Moyamoya disease is a disorder characterized by bilateral stenosis or occlusion of the terminal internal carotid artery and proximal portion of the anterior and middle cerebral arteries¹⁾. The pathogenesis of Moyamoya disease is unknown, but hyperactivity of cervical sympathetic nerves may contribute to stenosis of the cerebral arteries²⁾. This disease has been reported in association with various disease entities, including hypothalamic-pituitary dysfunction, systemic lupus erythematosus, and Down syndrome3,⁴⁾. Graves' disease is an autoimmune antibody-mediated disease of the thyroid gland that can lead to the development of Moyamoya disease⁴⁾. Many symptoms of thyrotoxicosis are similar to those of hyperactivity of the sympathetic nervous system, and thyroid hormones are thought to enhance the effects of sympathetic nervous activity⁵⁾. However, coexistence of thyrotoxicosis and Moyamoya disease is extremely rare⁶⁾. Until now, Moyamoya disease has been rarely reported in adolescent patients with thyrotoxicosis in Korea7,⁸⁾. We report two girls with concurrent Moyamoya disease and Graves' disease who presented episodes of syncope and right-sided hemiparesis.

Moyamoya disease is a cerebrovascular condition that results in the narrowing of the vessels of the circle of Willis and collateral vessel formation at the base of the brain2,⁸⁾. It becomes symptomatic whenever the collateral vessels fail to compensate for the cerebral blood flow deficit produced by the progressive stenotic lesion in the major cerebral arteries⁵⁾. Although relationships between Graves' disease and cerebrovascular accidents in Moyamoya disease are obscure, the coexistence of both diseases is rare and noteworthy. To our knowledge, only 33 cases, including our case, of concurrent Moyamoya disease or intracranial arterial stenosis/occlusion and Graves' disease have been described in the English literature1,2,4,⁵⁾. The interrelationship of these disorders is significant because the common pathogenesis to the two diseases may finally help us to elucidate the etiology of Moyamoya disease.

Cerebrovascular ischemic symptoms in Moyamoya disease are usually precipitated by activities associated with hyperventilation or thyrotoxicosis2,⁸⁾. In our case 1, the cerebrovascular ischemic symptom, syncope was aggravated by hyperventilation regardless of a state of euthyroid. Hyperventilation itself might cause cerebral vasoconstriction resulted in the decrement of cerebral blood flow to ischemic levels. Whereas it is believed that excess thyroid hormone in patients with Graves' disease is harmful to arterial walls because it may alter vascular reactivity and accelerate the formation of abnormal cerebral vessels⁷⁾. In the majority of cases, cerebrovascular accidents occurred when patients were thyrotoxic, suggesting that thyroid hormones could have facilitated these accidents, possibly through hemodynamic changes and (or) sympathetic nervous system-mediatedvasculopathy9,¹⁰⁾. Sympathetic nervous tone itself is not accentuated by thyrotoxicosis, but thyroid hormones are thought to increase sensitivity to the sympathetic nervous system⁴⁾. Other disorders associated with Moyamoya disease have well-established autoimmune mechanisms of pathogenesis or are associated with arteritis that affects the cerebral arteries⁷⁾. Such diseases include systemic lupus erythematosus, antiphospholipid syndrome, ulcerative colitis, tuberculosis, leptospirosis and postradiation arteritis⁷⁾. In clinical practice, the value of measuring sedimentation rate, protein S and C, antithrombin III, anticardiolipin antibodies, antinuclear factor, anti-Ro/SS-A, and anti-La/SS-B antibodies remains to be determined¹¹⁾. Another possible link between these disorders is atherosclerosis. Colleran et al.¹²⁾ demonstrated the positive correlation between free thyroxine levels and both homocysteine and methylmalonic acid, suggesting the possibility of thyrotoxicosis inducing hyperhomocysteinemia. As homocysteinemia has been implicated in atherosclerotic and embolic disorders, it would be another key to the pathophysiology of Moyamoya disease¹²⁾. It is practical to consider patients with both multiple arterial stenosis and Graves' disease as being at risk for ischemic cerebrovascular events. Therefore, careful control of thyroid function is essential.

A recently published study observed that patients with Moyamoya disease were more likely to have elevated thyroid auto-antibodies than those with non-Moyamoya disease strokes, despite being in a euthyroid state¹³⁾. Two patients in this study also had high levels TSH receptor antibody when syncope and right-side hemiparesis developed, even in a euthyroid state. This suggests a possible underlying immune process contributing to the development of Moyamoya disease⁴⁾. In addition, there are familial cases of Moyamoya disease and Graves' disease, indicating hereditary involvement in both diseases¹⁴⁾. Taken together, genetic factors and autoimmunity may play important roles in the pathogenesis of the coexistence of Moyamoya disease and Graves' disease⁶⁾.

On the other hand, therapy with steroids, vasodilators, antibiotics, and nerve blocks appear to be of questionable benefit. Miyamoto et al.¹⁵⁾ observed that superficial temporal artery-middle cerebral artery anastomosis with encephalomyosynangiosis was an appropriate surgical treatment for refractory cases of Moyamoya disease, and surgical revascularization may be considered for select patients. Adequate revascularization was confirmed on both cerebral angiography and SPECT studies, which were performed 3 to 6 months after surgery¹⁵⁾. Our patients underwent surgery as soon as a diagnosis was made, which resulted in successful resolutions of symptoms.

In conclusion, this is the first report of Moyamoya disease associated with Graves' disease in two adolescent patients with euthyroid in Korea. We suggest that Moyamoya disease should be considered when patients with Graves' disease, present with central nervous system symptoms, including headache, hemiparesis, and syncope. Further studies for large-scale national and multi-institutional patients are warranted to better understand the probable common underlying mechanisms of Moyamoya disease and Graves' disease.