Abstract
Summary
Moyamoya syndrome (MMS) refers to a rare cerebrovascular disorder characterized by progressive stenosis of the intracranial internal carotid arteries and their proximal branches, leading to an increased risk of stroke. While prevalent in Asia, this condition is considerably less common in Western countries, including Europe. The association between MMS and Graves’ disease (GD) has been well documented, primarily in Asian and American populations, notably Latin Americans. In this report, we report the first case of GD with MMS in a Caucasian woman from Western Europe. The precise mechanisms underpinning the correlation between these two conditions remain poorly elucidated but are hypothesized to involve hemodynamic alterations, the toxic effects of anti-thyroid-stimulating hormone receptor antibodies, or a shared genetic predisposition. Our clinical case underscores the significance of thyroid disease screening in suspected MMS cases, as the management of thyroid dysfunction may suffice to improve neurological symptoms.
Learning points
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The association between Graves’ disease (GD) and Moyamoya syndrome (MMS) can manifest in a Caucasian European patient.
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Screening for thyroid disease is essential when MMS is suspected, as treating GD might effectively alleviate neurological symptoms.
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The mechanisms linking GD and MMS remain incompletely understood but may involve hemodynamic shifts, the toxic effect of anti-TSH receptor antibodies, or shared genetic factors.
Background
Moyamoya syndrome (MMS) refers to a rare cerebrovascular disorder characterized by progressive narrowing of the intracranial internal carotid arteries and their proximal branches, leading to an increased risk of stroke (both ischemic and hemorrhagic). The development of collateral vessels gives rise to a distinct smoky appearance on angiography known as ‘moyamoya’ (1). While prevalent in Asia, this condition is considerably less common in Western countries, including Europe (2). Moyamoya can occur independently or in conjunction with various conditions (moyamoya disease vs MMS). The association between MMS and Graves’ disease (GD) has been extensively documented, primarily in Asian and American populations, particularly among Latin Americans (3). Here, we present the first documented case of symptomatic GD associated with MMS in a Caucasian woman residing in Western Europe.
Case presentation
A 25-year-old woman presented to the emergency department (ED) of a local hospital with a history of sensorimotor deficits in her left arm and hemi-face over the past few days. Additionally, she reported experiencing unusual fatigue, a weight loss of 5 kg, distal tremors, palpitations, excessive sweating, and exophthalmos for the preceding 2 months. Her medical history included two miscarriages: the first at 19 weeks of pregnancy and the second at 8 weeks. She had no history of smoking or alcohol consumption and no other cardiovascular risk factors. She was not taking any medication.
Investigation
In the ED, a diagnosis of hyperthyroidism was suspected based on her symptoms and swiftly confirmed by blood test results: TSH <0.01 mU/L (normal value (NV): 0.25–4), free T4 59.61 pg/mL (NV: 9.3–17), and free T3 25.17 pg/mL (NV: 2.3–4.5). Elevated levels of anti-TSH receptor antibodies (TRAb 10.4 IU/L; NV <0.4) coupled with diffuse hyperuptake of tracer during a 99Tc scintigraphy unequivocally diagnosed GD. Anti-TPO antibodies were also elevated (TPOAb 485 IU/mL; NV < 30), as were anti-thyroglobulin antibodies (TGAb 155 IU/mL: NV <70). Treatment began with thiamazole 60 mg and propranolol 20 mg.
Furthermore, the left sensorimotor deficit was confirmed upon clinical examination. Brain MRI revealed recent cerebral infarctions in the territory of the right middle cerebral artery (MCA) and deep left MCA (semi-oval center). Treatment with acetylsalicylic acid 80 mg and enoxaparin 4000 IU was initiated. Etiological assessment included transthoracic and transesophageal echocardiography, ultrasound of the neck vessels, 24-h Holter ECG, blood pressure monitoring, and thrombophilia screening, all of which yielded normal results. No imaging of major intracranial arteries was conducted at this stage.
Subsequent clinical and biological evolution proved satisfactory. The sensory-motor deficit completely resolved and the thyroid hormones normalized 1 month after treatment initiation. Thiamazole dosage was gradually reduced to 20 mg and combined with L-thyroxine in a ‘block-and-replace’ regimen, allowing long-term normalization of TSH levels.
However, 3 months later, she presented with a new transient brachio-facial sensorimotor deficit, this time on the right side, lasting 30 min. Brain MRI revealed no new lesions, leading to a diagnosis of transient ischemic attack (TIA).
One year later, she sought a second opinion at our neurology department. The anamnesis included headaches, cognitive impairments, and occasional paresthesias in her right hand. She remained unable to return to work following her stroke. A new brain MRI was conducted, incorporating an angiographic sequence of the circle of Willis (Figs 1 and 2), revealing focal ectasias of the proximal segments of both anterior cerebral arteries (ACA, A1) and middle cerebral arteries (MCA, M1).
Magnetic resonance angiography (MRA), showing stenosis of bilateral proximal anterior cerebral arteries (ACA – arrowheads), and middle cerebral arteries (MCA – arrows).
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 2; 10.1530/EDM-23-0138
Magnetic resonance angiography (MRA T2W1) showing moyamoya vessels (arrowheads) and stenoses of middle cerebral arteries (arrows).
Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 2; 10.1530/EDM-23-0138
Cerebral arteriography confirmed stenosis of the terminal internal carotid arteries and the origins of both left and right ACA and MCA, displaying a typical image of moyamoya neovascular network, predominantly on the left side. Common diseases associated with moyamoya were ruled out, with the exception of GD (vasculitis, HIV infection, syphilis, thrombophilia, anti-phospholipid syndrome, diabetes, sickle cell disease). Subsequent genetic analysis yielded inconclusive results (search for ACTA2 gene mutation, RNF213 p.R4810K variant, and karyotype analysis for detection of Xq28 deletion).
Treatment
Given the patient’s favorable cerebrovascular reserve on Tc 99m HMPAO scintigraphy (with Diamox stress test) and the absence of stroke recurrence or new lesions on a brain MRI performed 2 years post stroke, coupled with the surgical risk associated with revascularization procedures, a conservative approach was chosen. The patient underwent cognitive rehabilitation for 2 years, resulting in improvements in mild cognitive deficits related to memory, attention, and executive functions. Regarding GD, due to the persistence of a slightly elevated TRAb levels, a long-term treatment with thiamazole (>18 months) was deemed necessary to prevent hyperthyroidism recurrence, which could disrupt cerebral hemodynamics.
Outcome and follow-up
Thiamazole was eventually discontinued 3 years after onset. TRAb levels were then just below the normal range limit and thyroid ultrasonography revealed no goiter or abnormal gland vascularization. As of today, 10 years after disease onset, the patient has not experienced any recurrence of hyperthyroidism or stroke.
Discussion
The association between MMS and GD has been extensively documented, primarily in Asian and American populations, with a notable prevalence among Latin Americans (3). A review published in 2016 identified 79 cases of concurrent MMS and GD, with the majority being Asian patients (Asian n = 50, Caucasian Americans n = 2, Latin Americans n = 2, African n = 1, not mentioned n = 24). Additionally, a case series in Florida described eight patients (Latin Americans n = 7, Caucasian Americans n = 1) (3). However, the presentation of moyamoya appears to differ between European and Asian cohorts. For instance, in a German cohort of 200 patients, cerebral hemorrhages were rare, and there was a pronounced female predominance compared to Asian data. Thyroid disease was detected in 23.8% of this German population, but the specific type of thyroid disease was not specified (2). In a 2018 study of 37 Italian Caucasian patients, an association was found between the presence of autoantibodies to thyroid antigens and a more aggressive presentation of MMS (4). However, this study only focused on TgAb and TPOAb, with no information about TRAb, and none of the patients included had hyperthyroidism at the time of diagnosis. Therefore, we aimed to review the occurrence of MMS and GD in Europe. The various cases documented in European literature are summarized in Table 1.
Association of Moyamoya syndrome and Graves’ disease in European literature.
Parameters | Reference | ||
---|---|---|---|
Garcin et al. (5) | Utku et al. (6) | Nevin et al. (7) | |
Sex | Female | Female | Female |
Age (years) | 19 | 45 | 36 |
Country | France (Ivory Coast) | Turkey | Portugal |
Onset | Chorea, dysarthria | Encephalopathy | Right leg deficit |
Brain lesion | LA putamen infarction, head of the left caudate nucleus | No lesion | Left frontoparietal lobe infarction |
Location of stenosis | Bilateral ICA, left ACA, bilateral MCA | Bilateral ICA and PCA | Bilateral ICA, ACA, and MCA |
TSH (mIU/L) | <0.01 | <0.01 | Normal |
Diagnosis and antibodies | TRAb | Scintigraphy; TPOAb, TgAb | TRAb, TPOAb, TgAb, APL |
Treatment | Carbimazole | PTU, GC, plasmapheresis, RI | OAC |
Surgery | No | No | No |
Clinical outcome | Good | Good | No recovery |
ACA, anterior cerebral artery; APL, antiphospholipid antibodies; GC, glucocorticoid; ICA, internal carotid artery; LA, left anterior; MCA, middle cerebral artery; OAC, oral anticoagulation; PCA, posterior cerebral artery; PTU, propylthiouracil; RI, radioiodine ablation; TgAb, anti-thyroglobulin antibodies; TPOAb, anti-thyroperoxidase antibodies; TRAB, TSH receptor antibodies.
We identified only three cases of MMS associated with GD in European literature. The first case involved a patient treated in France but of African descent (Ivory Coast) (5), while the second case was situated at the border of Asia Minor (6). In the third case (7), there was no hyperthyroidism at the time of diagnosis, and the patient also had a history of antiphospholipid syndrome, another condition associated with MMS. For these reasons, our case appears to be the first to describe the association between symptomatic GD and MMS affecting a Caucasian patient residing in Western Europe. We attempted to find additional cases by consulting fellow neurologists and endocrinologists across Belgium, but none were reported to us.
Although the association between MMS and GD appears to be rare, it is likely not coincidental. Treatment for GD sometimes suffices to improve the neurological condition (3). In the American review of 79 cases associating MMS and GD, antithyroid therapy alone resulted in clinical improvement in 33 of 38 treated patients. However, eight patients later required surgical revascularization due to recurrent ischemic attacks or incomplete resolution of symptoms.
The link between GD and MMS can be explained through several mechanisms. Firstly, hemodynamic changes associated with thyrotoxicosis, including heightened sensitivity to catecholamines and activation of the sympathetic nervous system, may contribute to stroke occurrence. The clinical improvement observed upon returning to euthyroidism suggests a potential role of these hemodynamic alterations (8). Cerebral infarction is more commonly observed in GD, possibly due to transient changes in hemodynamics leading to vasospasm (3). While coronary vasospasms have been linked to thyrotoxicosis, less is known about cerebrovascular changes associated with hyperthyroidism.
Additionally, cases of MMS and GD occurring in a euthyroid state suggest a direct toxic effect of TRAb on brain vasculature. TSH receptors in blood vessels contribute to angiogenesis and vascular smooth muscle proliferation (9). Excessive stimulation of these receptors by TRAb may lead to intracranial artery stenosis. Similar toxic effects of TRAb have been noted in cases of pulmonary hypertension associated with GD, suggesting that autoantibodies could cause endothelial damage or dysfunction (10).
Another hypothesis involves a shared genetic background predisposing individuals to both diseases. However, specific mutations implicated in this predisposition have not been clearly identified. Interestingly, a locus associated with both Hashimoto’s and GD (8q24, locus for thyroglobulin) is proximal to the gene 8q23 associated with moyamoya (MM3) (3).
Treatment for MMS aims to improve cerebral blood flow, prevent stroke recurrence, reduce collateral circulation associated with MMS, and alleviate symptoms such as headaches. It typically involves a combination of medical therapy (antiplatelet agents, calcium channel blockers) and revascularization procedures (external carotid artery anastomoses) (1). Screening for GD is crucial, as treatment of thyrotoxicosis may improve neurological symptoms and stabilize MMS (3). Antithyroid drugs such as Thiamazole and PTU are the mainstay of GD treatment, while radioiodine therapy should be used cautiously due to its potential to transiently increase anti-TSH receptor antibodies. Thyroidectomy is reserved for cases where medical therapies fail.
Conclusion
We present the first documented case of symptomatic GD associated with MMS in a Caucasian woman from Western Europe. While cases have been reported in Asian and Latin American populations, the clinical presentation of MMS can vary globally. The mechanisms underlying the potential association between GD and MMS remain poorly understood, with hypotheses suggesting hemodynamic changes, toxic effects of TRAb, or a shared genetic background. Screening for thyroid disease is essential when MMS is suspected, as treatment may suffice to improve neurological symptoms. Further cases are needed to confirm this association in the Caucasian population of Europe.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this case report.
Funding
This study received funding from Boehringer Ingelheim, which was used to cover editorial fees.
Patient consent
Written informed consent was obtained from the patient for publication of the submitted article.
Author contribution statement
G Pierman wrote the manuscript. E Delgrange and Y Vandermeeren were responsible for the clinical management of the case. Y Vandermeeren, C Jonas, and E Delgrange reviewed and edited the manuscript.
Acknowledgements
We warmly thank Dr Linda Bombyl for proofreading and correcting the English manuscript.
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