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Cerebrovascular

Moyamoya Disease

A rare, progressive narrowing of the brain’s main arteries — treatable with specialised bypass surgery.

In brief

Progressive narrowing of the internal carotid arteries
Named for the “puff of smoke” appearance of compensating vessels
Causes stroke, TIA, haemorrhage, seizures and headache
Inevitably progresses in most patients; medication does not halt it
Revascularisation (bypass) surgery dramatically reduces stroke risk

What is moyamoya disease?

Moyamoya disease is a rare, progressive cerebrovascular disease caused by slow and continuous narrowing of the main arteries to the brain (internal carotid arteries, ICA). This leads to insufficient cerebral blood supply known as ischaemia, and an increased risk of stroke or cerebral haemorrhage. Reduced blood flow within these large vessels leads to compensatory development of a tangle of tiny vessels surrounding the carotid artery termination that looks “hazy or smoky” on a cerebral angiogram. This led to the condition being known as moyamoya, Japanese for “puff of smoke.” Typically, the disease affects both sides of the brain, however this is not always the case, with approximately half of those who initially present with one-sided disease eventually developing moyamoya changes on the other side. Moyamoya is an extremely rare condition. Its incidence in Australia is not truly known, however is somewhere in the vicinity of one case per million population. It is approximately 10 times more common in East Asian countries. Moyamoya affects people of all ages, however there are two separate peak incidences: the first at approximately 5 years of age and the second around 45 years of age. Females are affected approximately twice as often as males.

What causes moyamoya?

The direct cause of moyamoya is unknown, though there are likely both genetic and environmental factors involved. The inheritance mode of moyamoya disease is multifactorial and thought to be autosomal dominant with incomplete penetrance. As a result, moyamoya may cluster within families, and in Japan approximately 10% of patients have a positive family history.¹ A significant advance in our understanding of moyamoya has been the identification of variants in the RNF213 gene on chromosome 17q25.3, now established as the strongest known genetic susceptibility factor for the disease, particularly in East Asian populations.² The RNF213 p.R4810K variant is found in approximately 95% of familial and 80% of sporadic moyamoya cases in Japan, and is associated with earlier disease onset and greater severity. This variant is rarely identified in Caucasian patients, where different, often rarer variants appear to be implicated. Importantly, the variant has low penetrance, meaning that carrying the gene variant does not guarantee developing the disease.² More than half of people found to have the characteristic moyamoya vessel findings on angiography have no associated conditions, which is termed moyamoya disease. However, certain diseases have a well-recognised association with moyamoya, and in this setting the condition is known as moyamoya syndrome.

What are the symptoms?

Moyamoya can occur at any stage of life, though symptom onset is typically between the ages of 5–10 years in children and 30–50 years in adults. Symptoms in moyamoya are due to restriction of flow resulting from the narrowing of the internal carotid arteries. Broadly speaking, symptoms are either directly attributable to brain ischaemia (i.e. stroke, transient ischaemic attacks (TIAs) and seizures) or indirectly, because of compensatory mechanisms secondary to the ischaemia (i.e. haemorrhage from fragile collateral vessels and headache from dilated abnormal collaterals).

Age-related differences

Most children and adults present with ischaemic symptoms, although haemorrhage may be as much as seven times higher in adults compared to children (approximately 20% versus 2.8%). Rates of haemorrhage within the adult Asian population are often higher again. Children present with higher rates of completed strokes and thus permanent neurological deficits, thought to be due to poorer communication of TIA symptoms and subsequent delayed diagnosis.

Ischaemic symptoms

Symptoms of ischaemia in moyamoya are typically associated with brain regions supplied by the internal carotid arteries. Weakness, sensory changes (tingling and/or numbness), visual deficits, speech deficit, and cognitive impairment are common. These symptoms may be transient (TIA) or permanent (stroke). Brain ischaemia may be provoked by hyperventilation and crying (especially in children), as these activities result in reduced carbon dioxide levels which further reduces already tenuous brain blood supply. Dehydration may also precipitate such symptoms.

Haemorrhage

Much more common in adults, it is however also described in children. Haemorrhage is typically due to rupture of the fragile compensatory moyamoya vessels, though less commonly may be from an associated brain aneurysm. Most commonly bleeding is within the brain tissue itself (intracerebral haemorrhage, ICH), though it may occur within the large fluid cavities of the brain known as ventricles (intraventricular haemorrhage, IVH), or within the smaller fluid spaces overlying the brain (subarachnoid haemorrhage, SAH). Patients who have already experienced a haemorrhage carry a natural re-bleeding risk of approximately 7.6% per year without surgical treatment.³

Seizures

A common presenting symptom, this may be due to either a stroke, brain haemorrhage, or chronic severe lack of blood supply to an area of the brain.

Headache

Headache is a frequent presenting symptom, typically migraine-like in quality and often resistant to standard medical therapy. Unfortunately, headaches may persist even after successful revascularisation surgery. It is thought to be due to dilation of the compensatory vessels causing stretch on the painful outer coverings of the brain, known as the dura, though this is not absolutely clear.

Choreiform movements (children)

Dilated moyamoya compensatory vessels within the inner part of the brain known as the basal ganglia have been implicated in the development of abnormal jerking or writhing (choreiform) movements in children. These may be very disabling and difficult to treat, though they are often reported to resolve following revascularisation surgery.

Cognitive decline

Seen in more than half of the moyamoya patient population, this may be due to either an accumulation of multiple small strokes or simply from chronic cerebral ischaemia.

What is the prognosis of moyamoya?

The natural history of moyamoya is variable, ranging from a slow and intermittent course to fulminant and rapid neurological decline. Regardless, moyamoya inevitably progresses in most patients. Medical treatment alone does not alter the disease course.⁴It has been estimated that up to two-thirds of moyamoya patients will have symptomatic progression over the five-year period from initial diagnosis with a typically poor outcome without treatment.⁵ A large meta-analysis of over 1,150 patients demonstrated that 87% of those who underwent surgical revascularisation had symptomatic benefit in the form of reduction or complete disappearance of ischaemic symptoms.6 In comparison, a large study involving over 1,000 patients found that symptomatic progression may be reduced to as little as 2.6% following surgery.⁶ Even patients who appear to have no symptoms should not be assumed to be entirely safe. The Asymptomatic Moyamoya Registry (AMORE) study demonstrated a 5-year annual risk of ischaemic or haemorrhagic stroke of 1.0% per affected brain hemisphere in asymptomatic patients, supporting the importance of ongoing monitoring in this group.⁷ Neurological burden at the time of diagnosis is the major predictor of long-term outcome. Approximately 50–60% of affected individuals experience gradual deterioration of cognitive function, presumably due to multiple strokes. Mortality from moyamoya is approximately 10% in adults and 4.3% in children. Death is typically due to a severe brain bleed (intracerebral haemorrhage, ICH).

How is moyamoya diagnosed?

Moyamoya should be considered in patients, especially children, presenting with unexplained acute neurological deficits or symptoms referable to brain ischaemia. Delayed diagnosis may result in delayed treatment and potential increased risk of permanent disability secondary to stroke. Following an appropriate review of the patient’s history and complete physical examination, the presence of moyamoya can be confirmed via radiological imaging.

Medical imaging tests will often include the following:

Computed tomography (CT) — rapid and non-invasive test using X-rays to determine if there has been a brain bleed. This is then combined with a separate contrast dye scan called CT angiography (CTA) to show the blood vessels within the brain, looking for the characteristic vessel narrowing and moyamoya phenomena.
Magnetic Resonance Imaging (MRI) — non-invasive, using radio waves and a magnetic field to create brain images without radiation. This process can also show the brain blood vessels using MR angiography (MRA), and give critical information regarding evidence of brain ischaemia and prior stroke. MRI/MRA is the preferred initial imaging modality and treatment decisions can often be made based on this alone.
Cerebral angiography — a minimally invasive imaging technique that involves a small puncture within the groin, passing a thin tube up the arteries to the brain and injecting contrast to obtain very high-quality images of the brain blood vessel anatomy, collateral supply, and cerebral perfusion timing. This remains the gold standard for definitive diagnosis and surgical planning, though nowadays it is often not required for most management decisions.
Cerebrovascular reactivity (CVR) testing — an indicator of brain health, this test assesses the responsiveness of the cerebral blood vessels to alter the brain’s blood flow as physiologically required. The normal healthy brain can increase its blood supply approximately 50% from baseline when required. Moyamoya severely restricts this. In particularly severe cases, the blood supply to the diseased region of brain may actually reduce when stimulated, which is known as “steal,” and indicates an especially increased stroke risk. This may be assessed by multiple techniques, including CT-SPECT, MR-BOLD, and PET scans, with the aid of a stimulus that naturally increases brain blood flow, such as acetazolamide or carbon dioxide. The European Stroke Organisation guidelines recommend haemodynamic assessment during diagnostic workup for all patients to guide treatment decision-making.⁸

What medicines are used in treating moyamoya?

Medication can be used in the treatment of moyamoya, however there is no good evidence that medications significantly alter the natural history of the disease. More commonly used drugs may include:

Blood thinners — aspirin thins the blood and may help prevent emboli and subsequent stroke.
Calcium channel blockers — occasionally used to reduce headaches and possibly TIA.
Anti-seizure medications — when patients present with seizures.

What neurosurgical treatments are available to treat moyamoya?

Broadly speaking, there are two forms of surgical revascularisation treatment for moyamoya, both of which typically use the external carotid artery as a source of new blood supply, as for reasons unknown the disease does not affect this vessel. Aspirin is started one week prior to surgery if the patient is not already on this, as this reduces the risk of the newly fashioned bypass failing.

Direct bypass

Here an artery from outside the skull (usually one of the two superficial temporal artery, or STA, branches) is directly connected to a peripheral artery on the surface of the brain (usually a distal middle cerebral artery, or MCA, branch), and is known as an STA-MCA bypass. The 2 branches of the STA are dissected from the scalp tissues under a microscope to ensure they are not damaged, then set aside. An opening in the skull is then created, called a craniotomy, and the underlying leathery covering of the brain called the dura is opened to expose the brain surface. An appropriate recipient MCA vessel is then looked for under the microscope, aiming for a vessel at least 1mm in diameter. Sometimes this is not available, and only an indirect bypass can be fashioned. If sufficient, the vessel is then prepared for bypass and the 2 arteries sutured together, such that blood flows directly from the STA into the MCA branch, providing an immediate increase in blood supply to the brain. This operation should only be performed by an appropriately trained and experienced neurovascular surgeon, as it is technically very demanding. In such hands, it is successful more than 95% of the time.

Direct bypass has been demonstrated to be particularly important in patients who have previously had a haemorrhage. The Japan Adult Moyamoya (JAM) Trial — the only randomised controlled trial specifically examining surgical treatment in haemorrhagic moyamoya — demonstrated that direct EC-IC bypass reduced the annual re-bleeding risk from 7.6% (no surgery) to 2.7% per year, a statistically significant reduction.³

The major risk of the operation is stroke, which can be due to the blood pressure dropping too low during anaesthesia, or from temporarily halting blood flow in the MCA branch to allow the bypass connection to be fashioned. This occurs in around 5% or less of cases, and may cause temporary or permanent weakness, sensory changes, or speech difficulty. Other more common risks include post-operative bleeding requiring further surgery (<5%) and wound healing problems as the main blood supply to the scalp (i.e. the STA) has been removed (5–10%). Less common concerns include delayed occlusion of the bypass, seizures, and blood sodium changes. Mortality rates from the procedure are less than 1%.

Link to STA-MCA bypass video: https://www.youtube.com/watch?v=36V7rHLN2ms

Indirect bypass

Like a direct bypass, usually the STA is also used to supply blood to the ischaemic brain, however no direct connection is made between the vessels, and thus blood flow is increased to the brain slowly over time. The most common indirect procedure involves the STA being placed directly onto the brain surface, and over 3 to 6 months small connections form and grow into the brain surface, increasing its blood supply. This is known as an encephalo-dural-arterio-synangiosis, or EDAS, though there are several similar variations. Technically much less demanding than a direct procedure, it is still a challenging operation and should only be performed by an appropriately trained neurovascular surgeon. Children often receive an indirect procedure, as their vessels are very small and may be too challenging for a successful direct connection. Risk profile is similar to a direct procedure, though typically lower stroke rates are seen as the blood supply to the brain is not temporarily halted. Link to EDAS bypass video: https://www.youtube.com/watch?v=vYU0bACFhI4 Where feasible, a direct procedure is preferred as it achieves an immediate improvement in brain blood supply and thus symptom improvement. Often a combination procedure can be achieved where the frontal STA vessel is joined directly (i.e. STA-MCA bypass) and the more posterior STA branch is on-layed indirectly (i.e. EDAS bypass), offering the best of both procedures. Long-term outcome from all these procedures appears to be roughly equivalent, with clinical improvement typically seen with all variations.⁶

Who is a candidate for these procedures?

Symptomatic patients, in otherwise good general health, who demonstrate a lack of blood supply to the territory involved by the moyamoya vessels, are candidates for a revascularisation procedure. The European Stroke Organisation guidelines recommend revascularisation surgery in symptomatic adults with clinical symptoms and/or imaging markers of haemodynamic impairment, as well as in paediatric patients with ongoing ischaemic symptoms or cerebral haemodynamic impairment.⁸ Typically, surgery is also considered for patients who demonstrate cerebral steal on CVR testing. In asymptomatic patients, the guidelines recommend conservative management except when both cerebral haemodynamic impairment and silent ischaemic lesions are present in the same brain region.⁸ Treatment in asymptomatic patients is otherwise guided by annual clinical and radiological review, with surgery offered should their condition progress.

Moyamoya Screening

Screening of family members is an evolving area. Current guidance from the American Heart Association recommends imaging of unaffected first-degree relatives when there is more than one affected relative with documented moyamoya, a relative with a clinical history strongly suggestive of moyamoya (e.g. TIA, stroke, severe unexplained headaches or seizures), or in the setting of identical twins.¹ In patients of East Asian heritage, genetic testing for the RNF213 p.R4810K variant may be considered, as familial penetrance in carriers is estimated at approximately 23%, with a near 50% likelihood of manifesting arteriopathy if the variant is present.² In patients with one of the more common associated conditions (see above), a low threshold for screening with MRI/MRA is reasonable, even in the absence of neurological symptoms.

References

Helpful links

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Moyamoya Disease — patient information sheet PDF · prepared by Mr Jeremy Russell

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Content on this page is for education and information only and is not a substitute for advice from your doctor. Medically reviewed by Mr Jeremy Russell.

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