it typically involves the distal internal carotid arteries ( icas ) , the proximal anterior cerebral arteries ( acas ) and the middle cerebral arteries ( mcas ) , accompanied by the development of an abnormal collateral vascular network at the base of the brain ( 13 ) . thus far , the majority of mmd cases have been reported in eastern asia ( 4 ) ; however , even in that region , the coexistence of mmd and graves ' disease ( gd ) is rare . in 1991 , kushima et al first reported two cases of females suffering from mmd and gd simultaneously ( 5 ) . to the best of our knowledge , only ~50 cases of simultaneous mmd and gd have been described in the literature available in the medline database to date . the patients were predominantly women , and their ages ranged between 10 and 54 years ( mean , 29.3 years ) . the majority of the cases showed thyrotoxicity when the cerebral ischemic event occurred and eventually recovered from the neurological symptoms after medical and/or surgical treatment ( 6 ) . although the association between mmd and gd remains unclear , a number of previous studies have suggested that gd could induce the development of mmd through thyroid storm ( 7,8 ) ,  cerebrovascular hemodynamic changes ( 9 ) and  autoimmune arteritis ( 1013 ) . von willebrand factor ( vwf ) is a useful marker of endothelial activation or dysfunction ( 14 ) . increasing evidence has demonstrated that vwf is involved in cardiovascular ( 15 ) and ischemic cerebrovascular diseases ( 16,17 ) . in addition , coagulation factor viii ( fviii ) is involved in the process of thrombosis , and elevated fviii levels are a prothrombotic risk factor for thromboembolism ( 18 ) . the correlation of hyperthyroidism with elevated fviii and vwf activities has been previously reported ( 19 ) . the present study reported the case of a 12-year - old male with significant overactivation of vwf and fviii . thus , a comprehensive investigation of a potential correlation between gd and the overactivation of vwf / fviii and mmd was performed . a 12-year - old chinese male was admitted to the beijing tian tan hospital ( beijing , china ) in may 2013 with a rapidly progressive mild quadriplegia , aphasia and urinary incontinence . at 5 days prior to admission , the patient experienced several episodes of vomiting , paroxysmal aphasia and mild hemiplegia on his left side , along with recurrent brief convulsions . the patient had previously suffered irritability , tremors , excessive sweating and frequent palpitations following moderate physical activity for approximately 1 year . he had no other disease history and a relevant family disease history . on admission , the patient was dysphoric with slurred speech , and had a high blood pressure ( 165/95 mmhg ) , and rapid and regular heart rate ( 110140 bpm ) . in addition , the patient presented facial paralysis ( skewing of the mouth to the right side ) and mild quadriplegia with globally increased muscle tone . emergency head magnetic resonance imaging ( mri ) scans revealed multiple regions of cerebral infarction that could not be attributed to a single vascular territory ( fig . , magnetic resonance angiography ( mra ) revealed severe stenosis at the bilateral terminal portion of the icas , while the bilateral mcas and acas had almost disappeared ( fig . combined with the patient 's symptom of progressive mild quadriplegia , aphasia , recurrent convulsions and urinary incontinence that appeared 5 days prior to the first admission , and the signs of globally increased muscle tone , hyperactive deep tendon reflexes and positive bilateral babinski signs on admission and the results of the head mri , a diagnosis of multiple cerebral infarction was made definitely . blood examination showed the following results : thyroid - stimulating hormone ( tsh ) , < 0.001 u / ml ( reference range , 0.354.94 u / ml ) ; and free triiodothyronine ( ft3 ) , 29.17 pmol / l ( reference range , 2.635.7 pmol / l ) . positive thyrotropin receptor antibody ( tr - ab ) , as well as elevated levels of thyroid peroxidase antibody ( tpo - ab ; 396.44 u / ml ; reference range , < 12 u / ml ) and thyroglobulin antibody ( tg - ab ; 134.56 u / ml ; reference range , < 34 u / ml ) , were also detected in the blood ( table i ) . due to the above symptoms of irritability , tremors , excessive sweating , frequent palpitations and enlarged thyriod gland with elevated tpo - ab , elevated tg - ab and positive tr - ab in blood , a thyroid gland needle biopsy revealed thyroid follicular epithelial cell proliferation , which confirmed the diagnosis of gd . in addition , quantification of coagulation factor activity demonstrated that fviii activity was 261.6% ( reference range , 50150% ) and vwf activity was 324.2% ( reference range , 40120% ) , while other coagulation parameters were all within the normal ranges , as shown in table i. the patient was managed with standard antithyroid treatment ( 20 mg / day thiamazole , merck serono , darmstadt , germany ; 100 mg / day metoprolol , astrazeneca co. , ltd . , wuxi , china ) until the submission of this manuscript , in combination with a low iodine diet . in beginning of the treatment , other management included 30 mg / day adalat for 2 weeks ( bayer schering pharma ag ) for control of blood pressure , sedative administration ( 5 mg diazepam , zhejiang medicine co. , ltd . , zhejiang , china ) lasting until the calming of irritability after 1 week . after 2 months of treatment , the neurological symptoms had improved significantly ; the patient had recovered from paralysis , walked with a steady gait and no slurred speech was observed . further blood tests showed that the patient 's thyroid function had almost returned to normal ( tsh , 0.027 u / ml ; ft3 , 3.21 pmol / l ) , with depressed vwf and fviii activity ( 117.10 and 122.40% , respectively ) , although the thyroid autoantibodies persisted at high levels ( table i ) . digital subtraction angiography ( dsa ) was then performed , which demonstrated severe stenosis of the bilateral distal segments of the icas , and of the acas and mcas . a network of collateral vessels was also visible at the base of the brain and in the bilateral basal ganglia areas ( fig . 2 ) . to prevent further attacks , revascularization surgery was performed initially on the right side superficial temporal artery binding to the middle meningeal artery at 3 months after the first admission . this results of dsa associated with the symptoms of gradually emerged quadriplegia , aphasia , convulsions and the head mri results which showed bilateral basal ganglia and subcortical multiple infarction , together , could meet the diagnostic criteria for mmd ( 20 ) . after a further 3 months ( 6 months after the first admission ) , an encephalo - duro - arterio - synangiosis procedure was performed successfully on the left side superficial temporal artery attaching to the endocranium and arachnoid . during the 20-month follow - up period , a continuous 20 mg / day thiamazole and 100 mg / day metoprolol was administrated , the thyroid function , thyroid autoantibodies and coagulation parameters were measured every 3 months . during this period , a correlation was observed between the patient 's thyroid function and vwf / fviii activity . after 3 months , following the administration of propranolol and metoprolol , his thyroid function ( ft3 and ft4 ) recovered to the normal range . notably , a decline in fviii / vwf activity was observed simultaneously . after a further 3 months , while ft3 and ft4 in the patient 's blood were higher than the normal range , a homologous elevation of the patient 's fviii / vwf activity in the blood was observed . a similar phenomenon was observed during the next 12-month follow - up period ( table i ) . when the thyroid function recovered to the normal range , a corresponding decline in fviii / vwf activity was observed ( table i ) . at the same time , the thyroid autoantibodies persisted at high levels , whereas other coagulation parameters were consistently around the normal ranges . the manifestations observed were mainly due to cerebral infarction , while the clinical features of thyrotoxicosis had appeared approximately 1 year prior to admission . this is consistent with the features of previously reported cases , which suggest that transient ischemic attacks and cerebral infarction were the common symptoms and thyrotoxicity was showed when the cerebral ischemic event occurred ( 6 ) . due to the limited incidence of co - existing gd and mmd , extensive studies have not been possible , and no specific mechanism underlying this association has been elucidated to date . previous hypotheses on the underlying mechanism have been proposed that presume the existence of a pathoetiological association between gd and mmd , such as genetic background , autoimmunization ( 10,11 ) , thyrotoxic states ( 9,21 ) and significant hemodynamic changes ( 9 ) . there are certain evidence - based medicine practices and epidemiological data that support these theories . for instance , kim et al concluded that elevated thyroid autoantibodies are associated with mmd , based on a prospective study ( 11 ) . this theory was supported by a case - control study conducted by li et al , which demonstrated that increased thyroid function and elevated thyroid autoantibodies are associated with mmd , particularly in pediatric patients ( 10 ) . furthermore , improvement in the ischemic symptoms without recurrence has been reported following antithyroid drug administration alone in two patients affected by hyperthyroidism combined with bilateral internal carotid artery stenosis ( 21 ) . in another study , two patients had recurrent stroke subsequent to antithyroid drug withdrawal for 6 months , while the majority of patients in the same study did not present recurrence of stroke with regular use of antithyroid drugs ( 9 ) . however , the mechanism by which elevated thyroid autoantibodies or increased thyroid function evoke the development of stenosis of the intracranial arteries , as seen in mmd , remains to be elucidated . the patient in the present study was diagnosed with mmd associated with gd , based on the symptoms of irritability , tremors , excessive sweating , frequent palpitations , the enlarged thyroid gland and the examination results of elevated tpo - ab , elevated tg - ab and positive tr - ab in blood , along with thyroid gland pathology by needle biopsy . furthermore , his multiple cerebral infarction and the results of dsa that showed a serious stenosis at the bilateral terminal portion of the icas , the bilateral mcas and acas ( fig . notably , significant overactivation of fviii and vwf were identified in the plasma on admission , which are considered to serve an important role in vascular diseases ( 1518 ) . the correlation of high plasma levels of vwf / fviii with cardiovascular disease ( 15 ) , cerebral sinus and deep venous thrombosis ( 18 ) , as well as ischemic stroke ( 16,17 ) , has been extensively investigated . certain studies have concluded that high plasma levels of vwf are predictive of ischemic stroke ( 22,23 ) , and may even be an independent risk factor for the prediction of ischemic stroke ( 23 ) . the pathophysiologic role of fviii- or vwf - associated processes in ischemic brain injury is unclear . it is well - known that vwf and fviii serve crucial roles in primary thrombosis . in addition , vwf mediates the initial adhesion of platelets at sites of vascular injury , and this subsequently leads to fibrin coagulation and the formation of a platelet thrombus via a complex coagulation cascade , platelets adhesion mediated by vwf is a prerequisite for normal hemostasis ( 2427 ) . vwf is synthesized and stored in endothelial cells , and plasma levels are increased in response to different states of endothelial damage ; therefore , vwf has been proposed as a useful marker of endothelial activation or dysfunction ( 14 ) . earlier studies have identified that concentric and eccentric fibrocellular thickening of the intima , which induce stenosis of the vascular lumen , are typical pathological changes in the terminal of the internal carotid artery in mmd ( 28,29 ) . recent studies using high - resolution 3 t mri of a cross - section of the mca showed no plaque or enhancement in the mca wall ( 9,30 ) , the artery blood vessel image under 3 t mri from mmd is at variance with atherosclerotic features . furthermore , in another study , thromboemboli in the internal wall of the moyamoya artery were observed in ~50% of cases at autopsy ( 31 ) . previous studies have demonstrated that vascular endothelium is a specific target of thyroid hormones ( 32 ) , and that hyperthyroidism tends to be associated with endothelial dysfunction or damage . this endothelial dysfunction depends not only on the cause but also on the degree of hyperthyroidism ( 19 ) . hyperthyroidism is known to result in high sympathetic nerve activity , thus plasma adrenaline levels are increased , acting as a strong stimulus of vwf secretion by endothelial cells ( 33 ) . clinical studies have also demonstrated that the elevated vwf levels in hyperthyroid patients returned to the normal range following administration of propranolol ( 34,35 ) . in accordance with the observations of the current study , hyperthyroidism has a significant correlation with the elevation of fviii and vwf activity . considering the pivotal role of vwf and fviii in thrombogenesis , gd could be expected to be involved in the mechanism underlying the development of mmd , which is mediated by vwf / fviii overactivation . gd is such a complex disease that may influence multiple aspects associated with the pathophysiologic process of mmd , including cerebral hemodynamic changes ( 9 ) , autoimmune inflammation ( 10,11 ) and endothelial dysfunction ( 19 ) . in addition , thrombogenesis is mediated by vwf and fviii activities , which may be due to injury to the intima or vessel wall , while the injury of intima or vessel wall could be a result of cerebral hemodynamic changes or autoimmune inflammation . further evidence of vwf and fviii mediating the development of mmd is the varying trend of vwf and fviii activities during the follow - up period in the present study . upon admission , the current patient had significantly elevated vwf and fviii activities , and presented with rapid neurological deterioration . following the administration of thiamazole and metoprolol , the patient 's thyroid function returned to normal , while vwf and fviii activities were simultaneously suppressed , with a correlation observed in their fluctuations ( table i ) . during the follow - up period , the thyroid autoantibodies tr - ab , tg - ab and tpo - ab persisted at high levels in the patient 's blood , whereas other coagulation parameters were consistently within or close to the normal range . therefore , the effect of thyroid autoantibodies on the development of mmd was unclear in the present patient . however , an evident limitation of the present study is that only one case was included . nevertheless , during the 20-month follow - up period , correlations were identified among gd , overactivation of vwf / fviii and intracranial arterial stenosis , which require further confirmation in more cases and in - depth studies in the future .
the present study reported the case of a chinese boy who was diagnosed with moyamoya disease ( mmd ) associated with graves ' disease ( gd ) . 
 an overactivation of von willebrand factor ( vwf ) and coagulation factor viii ( fviii ) was identified in the plasma of the patient . 
 thiamazole and metoprolol treatment was thus administrated . 
 after 2 months of treatment , the patient 's thyroid function returned to normal and the neurological symptoms improved gradually . at the same time , the activities of vwf and fviii were depressed . during the 20-month follow - up , information regarding the neurological symptoms , cerebrovascular imaging , thyroid function , thyroid autoantibodies and coagulation parameters was collected . 
 high levels of thyroid autoantibodies persisted throughout the follow - up period , while other coagulation parameters remained in the normal range . in conclusion , considering the vital role of vwf and fviii in vascular diseases , it is hypothesized that these two factors may serve an important role in the occurrence of gd associated with mmd .