Pathological haemodynamics of a middle cerebral artery stenosis validated by computational fluid dynamics
- 1 Neurosurgery, Mie Chuo Medical Center, Tsu, Mie, Japan
- 2 Neurosurgery, Faculty of Medicine, Mie University Graduate School, Tsu, Mie, Japan
- Correspondence to Dr Katsuhiro Tanaka; tk_0303_ns@yahoo.co.jp
Abstract
Intracranial arterial stenosis (ICAS) is one of the important causes of ischaemic stroke. However, the treatment for ICAS is not optimised, including medical therapies, because the mechanisms are diverse. The authors report a case of severe middle cerebral arterial stenosis accompanied by a floating thrombus, which caused artery-to-artery cerebral emboli. The patient was successfully treated with multiple antithrombotics including an anticoagulant, and the thrombus disappeared. Local haemodynamics around the middle cerebral arterial stenosis was analysed by computational fluid dynamics (CFD) using the patient-specific model. CFD analysis demonstrated that thrombus formation occurred at the poststenotic area with severe stagnant flow, which was judged by both wall shear stress and shear rate less than the specific thresholds. These findings suggest that CFD may be useful to diagnose the risk of stagnant flow-induced thrombosis and to predict the effectiveness of anticoagulant agents to prevent distal embolisms in ICAS.
Background
Intracranial arterial stenosis (ICAS) is one of the crucial pathologies of ischaemic stroke, which is more prevalent among Asian and Hispanic populations including Japanese.1 It accounts for up to about 10% of ischaemic stroke in North America,2 3 33%–50% in China, 10%–25% in Korea4 and 18% in Japan.5 The recurrence rate of ischaemic stroke in ICAS under medical treatments with antiplatelets is reportedly as high as 21% in the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial (more than 50% stenosis with mean follow-up period of 21.6 months),6 15% in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial (more than 70% stenosis with mean follow-up period of 32.4 months)7 and 9% in the Chinese Intracranial Atherosclerosis (CICAS) study (more than 50% stenosis with mean follow-up period of 12 months).8 These incidences are likely to be higher than other cerebrovascular ischaemic pathologies. In addition, ICAS manifests various types of ischaemic events such as perforating artery disease, artery-to-artery embolism, haemodynamic insufficiency and the combined mechanisms, and therefore the complicated pathologies would exacerbate the outcome.9 In this report, we analyse a case of artery-to-artery embolism from severe stenosis of the middle cerebral artery (MCA) with a floating thrombus in terms of local haemodynamics calculated with computational fluid dynamics (CFD) using the patient-specific model, and discuss the potential usefulness of anticoagulant therapy for ICAS with a stagnant flow condition.
Case presentation
A man in his 60s was transferred to our hospital because of sudden onset of speech disturbance and mild right hemiparesis (National Institutes of Health Stroke Scale (NIHSS) score: 2/42). An MRI revealed multiple cerebral cortical infarctions in the left MCA territory (figure 1A). A digital subtraction angiography (DSA) revealed 85% stenosis of the left distal M1 segment and a contrast-medium defect indicating the presence of a poststenotic distal floating thrombus adhering to the inferior wall of the MCA (figure 1B,C). The patient was diagnosed with artery-to-artery embolic stroke due to ICAS 180 min after stroke onset, and was determined to skip intravenous tissue plasminogen activator therapy because of low NIHSS score and to start intensive and immediate antithrombotic therapy considering the risk of stroke progression. And the patient was treated with the combination therapy of acetylsalicylic acid (ASA), argatroban and edaravone, followed by the dual antiplatelet therapy of ASA and cilostazol. The thrombus disappeared on DSA at 8 days poststroke (figure 1D). A single photon emission CT at 14 days poststroke showed a 10% decline of the resting cerebral blood flow in the left MCA territory compared with that in the right one.
MRI and digital subtraction angiography. Diffusion-weighted image on admission showing multiple acute cerebral infarctions in the cortical area of the left middle cerebral artery territory (A). Left internal carotid angiography revealing severe stenosis at the distal M1 and a distal thrombus (inside the black square; B). 3D rotation angiography of the stenotic lesion showing a contrast-medium defect indicating a thrombus (black arrow; C), which disappears 8 days later (black arrow; D).
Investigations
The patient-specific geometry model was generated based on three-dimensional rotational angiography. The stenotic lesion and the distal floating thrombus were verified by stereolithography (STL) registration by Magics (Materialise Japan, Yokohama, Japan); the STL was remeshed with integrated triangles by 3-matic (Materialise Japan, Yokohama, Japan) and the hybrid meshes were generated with tetrahedral and prism elements (ANSYS ICEM CFD 2019 R3; ANSYS, Canonsburg, Pennsylvania, USA). Total number of elements amounted up to about 12 million to ensure accuracy of the laminar flow model, which was 20 times as many as normal meshing (figure 2A). Numerical modelling with Newtonian fluid and transient analysis were performed using a commercially available CFD package (ANSYS CFX 2019 R3; ANSYS, Canonsburg, Pennsylvania, USA), and we calculated shear rate (SR) and time-averaged wall shear stress (WSS).10–12
Computational fluid dynamics (CFD) analyses. Regular-sized meshing (A left) and precise, high-volume meshing (A right) of the distal M1 stenosis. CFD analysis revealing 3D stream lines and the flow-stagnant area (B left) with decreased wall shear stress lower than 0.17 Pa (light green; B middle) and decreased shear rate lower than 49/s (colours other than red; B right), which corresponds to the thrombus formation area (black arrow).
Corbett et al reported WSS less than 0.17 Pa and SR less than 49/s as threshold values to induce clot formation inside an experimental circuit.13 Our previous studies validated these thresholds for thrombosis formation in clinical settings by CFD analyses.14 15 The thresholds were adopted in the present case.
CFD analysis revealed a decrease in blood flow velocity and severe stagnant flow distal to the stenotic lesion. The localised area with SR and WSS lower than the specific threshold values corresponded with the thrombus formation domain (figure 2B).
Treatment
The patient was treated with the combination therapy of ASA (200 mg once on the first day, and 100 mg once daily), argatroban (60 mg daily for first 2 days, and 10 mg two times per day for following 5 days intravenously), and edaravone (30 mg two times per day for 14 days intravenously), followed by the dual antiplatelet therapy of ASA (100 mg once daily) and cilostazol (100 mg two times per day). Pitavastatin (1 mg once daily) was also started from the second day and continued.
Outcome and follow-up
This patient gradually recovered and was transferred to a rehabilitation facility at 40 days poststroke (modified Rankin scale, 2).
Discussion
ICAS potentially causes various types of ischaemic stroke such as perforating artery disease, artery-to-artery embolism and hypoperfusion-induced ischaemia that disturbs microemboli clearance.16 17 Therefore, the cerebrovascular disease (CVD) requires not only antiplatelet therapy but also aggressive medical treatment including intensive blood pressure control, serum lipid reduction and management of other CVD risk factors. The comprehensive approach has gradually improved treatment outcomes of ICAS-related CVD. However, as the CICAS study reported in 2014, 12-month recurrent CVD rates still accounted for up to 3.82% and 5.16% in ICAS patients with 50%–69% and 70%–99% stenosis, respectively.6–8 16
According to Mori classification about ICAS, our case with 85% stenosis, 6.2 mm in length, an eccentric plaque and a floating thrombus was categorised as type B.18 It was reported that cumulative risks of all ischaemic strokes or ipsilateral bypass surgery after percutaneous transluminal angioplasty alone reached 26% in type-B ICAS.18 Moreover, randomised control studies revealed that intracranial stenting for ICAS during an acute or subacute phase of ischaemic stroke was not superior to aggressive medical treatments.7 19 These evidences indicated that the additional endovascular treatments for ICAS were not enough to provide further beneficial effects over medical treatments at the present moment.
The present study reported a case of ICAS in MCA with a floating thrombus, which manifested distal embolisms, and showed that the mechanism of thrombus formation could be explained based on the haemodynamics using CFD. A previous study revealed that thrombosis developed in in-vitro blood loop under a WSS threshold of 0.17 Pa and a SR threshold of 49/s using CFD.13 Our previous studies validated the specific thresholds for either intra-arterial or intra-aneurysmal thrombosis in a clinical setting of cerebral aneurysms treatments.14 15 In this case, CFD analyses revealed that a local domain with severe stagnant flow, which was below the specific thresholds, was observed just distal to the M1 stenotic lesion. The findings suggested that local haemodynamics could influence thrombogenesis in ICAS. The characteristic blood flow stagnancy may activate coagulation factors and form red thrombi inside vessels. In the present case, the thrombus disappeared after the combination therapy of antiplatelet and anticoagulant. A previous study showed the efficacy of anticoagulant therapy for cardiogenic embolisms in patients with intracardiac flow stagnancy.20 Besides, Takeda et al and Yamamoto et al reported the combination therapy, which consisted of anticoagulant (argatroban), antiplatelet (cilostazol), and free radical scavenger (edaravone) improved the prognosis of branch atheromatous disease patient which might harbour less than 50% ICAS.21 22 Taken together, anticoagulant therapy is potentially efficacious as adjunctive management for ICAS associated with intra-arterial stagnant flow.
There have been few studies about CFD analysis conducted on ICAS. Leng et al analysed 85 cases of ICAS in MCA with 50%–99% stenosis using CFD, and reported that higher age and larger pressure differences between prestenotic and poststenotic lesions were independent predictors for good ipsilesional leptomeningeal collateral status.23 Whereas the study focused on cerebral hypoperfusion in ICAS, our CFD study, for the first time as far as we know, analysed the local thrombosis and distal embolisms of ICAS. In the future comprehensive study considering thrombosis, perfusion pressure and collateral vessel networks, the pathology of ICAS would be more precisely figured out. Better understanding of ICAS pathologies could lead to optimisation of medical treatments and improvement of outcomes.
The present study has certain limitations. First, this CFD analysis of the ICAS model was conducted under condition of the Newtonian fluid. Since blood viscosity has a certain role in a domain of low flow velocity, we need to examine this model in the non-Newtonian setting.24 Second, there have been fewer reports about efficacy of additional anticoagulant therapy for ICAS cases, and single or multiple antiplatelet therapy is generally provided for this disease. Therefore, a large-scale study is required to validate the efficacy of the therapy and to investigate the diverse flow dynamics of ICAS, using more specific CFD in the future.
Learning points
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Computational fluid dynamics analysis using the patient-specific model demonstrated stagnant flow and risk of thrombus formation around an intracranial arterial stenosis.
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Wall shear stress and shear rate may be used to diagnose risks of thrombogenesis.
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Anticoagulants may be effective for cases with stagnant flow-induced thrombosis, but further large-scale studies are required to verify the effect of this therapy.
Ethics statements
Patient consent for publication
Ethics approval
This study was conducted in accordance with the guideline and under the approval of the ethics review board of Mie Chuo Medical Center (approval number: MCERB 201820). The requirement for informed consent was waived. Patient records and geometric data were anonymised before the analysis.
Footnotes
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Contributors TK and IF made substantial contributions to the conception and design of the work, acquisition, analysis, interpretation of the data and draft of the work. TS and SH was involved in revising it critically for important intellectual content. All authors approved the final version to be published.
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Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
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Case reports provide a valuable learning resource for the scientific community and can indicate areas of interest for future research. They should not be used in isolation to guide treatment choices or public health policy.
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Competing interests None declared.
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Provenance and peer review Not commissioned; externally peer reviewed.
- © BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.
References
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