Moyamoya disease

OVERVIEW: What every practitioner needs to know

Are you sure your patient has moyamoya disease? What are the typical findings for this disease?

Moyamoya disease is a cerebrovascular occlusive disorder of unknown origin resulting from progressive stenosis of the distal intracranial internal carotid arteries (ICA) and the proximal branches of the anterior and middle cerebral arteries. In response to brain ischemia distal to the occlusion, there is parallel development of collateral vessels from the leptomeninges, external carotid arteries, and internal carotid arteries. This collateral vasculature leads to the characteristic angiographic appearance of moyamoya vessels.

Children affected with moyamoya disease typically present with signs and symptoms of cerebral ischemia secondary to transient ischemic attacks and/or cerebral infarctions.

Patients may present with:

hemiplegia

sensory loss

aphasia

cognitive impairments

visual impairments

headaches

seizures

What other disease/condition shares some of these symptoms?

Tumor/Mass-occupying lesion
Hydrocephalus
Ischemia/Infarction

Would imaging studies be helpful? If so, which ones?

Evaluation for a patient with suspected moyamoya disease begins with a head computed tomography (CT) study to assess for more common pathologies such as tumors or hydrocephalus. The classic head CT findings for moyamoya disease in a pediatric patient are hypodensities in watershed areas, basal ganglia, deep white matter, and periventricular regions, suggesting prior infarcts. Cerebral atrophy and encephalomalacia may be found in severe cases of infarctions. Rarely in pediatric patients with moyamoya, hemorrhage may also be revealed with head CT imaging. CT angiography may also used to diagnose moyamoya and to evaluate neovascularization after surgical intervention.

Magnetic resonance imaging (MRI) is also used to diagnose moyamoya. Diffusion-weighted imaging is used to evaluate for acute cerebral infarcts while both T1- and T2-weighted imaging are used to evaluate chronic infarcts. MR angiography (MRA) is used to assess the degree of vessel stenosis and collateral formation. Findings suggestive of moyamoya disease include: diminished flow voids in the ICA, ACA, and MCA bilaterally with parallel large flow voids in the basal ganglia and thalamus from newly formed collaterals. While not the gold standard, MRA and MRI are sensitive and specific enough to provide a reliable diagnosis and evaluation of moyamoya disease without the need for invasive testing.

Conventional angiography is the gold standard for both the diagnosis and surgical planning for patients with suspected moyamoya disease. Studies should include imaging of the bilateral ECA, ICA, and one or two vertebral injections. The classic angiogram appearance of moyamoya vessels results from stenosis of the supraclinoid ICA, proximal ACA, and proximal MCA, with concurrent ICA, leptomingeal, and transdural collaterals. Angiography will also detect possible aneurysms and arteriovenous malformations that can be associated with moyamoya disease. Post-operatively, angiography is typically used to assess neovascularization and cortical perfusion.

Cerebral blood flow can be monitored in children diagnosed with moyamoya pre- and post-operatively with transcranial Doppler ultrasonography, CT and MR perfusion imaging, xenon enhance CT, positron-emission tomography, and single-photon-emission CT.

Electroencephalography (EEG) can also be used as a diagnostic tool for children suspected with moyamoya disease. Children with moyamoya exhibit a characteristic pattern of high voltage, monophasic slow waves following the end of hyperventilation known as the re-buildup phenomenom, which is thought to represent a diminished cerebral perfusion reserve.

If you are able to confirm that the patient has moyamoya disease, what treatment should be initiated?

Early diagnosis and prompt surgical treatment provide the best chances to improve neurological outcome for pediatric patients with moyamoya.

Medical Treatment

While there are no definitive medical treatments to reverse or stabilize the course of moyamoya disease, antiplatelet agents and calcium-channel blockers have an adjuvant role in managing patients with moyamoya. Daily, lifelong aspirin use is prescribed to prevent ischemia associated with emboli arising from sites of arterial stenosis. Evidence shows that calcium-channel blockers reduce the frequency and severity of refractory TIAs in children with moyamoya.

Surgical Treatment

Surgical intervention in moyamoya disease has been shown to have a favorable outcome, especially in the reduction of ischemic events. There are a variety of surgical revascularization procedures which have been shown to be successful in children with moyamoya, however there is no published prospective randomized controlled clinical trial to define which procedure is superior. These revascularization techniques can be divided into two groups: direct and indirect types.

Direct bypass provides rapid, instant increases in cerebral perfusion, but is technically difficult due to the smaller diameter of vessels in the pediatric population. Direct bypass typically only addresses the MCA distribution with no direct effect upon the ACA or PCA territories.

Indirect procedures rely on delayed neovascularization and were developed as an alternative to direct bypass due to the difficulties encountered in anastomosing pediatric-sized vessels. Indirect procedures tend to be less invasive, technically easier, do not restrict treatment solely to the MCA distribution, and require shorter operative time. The major disadvantage in indirect procedures is that angiogenesis occurs over several weeks to months.

What are the adverse effects associated with each treatment option?

Following revascularization surgery for Moyamoya, children are still at risk of stroke, particularly in the first 30 post-operative days. However, this risk decreases after the first month with a 96% probability of remaining stroke-free over the subsequent 5-year period.

What are the possible outcomes of Moyamoya disease?

The natural history of untreated moyamoya disease is variable, ranging from slow progression with few intermittent ischemic events to rapid neurological decline. Progression occurs in the majority of patients, with up to 66% of patients having symptomatic progression within 5 years of initial diagnosis and an overall mortality rate up to 4.3%.

Despite the progressive natural history, several recent studies have shown surgical revascularization to have a significant impact on long-term outcomes. One recent study of operative outcomes revealed that 51.2% of patients were completely asymptomatic, 35.5% of patients had definitive improvement, 10.5% of patients had no change, and only 2.7% of patients had definitive deterioration post-operatively.

What causes this disease and how frequent is it?

Moyamoya disease accounts for 6% of all causes of pediatric ischemic stroke. Initial descriptions focused on Japanese populations, however, moyamoya disease is observed throughout the world affecting various ethnic backgrounds. The incidence of moyamoya disease varies significantly based upon ethnic and geographic background: the reported incidence in the USA is 0.086 per 100,000 patients as compared to 0.35 per 100,000 in Japan.

There is a bimodal age distribution: the first peak occurring in the first decade of life and a second peak between 30 – 40 years of age.

Moyamoya has a significant female preponderance with a female to male incidence ratio of 2:1.

Familial occurrence accounts for 6 – 12% of cases.

The etiology and pathogenesis of moyamoya disease is currently unknown, however there are clear environmental and genetic associations. Prior head and neck irradiation and prior skull base infection appear to be risk factors for developing moyamoya disease. A genetic association is suggested by the higher familial occurrence of moyamoya in the Japanese population in comparison to the USA population. Several studies have linked moyamoya to genetic markers on chromosomes 3p, 6q, 8, and 17q. On a molecular level, basic fibroblast growth factor (bFGF), an angiogenic substance, has been implicated in the etiology of moyamoya. Overall, further studies are needed to elucidate the development of moyamoya disease.

While moyamoya disease refers to the idiopathic progressive vasculopathy, when this occurs in association with a recognized clinical disorder, patients are classified as having moyamoya syndrome. Moyamoya syndrome has been shown to be linked with several disorders, including Down syndrome, neurofibromatosis type 1, facial hemangiomas, sickle cell anemia, Grave’s disease, Marfan’s syndrome, congenital cardiac anomalies, renal artery stenosis, and fibromuscular dysplasia.

How do these pathogens/genes/exposures cause the disease?

Histologically, the vascular changes in moyamoya involve endothelial hyperplasia, fibrocellular thickening of the intima, and torturosity of the internal elastic lamina. A combination of smooth muscle cell hyperplasia and formation of an intraluminal thrombus leads to progressive narrowing of the vessel diameter, which inevitably causes the characteristic arterial occlusion. In response to brain ischemia, collateral vessels form. However, these collaterals have abnormal histology and their thinned walls are prone to microaneurysm formation and subsequent intracranial hemorrhage.

Pediatrics