Alagille syndrome (ALGS) is an autosomal dominant, rare genetic disorder that consists primarily of hepatic, renal, and cardiac abnormalities with an incidence of 1 in 30,000 people [12]. ALGS is also called arteriohepatic dysplasia due to associated vascular abnormalities. One such vascular abnormality is Moyamoya. Moyamoya is a progressive steno-occlusive disease of the terminal portion of the internal carotid artery. Moyamoya is classified into two categories based on its cause. If the moyamoya vasculopathy occurs alongside other known medical conditions, it’s called moyamoya syndrome (MMS). If it occurs on its own, without any identifiable associated factors, it’s called moyamoya disease (MMD). The association between ALGS and MMS was first reported in 1989 [17]. Symptoms of moyamoya include recurrent transient ischemic attacks, ischemic strokes, and intracranial bleeding. The moyamoya phenomenon of being silent in childhood, with its first occurrence in adulthood, has been rarely described in ALGS [5,9]. Here, we describe a similar case of ALGS in a patient with congenital narrowing of bilateral ICAs, intracranial arteriopathy, and MMS presenting for the first time as an adult.

A 34-year-old female with a history of ALGS and hypertension presented in the emergency room with 4 days of progressive blurring of vision in her right eye, headache, and dizziness. She had been diagnosed with ALGS at 6 years of age after developing chronic liver disease requiring liver transplant. Her initial vital signs were normal except for high blood pressure (176/59 mmHg). Her initial NIH stroke scale was 0, which indicated no focal neurological deficit. Images were obtained due to concerns for stroke due to vision abnormalities, and she was admitted. A non-contrast head computed tomography (CT) revealed hypodensity in the right frontal lobe consistent with ischemia. A CT angiogram of the head and neck showed markedly attenuated bilateral internal carotid arteries (ICA) with no definite flow through cavernous segments (Fig. 1B) and minimal flow in the anterior circulation (Fig. 1C). Due to the presence of narrow canals, suspicion for congenital narrowing was high (Fig. 1A). Subsequently, a magnetic resonance imaging (MRI) of the brain showed no acute infarcts but revealed chronic right frontal lacunar infarct with surrounding gliosis. The MRI also showed diffuse leptomeningeal enhancement (also called ivy sign) on fluid-attenuated inversion-recovery (FLAIR) sequence. A diagnostic cerebral angiogram revealed intracranial occlusions of the bilateral ICA around the cavernous segment and reconstitution of the intracranial vessels through irregular, moyamoya-like collaterals (Fig. 2). The patient was given a loading dose of 324 mg aspirin for secondary stroke prevention.

Her right-sided vision abnormalities were highly concerning for branch retinal artery occlusion based on fundoscopic findings of retinal wool spots. The patient’s headache and dizziness improved, but she continued to have blurred vision. She was discharged with outpatient follow-up scheduled with ophthalmology. At the time of discharge, the patient started dual antiplatelet therapy (aspirin 81 mg and clopidogrel 75 mg) for secondary stroke prevention. She was also scheduled for an evaluation of possible bypass of the internal and external carotid arteries.

Over the next year, the patient remained asymptomatic, and the patient was contemplating surgery. A Diamox MRI of the brain was performed, which showed small areas of diminished cerebral vascular reserve on right anterior frontal convexity but did not demonstrate any new infarcts. A shared decision was made to continue long-term dual antiplatelet therapy until the decision was made on revascularization.

Our case highlights the importance of screening for MMS and other vascular conditions, such as aneurysms, in patients with ALGS by reporting a rare incidence of adulthood presentation of MMS in ALGS patients. ALGS is a rare, autosomal dominant disorder affecting multiple body systems, such as renal, cardiac, facial, and vertebral abnormalities, in addition to hepatic dysfunction. The heterogeneity in presentation of symptoms is attributed to the association with Notch signalling pathway. It was only in the late 1990s when the association of the disease with NOTCH signalling pathway was identified, involving the genes JAGGED 1 (JAG 1) [16] and NOTCH2 [13]. This pathway is involved in cell fate and differentiation. Animal studies show that the JAG1 homozygous knockout mouse demonstrates early lethality from vascular defects and guides towards its role in angiogenesis [19]. Vascular abnormalities include aneurysms, middle aortic syndrome, abnormalities in cerebral arteries, reno-vascular abnormalities, and Moyamoya syndrome. Patients with both ALGS and MMS are even rarer and thus, infrequently studied. MMS is characterized by the presence of bilateral ICA terminus narrowing on digital subtraction angiography (DSA), which was present in our patient. Emerick et al. [6] noted cerebrovascular abnormalities of all kinds in 10 of the 26 patients (38%) with ALGS they evaluated using MRI. Kamath et al.11) retrospectively evaluated the charts of 268 patients with ALGS and found non-cardiac vascular abnormalities in 25 patients (9%), with only one patient having MMS (0.4%). Cerron-Vela et al. [4] evaluated the frequency of cerebrovascular abnormalities in a pediatric population diagnosed with ALGS and found 18 of 32 children (56%) had cerebrovascular abnormalities, and one of the children had MMS. In a retrospective observational study involving 52 patients with ALGS by Carpenter et al. [3], 2 of 19 patients with dedicated neuroimaging (~10%) had MMS.

Despite the rarity of ALGS, 34% of the mortalities are attributed to vascular events, such as hemorrhage, stroke, and aneurysms [11]. Current data describe an incidence of about 14-16% for intracranial bleeds and a rate of 25% for mortalities secondary to bleeds in ALGS [7,10]. MMD accounts for about one-fifth of pediatric strokes [1]. While asymptomatic patients were monitored with serial imaging, those having cerebrovascular hemodynamic instability were treated with indirect revascularization. Our case illustrates the importance of providers considering the overall vascular risks for patients with ALGS and screening for MMS.

While DSA remains the gold standard for identifying structural narrowing, an MRI of the brain can show some signs of developing collaterals. A study by Montaster et al. [15] with 171 hemispheres showed that the ivy sign appeared in around half of the pediatric MMD patients at Suzuki stage III or IV, when blood flow was at its most unstable. It also showed reversal of the ivy sign provided both radiographic and clinical utility as a prognostic biomarker postoperatively [15]. In our patient, FLAIR MRI demonstrated the ivy sign, but ivy signs can also be revealed with contrast-enhanced MRI.

There are two treatment paths to consider for patients with ALGS and MMS. The first is surgical revascularization either by direct, indirect, or combined bypass. Surgical revascularization is currently the preferred treatment. While surgical bypass was only indicated for ischemic MMD, the Japan Adult Moyamoya trial has shown a decrease in rebleeding in hemorrhagic type [14]. As a secondary treatment to prevent stroke, aspirin is suggested for patients with MMD who develop ischemic strokes. The prophylactic use of aspirin in asymptomatic patients is not universally recommended. Given the potential for hemorrhagic complications in this vasculopathy, aspirin’s antiplatelet effect may increase the risk of intracranial hemorrhage, particularly in patients with the hemorrhagic type. Therefore, aspirin therapy should be reserved for patients with symptomatic moyamoya exhibiting ischemic manifestations, after careful risk-benefit assessment [18]. Our patient is currently being treated with dual antiplatelet therapy and statin while being monitored.

ALGS patients may have undetected MMS in childhood that places them at greater risk for catastrophic strokes, so a standardized screening protocol is needed. The American Heart Association stated in 2019 8 that there isn’t enough evidence to support screening asymptomatic people, or those with conditions that increase the risk of MMS. We concur with Ayoub et al.’s [2] recommendations that adults with suspected ALGS should undergo vascular imaging if they haven’t had prior screening for brain abnormalities. MRA is the preferred screening method because it’s non-invasive, doesn’t require contrast or radiation. Immediate imaging is also recommended if a patient experiences a sudden neurological problem or before any surgery needing general anesthesia, as these patients are at higher risk of stroke due to sedation. We do not recommend interval imaging for asymptomatic patients.

Our case illustrates the need for standardized screening for MMS and other vascular disorders in patients diagnosed with ALGS. While there are no established guidelines for this rare condition, the risks of disability and mortality risk support the development of guidelines. Our case illustrates how ongoing preventive medicine can prevent further stroke and its complications. Further research is needed to determine whether such preventive measures will reduce the need for ICA bypass surgeries in patients with ALGS.