Curiosities And Controversies In Moyamoya Disease Biology Essay

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Moyamoya disease is a cerebrovascular occlusive disease of rare incidence. We report a case series of 8 patients who were diagnosed as moyamoya disease at a tertiary care hospital in India. These included 5 males and presented at a median age of 6y. Stroke was the commonest presentation. Neuroimaging revealed bilateral vascular involvement in all 8 patients. In one patient each there was associated involvement of common carotid artery and vertebral artery. Only 2 patients underwent surgery while the remaining were managed conservatively. All the patients were discharged with neurological deficits. Physicians dealing with childhood stroke should consider moyamoya disease as a differential diagnosis. Till definitive therapeutic interventions become available, conservative management (aspirin/ calcium channel blockers/ physiotherapy), and surgical revascularization procedures are the mainstay of treatment.

Keywords: Moyamoya, stroke, magnetic resonance angiography, magnetic resonance imaging, digital subtraction angiography.


Moyamoya disease is an unremitting cerebrovascular occlusive disorder of unknown etiology. It is characterized by progressive narrowing (and ultimately occlusion) of the terminal internal carotid artery (ICA), proximal middle cerebral artery (MCA) and anterior cerebral artery (ACA) and near simultaneous formation of dilated intracranial ICA tributaries at the base of the brain. Although the incidence of moyamoya disease is not high, it accounts for ≥6% of strokes in children and if un-intervened can lead to distressing and permanent neurological disability (1). In the literature, moyamoya disease typically refers to the idiopathic form of arteriopathy whereas moyamoya syndrome signifies cases in which the characteristic angiographic findings occur in association with an underlying disorder (like Downs syndrome, sickle cell anemia etc.) (2). The distinction between the two is important from outcome and therapeutic aspect.

Previously thought to be prevalent only in Japan, cases have now been reported from across the world with > 1200 publications describing the various facets of this disorder. Whether the described patterns of the disease are universal and whether they play a role in long-term prognosis is an un-answered question. We describe herein, our clinical experience with moyamoya disease in a tertiary care hospital in India with review of literature.


We retrospectively analyzed the hospital records from 01 Jan 2007to 31 Dec 2009 to retrieve the details of all the patients diagnosed as moyamoya disease at a tertiary care centre in India. All the patients with an established diagnosis of moyamoya disease and age ≤ 12 years were included. The diagnosis was based on characteristic radiological findings on magnetic radiological angiography (MRA)/ digital subtraction angiography (DSA). Any patient with a predisposing etiology for cerebrovascular accident (CVA) or age >12 years was not considered for analysis.

The details regarding medical history, family history, physical examination including dysmorpohic and neurocutaneous markers, systemic examination, complete blood counts (for polycythemia/ thrombocytopenia/ thrombocytosis, abnormal cells), erythrocyte sedimentation rate, and radiological features were retrieved. Additional tests like hemoglobin electrophoresis (to rule out hemoglobinopathy), liver function tests including prothrombin time (PT), activated partial thromboplastin time (aPTT), international normalized ratio (INR), lipid profile (to exclude hyperlipidemia), serum ferritin, coagulation profile ( Factor V Leiden, Protein C and S, antithrombin III and lupus anticoagulant), arterial lactate,), CD55/59 (to exclude paroxysmal nocturnal hemoglobinuria), urine for homocysteinuria, antinuclear antibody (ANA), cytoplasmic antineutophil cytoplasmic antibody (c-ANCA), perinuclear antineutophil cytoplasmic antibody (p-ANCA), and anticardiolipin antibody (ACLA), cerebrospinal fluid (CSF) studies, mantoux test and chest X-ray (for detecting latent tuberculosis), echocardiography (to rule out congenital heart diseases), carotid Doppler were performed depending upon clinical setting and the details were noted when available. They were also subjected to ophthalmic examination to look for lenticular dislocation and opacities to rule out homocysteinuria.


Eight patients (5 males, 3 females) with a median age of 6 years (range 4y-9y) were diagnosed as moyamoya disease during the study period. Table 1 shows the patient details.

Hemiparesis was the most common presentation (n=8, 100%). Motor aphasia and dysarthria were present in 2 patients (25%) each. Two patients (25%) presented with generalized tonic-clonic seizures. Five patients (63.5%) were detected to suffer from recurrent transient ischemic attacks (TIAs). None of the patients were detected to have any inherited disorder in the family. Coagulation profile workup was normal in all patients.

All patients underwent MRI/MRA followed by DSA. Overall 30 vessels were involved in 8 patients with a mean of >3 vessels per patient. All the patients had bilateral vascular involvement with 7/8 (87.5%) having involvement of bilateral internal carotid artery (ICA). One patient each had unilateral occlusion of common carotid artery (CCA) and vertebral artery in addition to involvement of intracranial vessels. The degree of obstruction varied from stenosis to complete occlusion. The various sites of stenosis and occlusion included the supraclinoid portions of ICA, MCA, and ACA at specific segments or at their origins at the circle of Willis. All the patients revealed infarcts on MRI (4 acute and 4 chronic infarcts).

Two patients underwent surgical revascularization procedures (encephalomyosyngiosis). After surgery, one child had a recurrence of hemiparesis with in 30 days, which was managed conservatively. The other patient had unremarkable recovery post surgery. The 6 patients who were managed conservatively received symptomatic treatment. Anticonvulsants were administered to patients with seizures. Aspirin (3mg/kg/day, PO) was administered to all patients, including those managed surgically and conservatively.

There were no mortalities. All the patients were discharged with improved general condition. However, the neurological deficits persisted in varying degrees in all the patients and included hemiparesis, aphasia and dysarthria. During follow-up the neurological deficits have shown improvement in all patients with vigorous physiotherapy.


First described in Japanese literature in 1957 by Takeuchi and Shimizu as a case of "hypoplasia of the bilateral internal carotid arteries", moyamoya disease was initially considered to be an essentially Japanese domain) (3). Kudo subsequently introduced it to the English literature in 1968 when he described it as a "spontaneous occlusion of the circle of Willis" (4). Finally, in 1969, Suzuki and Takaku used the term, "moyamoya," a Japanese expression signifying "something hazy, like a puff of cigarette smoke drifting in the air" to describe the disease process because of the distinctive angiographic appearance of the dilated collateral arteries that develop at the base of the brain in this disorder (Fig. 1) (5). Presently the terminology "moyamoya disease" signifies disorder characterized by a chronic steno-occlusive vasculopathy affecting the terminal ICA, and proximal MCA, and ACA, with compensatory formation of an abnormal network of perforating blood vessels providing collateral circulation.

Moyamoya disease occurs worldwide; however, the greatest incidence continues to be in East Asia (6). In a nation-wide survey in Japan, this disease was found to have an annual incidence of 0.35 and annual prevalence of 3.16 per 100,000 in 1994 and the same had increased to 0.94 and 10.5 per 100,000 in 2003 (7,8). In contrast, the incidence in Europe is ~ one-tenth the incidence in Japan (9,10). Moyamoya disease affects both males and females; females being affected nearly twice as often as males (1,11,12). In addition, there is a bimodal age distribution, with patients typically presenting either in the 1st or 4th decade of life (13). For those presenting within the 1st decade, ischemic events such as transient ischemic attacks (TIA) or strokes are more common. In contrast, adult patients more commonly present with hemorrhage (9).

Etiology of Moyamoya disease is controversial. Even though several linkage studies have shown promising relations with gene loci, no specific locus has yet been identified (14, 15). However, these linkage studies, along with the familial occurrence of moyamoya, and its high incidence in Japanese population points towards a probable genetic basis underlying its etiology. Besides genetic factors, evidence supports a role for acquired or environmental triggers in the pathogenesis of moyamoya disease. The observation of moyamoya pathology as a delayed response in patients following irradiation of the skull base for treatment of tumors of the head and neck, especially hypothalamic-optic pathway gliomas and craniopharyngiomas, and also its occurrence following an infectious illness in some patients suggests a role for environmental factors (16,17,18). Although the etiological factors and their roles are still ambiguous, both genetic and environmental factors possibly play a vital role in triggering the disease process. Association of moyamoya syndrome, also known as secondary form of moyamoya disease with malformation of eyes, base of skull, panhypopituitarism and mid-facial malformations gives a clue that moyamoya syndrome maybe a consequence of a defect at the time of embryogenesis as these structures are in the vicinity of circle of Willis (19, 20). Common risk factors for moyamoya syndrome are neurofibromatosis, tuberous sclerosis, brain tumors, fibro muscular dysplasia, fanconi anemia, Apert syndrome, renal artery stenosis, Down syndrome, coarctation of aorta and factor XII deficiency.

Pathophysiologically, it is characterized by progressive bilateral stenosis or occlusion of the ICA, initially distally at the level of bifurcation of ICAs, with frequent subsequent involvement of the proximal anterior and middle cerebral arteries (21). Disease may be more extensive, involving posterior circulation; pulmonary, coronary and peripheral arteries (22, 23, 24). Histopathological studies of affected segments demonstrate eccentric fibro cellular thickening of the intima, proliferated smooth muscle cells, prominently tortuous and often duplicated internal elastic lamina, with no inflammatory or atheromatous involvement (25). Vessel occlusion results from excessive accumulation of smooth muscle cells and thrombosis within the lumen. Concomitant with stenosis, collaterals develop at the base of the brain in response to chronic ischemia. These collateral vessels can be categorized as (26): intracerebral anastomoses, dilated basal collateral networks, cortical-leptomeningeal end-to-end anastomoses, dural networks and extracranial networks. It is hypothesized that in the setting of arterial stenosis or occlusion, hypoxic regions of the brain induce collateralization through the formation of dilated and tortuous perforating arteries. This native revascularization strategy is orchestrated by the expression of various growth factors involved in angiogenic signaling cascades, including HIF-1, VEGF, bFGF, transforming growth factor-ß1, hepatocyte growth factor, and MMP's (21, 25, 27, 28). Taken together these studies indicate the existence of a pro-angiogenic intracranial milieu in these patients. Histopathologically, moyamoya collateral vessels display thinned media with fibrin deposition in the vessel wall, fragmented elastic laminae, and microaneurysm formation. Such changes may predispose these vessels to rupture, making them a possible source of hemorrhage, especially in adults (29). In addition, the typical saccular aneurysms, many of them are located in posterior circulation (with the basilar tip being the most common), are seen more frequently in adults. Saccular aneurysms and pseudoaneurysms, which can develop along peripheral portions of perforating moya- moya vessels and the anterior and posterior choroidal arteries, also represent potential sources of hemorrhage (30). The incidence of aneurysms in children with moyamoya disease is ~ 1%, whereas that in adults is ~ 6.2%, explaining the higher incidence of hemorrhage in adults vis-à-vis in children(9).

Clinically, children with moyamoya disease typically present following an ischemic stroke in 80% (9). Of these, the majority have extremity weakness or paralysis as the initial presentation. In some patients ischemic events are precipitated by crying, coughing, blowing, or hyperventilation since such activities lead to hypocapnia-induced vasoconstriction and transient reduction in CBF in an already compromised cerebral circulation. Patients can also present with headaches, seizures, involuntary movements and/or a progressive decline in neurocognitive function. Cerebral hemorrhage, though a common presentation in adults (40-65%) with predilection for the basal ganglia and thalamus, is rare in children. Symptoms representing posterior circulation ischemia like visual field defects, decreased visual acuity, transient blindness, scintillating scotomas, diplopia, ataxia, and vertigo, are uncommon but have been reported.

Mostly patients present with bilateral vascular involvement, but up to 18% may have unilateral involvement (31). Unilateral involvement typically progresses to bilateral involvement within 1-2 years (32). Extensive search should be carried out to find out the cause for recurrent stroke like sickle cell anemia and other hemoglobinopathies, cardiac defects, metabolic disorders, antiphospholipid antibody syndrome, protein C and S deficiency etc (9).

A head-CT is often the initial investigational modality in these patients, and it frequently shows areas of hypodensity consistent with infarct in cortical watershed zones, basal ganglia, deep white matter, or periventricular regions. Atrophy of the affected hemisphere is frequently seen in patients who have had severe stroke, and gyral enhancement can also be observed after contrast administration (33). MRI and MRA are helpful in the diagnosis of moyamoya disease because they provide greater parenchymal and vascular details. MRI typically reveals diminished flow voids in the ICA, MCA, and the ACA, and prominent flow voids in basal ganglia and thalamus from dilated moyamoya vessels that traverse these regions to supply hypoperfused brain distal to the occluded vessels. Such flow voids are virtually diagnostic of moyamoya disease. MRI may also demonstrate multiple, small, asymptomatic areas of cerebral infarction, which are typically found in watershed regions between the cortical areas, vascularized by the ACA and MCA. Likewise, diffusion weighted, perfusion echo planar, and gradient echo MRI techniques are useful for evaluating cerebral ischemia, with diffusion-weighted imaging leading to significant earlier detection of ischemic lesions in patients with moyamoya disease. MRA has a sensitivity of 73% and specificity of 100% for diagnosing moyamoya disease (34, 35). Sensitivity increases to 92% when MRA is combined with MRI or when MRA is performed with selective maximum intensity projection (35). Because of its excellent diagnostic yield and non- invasiveness, some have suggested that MRA be used instead of conventional cerebral angiography for the diagnosis of moyamoya disease. However, the smaller moyamoya collaterals are visualized more clearly with conventional cerebral angiography, which is still the gold standard for diagnosing moyamoya disease.

Other investigative modalities used include the techniques to assess cerebral blood flow and electroencephalography (EEG). In nearly 50% of children with moyamoya disease, electroencephalography will show a hyperventilation-induced diffuse pattern of monophasic slow waves (36). Techniques to evaluate the cerebral blood flow including Xe-enhanced CT, PET, and SPECT, can identify regional perfusion instability prior to treatment and ascertain the extent of improvement of functional perfusion following therapy (37, 38).

Some patients with moyamoya disease stabilize clinically without intervention; however, this usually occurs after they have suffered a permanent and debilitating disability. Currently, there is no medical treatment to halt the progression or stabilize the course of moyamoya disease. Nevertheless, 2 types of medication play a role in the treatment of this disorder: aspirin and calcium channel blockers (CCB's). Aspirin (3mg/kg/day, PO) is taken daily and continued indefinitely in an attempt to prevent the formation of emboli from micro thrombi at sites of arterial stenoses (39, 40, 41). CCBs are also effective in treating certain symptoms in patients with moyamoya disease, such as persistent postoperative TIAs and intractable headaches (9, 41). Although currently there is no evidence that medical management alters the clinical course or outcome of individuals with moyamoya disease, future treatment will likely include the use of medical therapy. Conceivable examples of potential medical therapies include the use of the following: topical or systemic angiogenic growth factors to induce neovascularization; gene therapy to target genetically determined conditions that occur in association with moyamoya disease; and additional novel therapies that block or alter the arteriopathic disease process.

Revascularization surgical procedures are currently performed to increase the perfusion to the hypoxic brain tissue. The literature supports these procedures and long-term favorable outcome has been reported in terms of improvement in symptoms and positive angiographic follow-ups in all age groups (42, 43, 44). Four types of surgical procedures have been described (45): indirect procedures including encephalo-duro-arterio-myo-synangiosis, direct revascularization via the superficial temporal artery and the middle cerebral artery bypass, combined approaches and rarely, denervation of cerebral vasculature. In general, pediatric cases benefit from indirect revascularization procedures and the direct bypass is useful in most of adult cases. Surgery results in decreased incidence of TIAs and major complete strokes in the patients. Patients with reversible ischemia achieved a favorable clinical outcome and the factors predicting favorable outcome included: age >3 years, TIA on presentation, increased regional cerebral blood volume on perfusion MRI, decreased vascular reserve or decreased vascular reserve only with normal basal perfusion on SPECT, and re-buildup phenomenon on EEG (44). Potential risks of surgery include complications in handling the thin cortical vessels, post- operative hemorrhage from the neovascular channels and a delay or even failure of effective resupply of blood.

We believe that moyamoya disease, although rare in India is also under-diagnosed due to lack of available infrastructure required for the diagnosis. And even in the cases that are diagnosed, majority of patients fail to undergo surgical management due to lack of available expertise. In our series of eight patients all had bilateral vasculopathy and consistent with literature, presented predominantly with motor focal neurological deficits. The interesting aspect in our series was that there was involvement of extracranial vessels in two patients (common carotid artery and vertebral artery in one patient each). Whether it was a phenomenon unique to the disorder in this region or if it is of universal significance is ambiguous due to lack of relevant data, but it is of extreme consequence because the involvement of extracranial vessels can hamper the collateral blood circulation and would have to be watched carefully.


Moyamoya disease, although relatively uncommon, is a widely recognized cause of recurrent stroke in children and must be considered in the differential diagnosis. One should be vigilant for moyamoya disease in individuals with risk factors like Down syndrome. Since the disease is not only limited to terminal internal carotid arteries, imaging studies should be planned to include other arterial circulations as well. Long-term better prognosis is achievable with prompt diagnosis, initiation of aspirin, and appropriate surgical management.