Moyamoya Disease with Graves Disease

1. Moyamoya Disease with Graves� Disease Chien-Wen Chou MD. Endocrinology & metabolism Division Chi-Mei Medical Center 11 Aug 2006

2. Table of Content Thyroid disease and Cerebrovascular Disease Moyomoya disease Graves� disease associated with moyamoya disease

6. Summary In overt hyperthyroidism, cardioembolic stroke is clearly associated to thyrotoxic atrial fibrillation, and in subclinical hyperthyroidism with serum thyroid-stimulating hormone levels 0.1 mU/L, the incidence of atrial fibrillation is increased. Although in vitro and in vivo studies indicate a hypercoagulability state in hyperthyroidism, there is insufficient evidence to prove that this state leads to an increased risk of cardiac emboli. However, the hypothesis that overt hyperthyroidism may cause acute cerebral venous thrombosis is intriguing. Possible associations between hyperthyroidism and Moyamoya or Giant cell arteritis have only been described in case reports. There is enough evidence that overt hypothyroidism is associated with several traditional and newer atherosclerotic risk factors, especially hypertension, hyperlipidemia, and hyperhomocysteinemia. For subclinical hypothyroidism, these associations are less certain. Hypothyroidism has been associated with signs of aortic or coronary atherosclerosis, but no case-control or cohort studies have ever investigated hypothyroidism as a possible risk factor for atherothrombotic stroke.

7. Moyamoya Disease Takaku, Suzuki and others described moyamoya disease in Japan in the sixties The term means a 'wavering puff of smoke' and was used to describe the abnormal vasculature at the base of the brain. Moyamoya disease is a cerebrovascular disease that features narrowing or stenosis, starting at the distal internal carotid and proximal portions of the anterior and middle cerebral arteries. Moyamoya syndrome is a phenomenon caused by an olegemic state similar in presentation but caused by various disease entities Once believed to be restricted to Japan, there have now been reports from all over the world, especially China and Korea Moyamoya is an intriguing disease and little is known about its pathogenesis. Most patients present with the symptoms of cerebral ischemia and a few, especially adults, present with cerebral hemorrhage. 

8. Etiology Etiology of the disease is still unknown. A genetic mode of inheritance is considered possible because of the higher incidence of the disease in Japan and Korea and the familial occurrence among the Japanese as well as in Caucasians. There have been recent reports of increased familial incidence of the disease. This apparent increase may partly reflect the fact that wide spread use of magnetic resonance imaging (MRI) and magnetic resonance angiography have been detecting the disease in asymptomatic patients. In a recent total genome search, a linkage was found between the disease and markers located at 3p24.2-26. Another linkage study using markers on chromosome 6, where the HLA gene is located, showed a possible linkage of the marker D6S441 to the disease. DNA typing of HLA also indicates that the disease is probably genetic in origin. There have also been reports of linkage to chromosome 17.

9. Factors involved in pathogenesis Fibroblast growth factor has been proposed as a possible mediator of the neovascular response. There is some evidence to show that CSF bFGF may play a role in the pathogenesis of the disease. Transforming growth beta factor 1 (TGF beta 1), a factor involved in angiogenesis and expression of connective tissue genes, was also shown to be elevated in the disease. An unknown CSF protein has been detected in some patients with moyamoya. Further analysis of this protein may reveal a clue by which the molecular mechanism of moyamoya disease may be elucidated. The role of prostaglandin in the pathogenesis of the disease has been studied. These studies have shown that the arterial smooth muscle cells in moyamoya activate cox2 in response to inflammation, and produce excess PGE.This can cause an increase in vascular permeability and decrease the tone, which may promote intimal thickening. A possible role for infection in the pathogenesis has been proposed. The evidence is still inconclusive but some studies have suggested a relationship with Epstein-Barr virus infection. This was based on the increased presence of EBV DNA and antibody in patients with moyamoya.

10. Clinical and angiographic criterion for moyamoya disease and syndrome There is stenosis or occlusion observed at the terminal portions of the internal carotid artery and the proximal anterior cerebral artery, middle cerebral artery or both. Abnormal vascular moyamoya networks are observed in the vicinity of the previously mentioned areas in the arterial phase and these findings are present bilaterally. These findings have to be confirmed angiographically. Magnetic resonance angiography is being used more often, especially in children, to confirm the diagnosis. Diseases known to cause similar changes also need to be ruled out. 

11. Clinical and angiographic criterion for moyamoya disease and syndrome Pathological criteria may be used instead. These are intimal thickening and occlusion or stenosis observed around the intracranial terminal portions of the internal carotid artery. In the main arteries (anterior, middle cerebral and posterior communicating arteries) of the circle of Willis, various degrees of stenosis and occlusions are observed. These vessels show intimal fibrous thickening, widening of the internal elastic lamina and thinning of the media. Many tiny vascular channels are observed around the circle of Willis and small vessels of conglomerated networks are observed in the pia mater. 'Definite moyamoya' fulfils the criteria entirely and the term 'probable moyamoya' is used to describe unilateral cases. The term moyamoya syndrome is used when similar findings are associated with a basic disease

12. Cerebral blood flow and metabolism in moyamoya The morbidity of moyamoya is directly related to cerebral blood flow. This was demonstrated in earlier studies using Xenon-133 inhalation. The cerebral blood flow was decreased most in the frontal region with relatively normal flow in the temporal and occipital region. After hyperventilation the blood flow was reduced in all regions. Positron emission tomographic studies have shown an increase in total blood volume, especially in the striatum and increased transit time. The cerebrovascular response to hypercapnia was shown to be impaired. These changes were reversed after reperfusion surgery. PET studies have also demonstrated the vasodilatation in normal areas after the termination of hyperventilation. This may cause a steal response increasing hypoperfusion. These studies may help to understand the effects of chronic cerebral occlusive disease. Xenon computed tomography has been used for pre and post surgical evaluation. These studies were found to correlate with angiographic studies and have been claimed to be superior in the study of basal ganglia and posterior circulation. Diffusion weighted imaging and perfusion magnetic resonance imagine using contrast have been used in the study of ischemic episodes. Serial studies have also shown the decrease in cerebral blood flow with advancing age

13. Clinical features (1) Moyamoya disease has the highest incidence during the first decade of life. Children present most frequently with transient ischemic attacks or ischemic strokes. Cerebral ischemia may also present as reversible ischemic neurological deficit, sensory attacks or acute infantile hemiplegia. Headaches, involuntary choreiform movements, seizures and other motor disturbances have been described. Motor disturbances are the most common mode of presentation occurring in 80.5% of the population. Convulsions occur in about 9%. Episodic symptoms are often precipitated by hyperventilation or rise in body temperature.  Moyamoya and intelligence quotient : There have been a number of reports suggesting a decline in the IQ of children with symptomatic moyamoya. This is one of the reasons often quoted for advocating early surgery. These scores were said to depend on the duration of symptoms and tend to stabilize after ten years. Some studies have shown an improvement in IQ after surgery 

14. Clinical features (2) Endocrine dysfunction : There have been a few case reports of hypothalamic-pituitary dysfunction associated with moyamoya. Patients have presented with evidence of pituitary and thyroid hypofunction. It has been suggested that children with moyamoya be closely monitored for hypothalamic-pituitary dysfunction. Hemorrhagic type moyamoya disease : Intracranial hemorrhage is more common in adults with the disease but can manifest in children. Factors, which may contribute to bleeding include hypertension and aneurysms. There seems to be an apparent racial difference with a statistically higher incidence of hemorrhage in Korean children compared to Japanese children. There is also a higher incidence in females. In one study hematoma at the basal ganglia was noted in 40% of cases, intraventricular hemorrhage (IVH) in 30%, thalamic hemorrhage with ventricular rupture in 15% and subcortical hemorrhage in 5%. Rebleeding can occur a long time after the first episode. The hemisphere in which it occurs and the type of bleeding is often unpredictable and hence the difficulty in preventing rebleeds. Blood pressure control may help prevent rebleeds. Mortality increases after rebleeds and generally the prognosis is worse after each rebleed. 

15. Angiographic features of moyamoya There is narrowing and occlusion of the supraclinoid portions of the internal carotid artery and the proximal portions of the anterior and middle cerebral artery The development of the moyamoya network may be seen at different sites The formation of network of vessels at the frontal base with blood supply from the branches of the ophthalmic artery is known as ethmoidal moyamoya. Dilatation of the basilar artery and formation of moyamoya network by perforating branches of the posterior cerebral artery is known as posterior basal moyamoya. Vault moyamoya is due to development of extra and intracranial transdural leptomeningeal collaterals between pial vessel and branches of the external carotid artery. A well-developed posterior callosal artery is seen. The large and proliferating irregular vessels and transdiploic collaterals of the external carotid artery that supplies the ischemic regions of the brain essentially cause the moyamoya network. Angiographic staging has been used with intensification of the moyamoya in the early stages and disappearance in the late stages The angiographic stage does not directly correlate with the distinct clinical presentations between pediatric and adult moyamoya disease

16. Imaging Computed tomography may be useful for detetecting hemorrhage. Low density areas may suggest infarction. There may be evidence of cerebral atrophy. Grey and white matter of the frontal lobe is most frequently affected.  Magnetic resonance imaging It has been used extensively in Japan for screening purposes. Moyamoya vessels are visualized as multiple small round or tortuous low intensity areas extending from the suprasellar cisterns to the basal ganglia. Occlusive changes in the distal internal carotid, anterior cerebral artery and middle cerebral artery and ischemic cerebral lesions and collaterals can also be visualized. Proton magnetic resonance spectroscopy (MRS) is an effective method to noninvasively investigate cerebral metabolism.  Electroencephalographic changes EEG changes reported in moyamoya include posterior slowing and centrotemporal slow activity. There is sleep spindle depression. A 'rebuilt up' phenomenon after cessation of hyperventilation has been reported. This rebuilt up corresponds to increase in cerebral blood flow in angiography. EEG has sometimes been used in the past for screening but has generally been replaced by magnetic resonance imaging. 

17. Surgery for moyamoya : When and what ? create collateralization on the brain surface. indirect revascularization procedures such as EDAS (encephaloduroarterio synangiosis), pial synangiosis, indirect revasularization using omental flaps etc. or direct revascularization procedures such as superficial temporal-middle cerebral artery bypass etc. indirect revascularization is preferred in treatment of children. The decision is based on angiography and cerebral blood flow studies. TlAs reduce in frequency and patients do not develop new strokes in successful cases. Medical treatment with vasodilators, corticosteroids, antiplatelet agents etc. has been tried with doubtful efficacy. Patients are often put on aspirin, even though there is no evidence that it stops or reverses arterial occlusion. 

18. Radiation-induced moyamoya syndrome (1) The moyamoya syndrome is an uncommon late complication after radiotherapy (RT) METHODS AND MATERIALS: A PubMed search of English-language articles, with radiation, radiotherapy, and moyamoya syndrome used as search key words, yielded 33 articles from 1967 to 2002 RESULTS: The series included 54 patients with a median age at initial RT of 3.8 years (range, 0.4 to 47). Age at RT was less than 5 years in 56.3%, 5 to 10 years in 22.9%, 11 to 20 years in 8.3%, 21 to 30 years in 6.3%, 31 to 40 years in 2.1%, and 41 to 50 years in 4.2%. Fourteen of 54 patients (25.9%) were diagnosed with neurofibromatosis type 1 (NF-1). The most common tumor treated with RT was low-grade glioma in 37 tumors (68.5%) of which 29 were optic-pathway glioma. The average RT dose was 46.5 Gy (range, 22-120 Gy).

19. Radiation-induced moyamoya syndrome (2) For NF-1-positive patients, the average RT dose was 46.5 Gy, and for NF-1-negative patients, it was 58.1 Gy. The median latent period for development of moyamoya syndrome was 40 months after RT (range, 4-240). Radiation-induced moyamoya syndrome occurred in 27.7% of patients by 2 years, 53.2% of patients by 4 years, 74.5% of patients by 6 years, and 95.7% of patients by 12 years after RT. CONCLUSIONS: Patients who received RT to the parasellar region at a young age (<5 years) are the most susceptible to moyamoya syndrome. The incidence for moyamoya syndrome continues to increase with time, with half of cases occurring within 4 years of RT and 95% of cases occurring within 12 years. Patients with NF-1 have a lower radiation-dose threshold for development of moyamoya syndrome.

20. Epidemiological study of moyamoya disease in Taiwan From January 1978 to December 1995, 92 cases of Moyamoya disease were collected from seven major medical centers in Taiwan. The data gave an annual incidence rate of 0.048 per 100,000 population. There were 40 males and 52 females and the ages ranged from 2 to 62 years with the peak incidence in the 31-40 year age group (23 cases). Cerebral infarction occurred in 20 out of 24 juvenile patients (83%), and in 24 out of 68 adult patients (35%). The difference was statistically significant. Haemorrhagic stroke was more frequent in adult patients. Computed tomographic scans following stroke showed cerebral infarction in 44 cases, ventricular haemorrhage in 26 cases, intracerebral haemorrhage in 14 cases and pure subarachnoid haemorrhage in eight. The most frequent initial symptom was motor disturbance (59%), followed by headache (49%) and impaired consciousness (35%). This survey showed an incidence rate much lower than that in Japan, but comparable with those in other Oriental countries and higher than those in Western countries.

21. Moyamoya Disease with Graves� Disease A 27-year-old Japanese woman had been found to have high blood pressure six months prior to admission. Two months later, she experienced transient attacks of dizziness and left hemiparesis several times. However, a brain CT scan performed at a local hospital revealed no abnormalities. During the same period, she noticed that her thyroid glands were swollen, and consulted an endocrinologist. She was diagnosed with Graves� disease with goiter and bilateral exophthalmos. She was then maintained on regular antithyroid medication and the attacks subsided.

22. Moyamoya Disease with Graves� Disease Three months later, she again experienced left-arm flaccidity, as well as dysarthria and headache, and was then admitted to our hospital. She had no other past history of disease and denied past head injury and previous oral contraceptive use. She was irregularly on antithyroid medication at that time. A physical examination revealed bilateral carotid bruits in the neck. Her thyroid gland showed symmetric enlargement. Her blood pressure was 150/80 mmHg, and heart rate 116 /min. On neurological examination, she had hemiparesis of the left upper limb and exaggerated deep tendon reflexes in the left extremities with a dorsiflexed plantar response on the left. Laboratory studies, including blood tests, urine analysis, coagulatory parameters, including prothrombin time, fibrinogen, antithrombin III activity, protein C and S antigens were within normal limits except for high alkaline phosphatase (ALP 613; AL2 6 AL3 94%).

23. Moyamoya Disease with Graves� Disease A thyroid function test using radioimmunoassay confirmed hyperthyroidism (TSH 0.08 �U/ml; fT3 5.5 ng/dl; fT4 1.4 ng/dl; TSH receptor antibody, TRAb 56.4%). Immunologically, the patient was negative for antinuclear antibody, anti-double-stranded DNA antibody, anti-cardiolipin antibody, p-ANCA and c-ANCA. A T2-weighted image (T2WI) of brain magnetic resonance imaging (MRI) revealed multiple ischemic lesions in the right upper frontal lobe and in the left paraventricular region. The latter also showed a high intensity area on T1WI, consistent with a hemorrhagic infarction (Fig. 1A-C). Single photon emission computed tomography (SPECT) using 99mtechnesium- hexamethyl-propylenamine oxime (99mTc-HMPAO) showed decreased regional cerebral blood flow in the right MCA region (Fig. 1D).

24. Moyamoya Disease with Graves� Disease An electroencephalogram (EEG) documented both build up and rebuild up phenomena during and after hyperventilation. Four-vessel cerebral angiography showed long narrowed segments at the cervical portions of both internal carotid arteries. A severe focal stenosis of bilateral M1 portion of the right middle cerebral artery (MCA) and typical net-like moyamoya vessels were also seen (Fig. 2). No retrograde anastomosis from the external carotid arteries was detected. After anti-thyroid hormone medication, the hemiparesis abated. Ischemic attacks were suppressed under euthyroid state through the course. In order to prevent further attacks, encephalo-duro-arteriosynangiosis (EDAS) was performed late

28. Immunologic Factors The cellular proliferation and vascular dysregulation in moyamoya and immunologic stimulation of the thyroid in Graves� disease were suggested to have a common pathogenic link involving T-cell dysregulation moyamoya-like vasculitic changes improved gradually after treatment with the combination of steroid and plasmapheresis in Graves disease Inflammation of the arterial wall due to an altered immune status may be a key link to the double disorders occurring in these patients.

29. Homocysteine Colleran et al demonstrated the positive correlation between free thyroxine levels and both homocysteine and methylmalonic acid, suggesting the possibility of thyrotoxicosis to induce hyperhomocysteinemia As homocysteinemia has been implicated in atherosclerotic and embolic disorders

30. Hemodynamic factors Graves� disease is an autoimmune disorder and the associated thyrotoxicosis is thought to enhance the effects of sympathic nervous activity. The carotid fork and arteries around cerebral base, main foci of moyamoya disease, are distributed with sympathetic nerves derived from superior cervical ganglion. Sato et al reported that cerebral blood flow increased 18.8% after dissection of superior cervical ganglion in moyamoya disease patients Regional sympathetic nervous stimulation may contribute to pathological changes involving the carotid arteries The superior cervical ganglion is adjacent to not only the cervical lymph nodes but also the thyroid. Inaba et al reported that arterial stiffness in the common carotid artery was increased in hyperthyroidism. thyrotoxicosis accelerated superior cervical ganglion and decreased regional cerebral blood flow, leading to TIA or stroke

31. References Thyroid Diseases and Cerebrovascular Disease A. Squizzato, MD Stroke. 2005;36:2302-2310 Moyamoya disease: a review.Gosalakkal JA Neurol India. 2002 Mar;50(1):6-10. Review. Co-morbidity of Moyamoya Disease with Graves� Disease. Report of Three Cases and a Review of the Literature Takahiro Sasaki DOI: 10.2169/internalmedicine.45.1543