Moyamoya disease

Moyamoya disease is a rare cerebrovascular disorder with unknown aetiology. It is characterised by progressive narrowing of arteries of the brain and the formation of a compensatory network of fragile vessels. Genetic studies have identified RNF213 (also known as mysterin) as a susceptibility gene but the low penetrance in genetically susceptible individuals suggests that a further factor is necessary to trigger disease onset.¹

How common is moyamoya disease? (Epidemiology)

Moyamoya disease (MMD) is a rare disorder of the brain arteries most commonly observed in East Asian populations with an annual incidence of 0.94–4.3/100 000 inhabitants.¹

Initially thought to be a disease occurring primarily in Asian countries, the number of patients diagnosed in Europe is increasing due to increased awareness of the condition.²

Moyamoya disease can present at any age, including early childhood.³

Recent development of a non-invasive MRI has increased the identification of asymptomatic patients with moyamoya disease who have experienced no cerebrovascular events.⁴

Moyamoya disease symptoms (Presentation)¹

The clinical presentation is typically determined by changes in blood flow resulting from the progressive stenosis and occlusion of the internal carotid artery and related proximal arteries and the formation of fragile collateral vessels.

Therefore, most symptoms are related to arterial stenosis and occlusion leading to temporary or persistent hypoperfusion or cerebral ischaemia with brain infarction, causing focal neurological signs such as altered speech (dysarthria, aphasia), motor disturbance (hemiparesis), sensory disturbance, visual symptoms, involuntary movements, seizures and other consciousness changes, and cognitive dysfunction.

The neurological symptoms may also result from the development of the fragile network of moyamoya vessels prone to vascular rupture leading to cerebral haemorrhage.

In adults, about half of cases first present with intracranial haemorrhage, mainly as the result of a rupture of the fragile, maximally dilated, collateral vessels and occurring mostly in the anterior circulation territory, although arteries from the posterior circulation may also be involved.
Psychiatric symptoms such as personality changes, psychosis, or depression may occur.
More general symptoms such as vertigo, dizziness, or headache may be present due to stroke, secondary orthostatic intolerance, or dilation of meningeal collaterals.

During childhood, disease onset may be triggered by events like coughing or crying that lead to a decrease in carbon dioxide, resulting in vasoconstriction and further cerebral hypoperfusion.

Differential diagnosis

• Cerebrovascular event.

• Basilar artery thrombosis.

• Subarachnoid haemorrhage.

• Blood dyscrasias.

• Cavernous sinus syndromes.

• Cerebral aneurysms.

• Craniopharyngioma.

• Dissection syndromes.

• Fibromuscular dysplasia.

• Anderson-Fabry disease.

• Homocystinuria.

• Hyperglycaemia/hypoglycaemia.

• Mitochondrial myopathy, encephalopathy, lactacidosis, stroke (MELAS).

• Methylmalonic acidaemia.

• Propionic acidaemia.

• Neurofibromatosis types 1 and 2.

• Pituitary tumours.

• Polyarteritis nodosa.

• Giant cell arteritis.

• Tolosa-Hunt syndrome (painful ophthalmoplegia caused by nonspecific inflammation of the cavernous sinus or superior orbital fissure).

Associated diseases

Associations have been made with leptospirosis, tuberculosis, certain anaemias and vascular disorders causing intimal thickening including hypertension and atherosclerosis.

Moyamoya disease (MMD) is also more common in association with a mixed bag of congenital syndromes (Down's syndrome, Turner's syndrome, Marfan's syndrome, Apert's syndrome) and diseases (neurofibromatosis type I, tuberous sclerosis, Hirschsprung's disease).

Investigations⁵

• If a patient has had a cerebrovascular event and the aetiology is unclear, a hypercoagulability profile should be arranged including protein C, protein S, antithrombin III, homocysteine and factor V Leiden levels.

• A raised ESR may rule out vasculitis, but a normal ESR does not exclude this diagnosis.

• Findings suggestive of the diagnosis of moyamoya disease (MMD) on CT scanning or magnetic resonance angiography (MRA) include:
  

  • Stenosis or occlusion at the terminal portion of the internal carotid artery or the proximal portion of the anterior or middle cerebral arteries.

  • Abnormal vascular networks in the vicinity of the occluded or stenosed areas.

  • The presence of these findings bilaterally.

• An enhancement of MRI, which produces a whole-brain histogram of diffusion tensor imaging (WBH-DTI), may be helpful in identifying moyamoya patients who have had a cerebral infarction from those who have not.⁶

Moyamoya disease treatment and management³

The main treatment focuses on neurological protection, cerebral blood flow reconstruction, and neurological rehabilitation, such as pharmacological treatment, surgical revascularisation, and cognitive rehabilitation.

Medical

If cerebral haemorrhage has occurred, strict control of blood pressure should be instituted. Medical management of ischaemic stroke or TIA as appropriate.

Surgical

Surgical treatment is the most effective method to restore the blood supply and increase cerebral perfusion in order to prevent secondary stroke in ischaemic MMD and to stabilise cerebrovascular haemodynamics to regress fragile moyamoya vessels and so prevent bleeding in haemorrhagic MMD.

• Endovascular treatment has become the current main-stream treatment for MMD-associated aneurysms.

• Direct revascularisation via anastomosis of the superficial temporal artery to the middle cerebral artery has been the most common procedure for addressing the middle cerebral artery territory, but also supports the anterior cerebral artery territory via leptomeningeal anastomoses.

• Indirect revascularisation relies on neovascularisation of the cortical surface using angiogenic mechanisms from pedicle-based grafts, such as pial synangiosis, and temporal muscle grafts. However, the haemodynamic protective effects may take months to develop and are not very predictable.

• Combined revascularisation includes direct and indirect bypasses, with indirect revascularisation to achieve both immediate and later haemodynamic improvement and serves as a fallback strategy in case the direct bypass fails.

Neurological rehabilitation

Neurological rehabilitation plays an essential part of recovery from ischaemic and haemorrhagic MMD, including for cognitive impairment.

Pregnancy

The prognosis for pregnant patients with moyamoya disease is generally good.⁷ However if the woman is diagnosed having presented with a stroke during the course of pregnancy or delivery, the prognosis is poor. Most deaths are the result of haemorrhage.

There is no evidence to suggest vaginal delivery should be avoided.

Prognosis⁴

The prognosis for ischaemic and haemorrhagic MMD depends on the severity and location of the cerebrovascular event. Surgery improves the prognosis for patients presenting with cerebral ischaemia. However, for patients presenting with haemorrhage, the prognosis is poor. Progressive neurological deterioration and disability occur.

The long-term prognosis in asymptomatic patients with moyamoya disease is not fully understood. It has been found that disease progression occurs in about 20% of patients during a mean follow-up period of 6 years. Therefore, asymptomatic moyamoya disease is not a “silent” disorder and readily progress to cause ischaemic and haemorrhagic stroke.