with excellent results: absence of clinical recurrence in >95% and good neovascularization in 83% 4
• Long-term stroke rate after pial synangiosis is 4.3% with minimum 5-year follow-up 3

Adult Patients

• Direct or combined (direct plus indirect) techniques are more effective in adults, providing immediate blood flow improvement and higher stroke-free survival at 5 years (95% vs 85%) 4, 5
• Meta-analysis of 1156 pediatric patients showed 87% derived symptomatic benefit with no difference between indirect and direct/combined approaches 3

Perioperative Management

Meticulous perioperative management is essential to minimize the 4%-10% risk of perioperative stroke. 3

Critical Perioperative Measures

• Pre- and postoperative hydration reduces stroke risk by minimizing blood pressure fluctuations 3
• Maintain systolic blood pressure at or above preoperative baseline where patient is asymptomatic; avoid systolic BP >180 mmHg 3
• Maintain normocapnia (end-tidal CO₂ 35-45 mmHg) - hypocapnia from hyperventilation causes vasoconstriction and ischemia 3
• Keep patients euvolemic to mildly hypervolemic intraoperatively; postoperative IV fluids at 1.5 times maintenance rate for 48-72 hours 3
• Avoid mannitol to prevent hypotension and decreased cerebral perfusion pressure 3
• Use neuroprotective anesthetic agents (propofol) during periods of intraoperative instability 3
• Minimize anxiety and pain (crying, hyperventilation lower PaCO₂ and induce ischemia) 3

Medical Management

Medical therapy has three major components: prevention of thrombosis, maintenance of intravascular volume, and mitigation of non-ischemic symptoms. 3

Antithrombotic Therapy

• Aspirin is most commonly used (81 mg daily in children, weight-based dosing) to prevent microthrombi at stenosis sites 3
• Some clinicians prefer low-molecular-weight heparin 3
• Antiplatelet use is more common in Western countries than Asia (where hemorrhagic presentation is more prevalent) 3
• Anticoagulants like warfarin are NOT recommended for most patients due to hemorrhage risk and difficulty maintaining therapeutic levels in children (Class III recommendation) 3

Fluid Management

• Careful monitoring to avoid dehydration is critical - focus on preventing fluid loss rather than supplementing intake 3
• Particular attention needed during illness (diarrhea, vomiting), exercise, or hot weather 3

Risk Factor Management

• Diabetes is an independent predictor of recurrent ischemic stroke in both surgical and non-surgical patients 3
• Hypertension and dyslipidemia are risk factors for cerebrovascular events in asymptomatic moyamoya 3
• Atorvastatin after surgical revascularization may improve collateral circulation 3

Headache Management

• Headaches in moyamoya are common and often migraine-like 3
• Avoid migraine therapies that cause vasoconstriction, inhibit vasodilation, or lower blood pressure 3
• Calcium channel blockers have been used for intractable headaches and refractory TIAs 3

Natural History Without Treatment

• Recurrent ischemia risk is 10-13%/year in symptomatic ischemic forms 4
• Hemorrhagic stroke risk is 2-7%/year 4
• 38.4% of conservatively managed patients eventually require surgery due to progressive symptoms 3

Key Clinical Pitfalls

• Perioperative stroke risk (4%-10%) mimics ischemic complications but may actually be hyperperfusion syndrome, requiring different treatment - postoperative blood flow assessment is critical to distinguish 5
• Posterior hemorrhages (from posterior cerebral or choroidal arteries) have higher rebleeding risk and obtain greater benefit from surgical intervention 3
• Even asymptomatic patients can experience significant cognitive decline from chronic ischemia 5