2025 Volume 12 Pages 505-509
Moyamoya disease is a progressive steno-occlusive cerebrovascular disorder that may be complicated by intracranial aneurysms, particularly, in the posterior circulation, which are at higher risk of rupture than those in the general population. Clazosentan, a selective endothelin A receptor antagonist, has been approved in Japan for the prevention of cerebral vasospasm after aneurysmal subarachnoid hemorrhage. However, cerebral hemodynamics after subarachnoid hemorrhage and safety of clazosentan in patients with moyamoya disease remain unknown. We report the case of a 46-year-old man with bilateral moyamoya disease who presented with severe subarachnoid hemorrhage caused by a ruptured saccular aneurysm in the right P2 segment of the posterior cerebral artery. Coil embolization was successfully performed, and clazosentan (10 mg/hr), along with cilostazol, was administered to prevent vasospasm. Fluid balance was carefully managed, and no clazosentan-related adverse events were observed. Follow-up radiological examinations showed no evidence of cerebral vasospasm or ischemic lesions. The patient made a favorable recovery and was discharged with a modified Rankin scale score of 1. Four months later, revascularization surgery was performed to reduce hemodynamic stress and the risk of hemorrhage from choroidal collaterals. The aneurysm remained occluded, the choroidal channels regressed, and no recurrent strokes occurred during 1 year of follow-up. To the best of our knowledge, this is the first report of successful clazosentan therapy for aneurysmal subarachnoid hemorrhage in a patient with moyamoya disease. Careful perioperative management allowed the safe use of clazosentan without complications. Further studies are needed to evaluate its broader safety and efficacy in this population.
Moyamoya disease (MMD) is a progressive cerebrovascular disorder characterized by stenosis or occlusion of the distal internal carotid arteries and the proximal segments of the anterior and middle cerebral arteries.1) Intracranial aneurysms are occasionally associated with MMD.2-5) These aneurysms are typically categorized into 2 types: those arising from major arteries within the circle of Willis and peripheral aneurysms that develop from pathologic moyamoya vessels. Most aneurysms involving major arteries are saccular and located in the posterior circulation, often presenting with rupture and resulting in aneurysmal subarachnoid hemorrhage (aSAH).2)
Clazosentan (CLZ), a selective endothelin A receptor antagonist, has shown efficacy in reducing vasospasm-related mortality and morbidity.6-9) In January 2022, CLZ was approved by the Pharmaceuticals and Medical Devices Agency in Japan for the prevention of cerebral vasospasm after aSAH. However, reports on the management of cerebral vasospasm and cerebral hemodynamics after aSAH in MMD are extremely limited, and the safety of CLZ in this context remains unclear. Here, we present the first documented case of successful CLZ therapy for vasospasm prevention after coil embolization of a ruptured posterior cerebral artery aneurysm in a patient with MMD, followed by revascularization surgery.
We previously conducted a multicenter, prospective registry study to investigate the effects of CLZ therapy.10) Between April 2023 and October 2024, a total of 104 patients with aSAH were enrolled. Among them, one patient was diagnosed with MMD and received CLZ therapy, as detailed subsequently. This study was approved by the Institutional Review Board of Hokkaido University Hospital (approval number: 022-0275). Informed consent was obtained from all patients or relevant persons.
A 46-year-old man presented to the emergency department with a sudden onset of headache and decreased consciousness (Glasgow coma scale score: E1V1M2). Head computed tomography revealed aSAH (World Federation of Neurosurgical Societies grade 5, Fisher group 3; Fig. 1A). Cerebral angiography showed bilateral MMD and a 3.5-mm saccular aneurysm in the right P2 segment of the posterior cerebral artery, considered the source of bleeding (Fig. 1B and C). On the day of admission, coil embolization using the simple technique was performed. A small neck remnant remained post-procedure (Fig. 1D). Diffusion-weighted imaging (DWI) on day 2 post-onset revealed a hyperintense lesion in the right frontal cortex, suggesting primary brain injury because of elevated intracranial pressure (Fig. 1E-G). CLZ (10 mg/hr) and cilostazol (200 mg/day) were initiated for vasospasm prevention. Single-photon emission computed tomography on day 7 demonstrated no abnormal decrease in cerebral blood flow, except in the region corresponding to the primary brain injury (Fig. 1H). On day 10, follow-up angiography confirmed the absence of cerebral vasospasm in the major arteries (Fig. 2A). A spinal drainage catheter had been placed from day 0 to day 8 to facilitate hematoma clearance. By day 14, DWI abnormalities had resolved, with no new ischemic lesions observed (Fig. 2B), and magnetic resonance angiography showed no evidence of vasospasm. CLZ and cilostazol were discontinued on day 15. During the acute phase, fluid management was carefully controlled to avoid a net positive balance exceeding 1,000 mL. The average daily intravenous fluid volume over the two-week period was approximately 1,500 mL, with no need for diuretics and no weight gain exceeding 2 kg. Systolic blood pressure was maintained within the normotensive range, and neither continuous antihypertensive nor vasopressor therapy was required. No complications, such as pulmonary edema, pleural effusion, or cerebral edema, were observed. The patient's consciousness fully recovered, and he was discharged from a rehabilitation hospital with a modified Rankin scale score of 1.
(A) Computed tomography reveals diffuse subarachnoid hemorrhage. (B, C) Right internal carotid artery angiography shows bilateral moyamoya disease and a saccular aneurysm in the right P2 segment of the posterior cerebral artery (arrow). (D) The aneurysm was successfully embolized using a simple coiling technique; a small neck remnant is visible (arrow). (E-G) Diffusion-weighted imaging and fluid-attenuated inversion recovery imaging on day 2 post-onset demonstrate primary brain injury in the right frontal lobe. Magnetic resonance angiography confirms bilateral moyamoya disease. (H) Single-photon emission computed tomography on day 7 shows no abnormal decrease in cerebral blood flow, except in the region of the primary brain injury.
(A) Carotid and vertebral angiography on day 10 post-onset show no evidence of vasospasm in the major cerebral arteries. (B) Diffusion-weighted imaging on day 14 reveals resolution of the right frontal lobe injury, with no signs of delayed cerebral infarction. (C) Slab maximum-intensity projection magnetic resonance angiography demonstrates dilation and extension of the right choroidal collaterals reaching the level of the lateral ventricle body (arrows).
At 4 months post-onset, right-sided combined direct and indirect revascularization surgery was performed to reduce the risk of aneurysmal recurrence because of hemodynamic stress on the posterior circulation and prevent hemorrhage from existing choroidal collaterals (Figs. 2C and 3A and B). The postoperative course was uneventful. Cerebral angiography 2 months after the revascularization surgery confirmed complete aneurysm occlusion, with disappearance of the previously noted neck remnant (Fig. 3C). At 1-year follow-up, the bypass remained patent, ipsilateral choroidal collaterals had regressed (Fig. 3D), and no recurrent strokes had occurred, indicating a favorable clinical outcome.
(A) Intraoperative view of superficial temporal artery to middle cerebral artery anastomosis. Indocyanine green angiography confirms patency. (B) Postoperative magnetic angiography also demonstrates patency of the anastomosis (arrow). (C) Right carotid angiography 2 months after revascularization confirms complete aneurysm occlusion (arrow). (D) One-year postoperative slab maximum-intensity projection magnetic resonance angiography shows regression of the ipsilateral choroidal collaterals.
Intracranial aneurysms occur in approximately 3%-15% of patients with MMD.2-5) Furtado et al.2) reported that 3.7% of patients with MMD in their registry at Stanford University between 2003 and 2014 had intracranial aneurysms, and 30.8% of these patients experienced SAH. In our prospective registry, only 1 of 104 patients with aSAH (1%) had underlying MMD.10) Thus, reports on vasospasm management in MMD-associated SAH are rare, and, to the best of our knowledge, this is the first case to describe CLZ use in such a context.
Endothelin, a potent vasoconstrictor produced by vascular endothelial cells, plays a key role in the pathogenesis of cerebral vasospasm after SAH.11,12) CLZ, a selective endothelin A receptor antagonist, has demonstrated efficacy in preventing vasospasm and is widely used in Japan since 2022.6-10) However, CLZ may lead to compensatory activation of endothelin B receptors, resulting in increased vascular permeability. This mechanism is thought to underlie several adverse effects, such as pulmonary edema, pleural effusion, hypotension, and anemia.6,7,10,13-15) CLZ may also affect the blood-brain barrier (BBB) and disrupt cerebral water homeostasis, potentially contributing to brain edema.16) Indeed, brain edema during CLZ therapy has been reported in approximately 4.8%-6% of patients. In patients with MMD, hypotension and anemia can exacerbate cerebral ischemia, and BBB dysfunction and increased vascular permeability are recognized intrinsic pathophysiological features.17-22) Despite these potential risks, the safety of CLZ and its effects on cerebral hemodynamics in patients with MMD remain uncertain. Careful fluid management is essential to minimize CLZ-related adverse events.10,14,15) In this case, daily fluid intake was approximately 1,500 mL, and net positive fluid balance was maintained below +1,000 mL during the acute phase. As a result, no complications such as pulmonary edema, pleural effusion, or cerebral edema were observed. Although the patient exhibited MRI signs of primary brain injury, no progression of brain edema or cerebral ischemia was observed. Despite presenting with severe SAH, the patient was successfully treated with CLZ, and no vasospasm occurred. The clinical outcome was favorable.
In MMD, aneurysms involving major arteries tend to develop in the posterior circulation because of hemodynamic stress caused by anterior circulation stenosis.2,4,5) Although surgical clipping may be feasible for anterior circulation aneurysms, posterior circulation aneurysms are often anatomically difficult to access, making endovascular coil embolization the preferred treatment. Although stent-assisted coiling has been reported in patients with MMD,23) the required dual antiplatelet therapy increases the risk of hemorrhagic complications, and stent placement in pathological vessels raises concerns about in-stent occlusion.5) Therefore, a simple coiling technique is preferable when feasible. For unruptured aneurysms where clipping or coiling is difficult, revascularization surgery alone has led to regression of aneurysms by altering hemodynamic stress.5) In the present case, revascularization surgery was performed after coil embolization to prevent aneurysm regrowth and reduce the risk of hemorrhage from choroidal collaterals, leading to a favorable outcome.
Although CLZ was used safely in this patient, its safety in those with more advanced stages of MMD or concurrent cerebral infarction remains uncertain, given the potential risks described previously. In hemorrhagic-type MMD, intracerebral and intraventricular hemorrhages predominate, whereas SAH is rare.24) Consequently, reports on the incidence, management, and outcomes of cerebral vasospasm in MMD-associated SAH are extremely limited, and distinctions from typical aneurysmal SAH remain unclear. Furthermore, preexisting arterial stenosis in MMD may complicate the assessment of vasospasm severity, necessitating serial evaluations. Previous studies have documented collateral vessel spasm and severe cerebral infarction following intraventricular hemorrhage in MMD.25,26) In addition, the reported association between the RNF213 variant and coronary artery spasm suggests that variant-related endothelial dysfunction and smooth muscle hyperactivity may contribute to increased vasospasm risk.27-30) Collectively, these findings imply that the incidence of cerebral vasospasm and the associated ischemic risk may be higher in MMD than in typical SAH. Further accumulation of cases is warranted to elucidate these issues, including the safety and efficacy of CLZ in this patient population.
This report describes the successful use of CLZ for vasospasm prevention after coil embolization of a ruptured posterior cerebral artery aneurysm in a patient with MMD. Subsequent revascularization surgery resulted in complete aneurysm occlusion and regression of periventricular collaterals. This case suggests that, with careful management, CLZ may be safely used in selected patients with MMD.
Author Miki Fujimura is one of the Editorial Board members of the Journal. This author was not involved in the peer-review or decision-making process for this paper.
All authors have no conflict of interest.
