ISCHEMIC STROKE / CLASSIFICATION AND ETIOLOGY

Moyamoya disease

Created 11/05/2023, last revision 07/11/2023

  • progressive stenoocclusive disorder affecting the terminal segment of the internal carotid artery (ICA) and proximal segments of the arteries forming the circle of Willis (ACA, MCA, PCA)
  • an abnormal network of fine collateral arteries (lenticulostriate arteries, thalamic perforators, and pial arteries) is formed near stenotic vessels, resembling smoke puffs (moya-moya)
  • the process is usually bilateral, but unilateral manifestation does not exclude the diagnosis
Moyamoya

Etiology

  • moyamoya angiopathy (moyamoya pattern) may be caused by a variety of congenital and acquired diseases (see table)
  • proliferation and thickening of the intima of the terminal ICA segment and proximal MCA segment predominate;  the proliferating intima may contain lipid deposits, but there is no evidence of inflammation  [Bang, 2015]
  • thrombi may be present
  • associated neovascularization occurs as a compensatory mechanism (collateral circulation)
  • in practice, moyamoya should be considered more as a radiologic entity that can be associated with several diseases
  • acquired (e.g., moyamoya syndrome in vasculitis) – see table
  • congenital – sporadic and familial forms (10% are reported, but the number is probably higher)
    • AD transmission with low penetrance has been demonstrated in familial cases of MMD with linkage to chromosomes 3,6,8,12 and 17 (e.g., 17q25.3 Raptor); Ring finger 213 (RNF213) appears to be an important gene, its exact function is unknown  [Bang, 2015]
    • the moyamoya pattern may be caused  by other inherited vasculopathies (Grange syndrome, ACTA2 mutations, etc.)

→ more about etiology can be found here

Enlarged intima (black arrow) and intraluminal thrombus (blue arrow) in moyamoya [Scott, 2009]
 Moyamoya disease
  • idiopathic with possible inherited abnormalities (several mutations have already been described)
  • known inherited disorders associated with moyamoya angiopathy (e.g., Grange syndrome, ACTA2 mutations, etc.)
 Moyamoya syndrome – acquired conditions

Epidemiology

  • predominantly in Asians, with the highest prevalence in Japan (3.16 cases/100,000 inhabitants)
  • rarely affects Caucasians, African Americans, and Hispanics
  • peak incidence around age 4 (2/3) and then at age 30-40 (1/3)
  • approx. 10% of cases are familial (inherited)

Clinical presentation

  • onset of symptoms occurs across a wide age range (4 months to 67 years), peaking in the 1st and 3-4th decade of life
  • the clinical course is variable, ranging from asymptomatic forms to TIAs or strokes with permanent neurological deficit
  • in children, common symptoms include mono- or hemiparesis, sensory disturbances, involuntary movements, headache, cognitive impairment, and epileptic seizures;  intracerebral bleeding is relatively rare
  • in adults, intraventricular, subarachnoid, or intraparenchymal bleeding is more common (up to 30% of cases)
    • hematomas most commonly result from ruptured collaterals  [Kim, 2017]
  • watershed infarcts are common
  • clinical presentation, especially the incidence of bleeding, is influenced by racial factors, with a higher prevalence of bleeding observed in Asians compared to Caucasians

Diagnostic evaluation

Diagnostic criteria

Radiological and histological diagnostic criteria for MMD
 Angiographic findings suggesting the diagnosis of moyamoya
  • stenosis or occlusion of the terminal ICA (TICA) and proximal segments of the MCA and ACA
  • abnormal vascular network near occlusions, seen in the arterial phase
  • the finding is usually bilateral
 Histopathologic findings suggesting the diagnosis of moyamoya
  • thickening of the intima leading to stenosis or occlusion of the artery, typically found in the terminal segment of the ACI and the origin of MCA and ACA
  • stenosis or occlusion of the arteries of the circle of Willis with intimal thickening
  • multiple arterioles occurring in the vicinity of the Circle of Willis
Moyamoya disease staging    [Suzuki 1969]
Stage 1 – narrowing of the carotid bifurcation
Stage 2 – formation of collaterals (“moyamoya arteries”), stenosis of the terminal ICA, dilatation of the MCA and ACA
Stage 3 – intensive formation of moyamoya arteries, progression of stenoses of ICA, MCA, and ACA
Stage 4 – gradual disappearance of moyamoya arteries, the disappearance of PCA, further narrowing of ICA, MCA, and ACA
Stage 5 – a further reduction of moyamoya arteries with occlusion of ICA, ACA, and MCA
Stage 6 – ICA essentially disappears; the brain is supplied by the ECA
  • the staging system, initially described by Suzuki and Takaku in 1969, is still used
  • staging is based on DSA findings, although a similar system may be applied to MRA or CTA
  • disease progression is more rapid in children compared to adolescents or adults

Imaging modalities

  • digital subtraction angiography (DSA) – the gold standard, practically replaced by MRA/CTA
  • MR+MRA / CT+CTA
    • parenchymal lesions
      • typically watershed or territorial infarcts
      • hemorrhages or asymptomatic microbleeds (GRE/SWI sequences)
      • cerebral atrophy
    • evidence of stenoses in typical locations (distal ICA, M1, or PCA) + a characteristic collateral network
      • unilateral finding is observed in up to 18%
    • vessel wall imaging can help in DDx (from  atherosclerosis or inflammation)
      • concentric stenosis
      • minimal or absent enhancement
      • homogeneous T2 signal
      • absence of atherosclerotic changes
    • detection of collaterals
      • perforator network (puff of smoke) is mainly visualized on DSA (to a lesser extent on CTA or MRA)
      • Ivy sign – increased signal intensity  on MR FLAIR and T1C+ in the leptomeninges and perivascular spaces – indicates slow or retrograde flow in the leptomeningeal and cortical arteries  Moyamoya - evidence of leptomeningeal collaterals (Ivy sign)  [Ohta, 1995]  [Tharayil, 2019]
  • neurosonology
    • the flow in the affected and distal segments  +  vasomotor reactivity (CVR) may be monitored ⇒ may help to indicate surgical treatment
  • genetic testing
    • mutations testing in the RNF213 gene located on 17q25 (in Asians) → see here
    • “moyamoya panel” (incl. ACTA2, Grange sy, etc.)

Moyamoya disease

Moyamoya with multiple collaterals on DSA and multi-infarct involvement on MRI
Moyamoya - evidence of collaterals on DSA

Differential diagnosis

  • moyamoya syndrome (see the table above) must be distinguished

Management

Surgery

  • always consider the risk-benefit ratio when evaluating treatment options
    • surgical treatment is mainly indicated in patients with a progressive, symptomatic course
    • EC-IC bypass may be considered in patients with stroke/TIA  (AHA/ASA 2021 2a/C-LD)
  • moya-moya syndrome with potential causal treatment (e.g., vasculitis) should be excluded before proceeding with surgery   [Fujimura, 2015]
  • procedures:
    • direct anastomosis between the superficial temporal artery (STA) and the middle cerebral artery (MCA) – STA-MCA anastomosis  [Golby, 1999]

      • vessel-to-vessel anastomosis offers immediate revascularization (convenient when symptoms are progressive)
      • a recipient vessel size of > 1-1.5 mm is required
      • problematic in pediatric cases
    • indirect anastomosis (flow improvement can be expected within weeks because a new capillary network is built; feasible in children)
      • encephalo-duro-arterio-synangiosis (EDAS)
      • encephalo-duro-arterio-myo-synangiosis (EDAMS)
      • pial synangiosis
    • direct + indirect anastomosis
  • the primary aim is to improve flow and prevent further formation of fragile collaterals
  • no clinical study comparing the effect of conservative and surgical treatment is available
    • the JAM trial showed marginal benefit in preventing rebleeding
    • several small-scale studies have produced conflicting results
  • according to a meta-analysis, better outcomes can be expected with direct and combined anastomosis compared to indirect anastomosis alone  (Nguyen, 2022)
  • the situation in asymptomatic forms remains unclear
STA-MCA bypass
Moyamoya disease - STA-MCA bypass

Conservative therapy

  • no specific drug therapy to alter the course of the disease
  • standard treatment protocols for ischemic and hemorrhagic strokes are applied
    • efficacy and safety of thrombolysis is unclear;  increased risk of bleeding from fragile collaterals needs to be considered
  • for secondary stroke prevention, antiplatelet therapy is commonly used
    • not an evidence-based approach; should be individualized, taking into account the type and severity of the stroke, angiographic findings, and a risk-benefit analysis of the therapy
    • increased risk of ICH should be taken into account
    • antiplatelet therapy is also accepted by the AHA/ASA Guidelines 2021 (2b/C-LD)
    • bleeding is common in Asians, complicating the use of antithrombotic agents
  • the role of antiplatelet therapy in primary stroke prevention is unclear

Prognosis

  • prognostic factors
    • rate and extent of vascular occlusions
    • patient’s ability to form functional collateral circulation
    • age
    • neurologic deficit severity
    • extent of cerebral infarction
  • some patients remain stable without surgical intervention; sometimes, they stabilize after severe cerebral infarction or hemorrhage with a permanent disability
  • approx. 50-60% of patients exhibit cognitive impairment due to multiinfarct dementia
  • mortality rate ~10% in adults and ~4-5% in pediatric patients
    • the most common cause of death is intracranial hemorrhage

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Moyamoya disease
link: https://www.stroke-manual.com/moyamoya-disease/