Mechanical thrombectomy for large vessel occlusion

Mechanical thrombectomy for large vessel occlusion

In the last years, clinical trial evidence has expanded the time window for successful endovascular treatment to 24 h. Current research is aimed at expanding patient selection to mild strokes, large ischemic cores and occlusions of smaller, more distal blood vessels. Further, Giles et al. developed understanding of how to manage blood pressure after thrombectomy and even had promising results for a neuroprotective agent in these patients. Thrombectomy has transformed the ischemic stroke treatment due to large-vessel occlusion. Recent research has focused on expanding patient candidacy for endovascular treatment and improving medical management to support better neurologic outcomes 1).

Mechanical thrombectomy for large vessel occlusion Indications.

see Mechanical thrombectomy anesthesia

Stent retriever mechanical thrombectomy

Penumbra aspiration. Until the introduction of stent retrievers, the penumbra device boasted the highest recanalization rate. A recanalization rate of > 80% is quoted in literature 2) 3).

This device includes a microcatheter that is advanced over a microwire, through the positioned guide catheter. The tip of the microcatheter is positioned adjacent to the proximal aspect of the clot. A separator is advanced through the microcatheter that is advanced back and forth through the clot to disrupt it. The proximal end of the microcatheter is connected to an aspiration pump that is turned on to aspirate the clot fragments. Unlike stent retrievers that a ect recanalization within minutes, Penumbra aspiration device takes longer, with median time of 49 min 4).

Its use is confined to the straight arterial segments because of risk of vessel perforation by the separator action.


In addition to above, other techniques to extract thrombus have also been employed with mixed results including, aspiration with a simple syringe attached to a microcatheter, usage of snares, angioplasty at site of thrombus, stenting etc…

There is an absence of specific evidence or guideline recommendations on blood pressure management for large vessel occlusion stroke patients. Until randomized data are available, the periprocedural blood pressure management of patients undergoing endovascular thrombectomy can be viewed in two phases relative to the achievement of recanalization. In the hyperacute phase, prior to recanalization, hypotension should be avoided to maintain adequate penumbral perfusion. The American Heart Association guidelines should be followed for the upper end of prethrombectomy blood pressure: ≤185/110 mm Hg, unless post-tissue plasminogen activator administration when the goal is <180/105 mm Hg. After successful recanalization (thrombolysis in cerebral infarction [TICI]: 2b-3), we recommend a target of maximum systolic blood pressure of < 160 mm Hg, while the persistently occluded patients (TICI < 2b) may require more permissive goals up to <180/105 mm Hg. Future research should focus on generating randomized data on optimal blood pressure management both before and after endovascular thrombectomy, to optimize patient outcomes for these divergent clinical scenarios 5).

Mechanical thrombectomy is recommended for selected patients 6–16 hours from onset with large vessel occlusion (LVO) in the anterior circulation who meet other DAWN or DEFUSE-3 eligibility criteria (Level I 6)).

Patients with large vessel occlusion and target mismatch on imaging may be thrombectomy candidates in the extended time window. However, the ability of imaging modalities including non-contrast CT Alberta Stroke Program Early Computed Tomographic Scoring (CT ASPECTS), CT angiography collateral score (CTA-CS), diffusion-weighted MRI ASPECTS (DWI ASPECTS), DWI lesion volume, and DWI volume with clinical deficit (DWI + NIHSS), to identify mismatch is unknown.

We defined target mismatch as core infarct (DWI volume) of < 70 mL, mismatch volume (tissue with TMax > 6 s) of ≥ 15 mL, and mismatch ratio of ≥ 1.8. Using experimental dismantling design, ability to identify this profile was determined for each imaging modality independently (phase 1) and then with knowledge from preceding modalities (phase 2). We used a generalized mixed model assuming binary distribution with PROC GLIMMIX/SAS for analysis.

We identified 32 patients with anterior circulation occlusions, presenting > 6 h from symptom onset, with National Institute of Health Stroke Scale of ≥ 6, who had CT and MR before thrombectomy. Sensitivities for identifying target mismatch increased modestly from 88% for NCCT to 91% with the addition of CTA-CS, and up to 100% for all MR-based modalities. Significant gains in specificity were observed from successive tests (29, 19, and 16% increase for DWI ASPECTS, DWI volume, and DWI + NIHSS, respectively).

The combination of NCCT ASPECTS and CTA-CS has high sensitivity for identifying the target mismatch in the extended time window. However, there are gains in specificity with MRI-based imaging, potentially identifying treatment candidates who may have been excluded based on CT imaging alone 7).

Patients with favorable imaging profiles on both modalities had higher odds of receiving endovascular thrombectomy (EVT) and high functional independence rates. Patients with discordant profiles achieved reasonable functional independence rates, but those with an unfavorable CTP had higher adverse outcomes. Trial registration: ClinicalTrials.gov NCT02446587 8).


The benefit of mechanical thrombectomy (MT) in patients with stroke presenting with mild deficits (National Institutes of Health Stroke Scale [NIHSS] score <6) owing to emergency large-vessel occlusion (ELVO) remains uncertain.

To assess the outcomes of patients with mild-deficits ELVO (mELVO) treated with MT vs best medical management (bMM).

Goyal et al. retrospectively pooled patients with mELVO during a 5-year period from 16 centers. A meta-analysis of studies reporting efficacy and safety outcomes with MT or bMM among patients with mELVO was also conducted. Data were analyzed between 2013 and 2017.

They identified studies that enrolled patients with stroke (within 24 hours of symptom onset) with mELVO treated with MT or bMM.

Efficacy outcomes included 3-month favorable functional outcome and 3-month functional independence that were defined as modified Rankin Scale scores of 0 to 1 and 0 to 2, respectively. Safety outcomes included 3-month mortality and symptomatic and asymptomatic intracranial hemorrhage (ICH).

They evaluated a total of 251 patients with mELVO who were treated with MT (n = 138; 65 women; mean age, 65.2 years; median NIHSS score, 4; interquartile range [IQR], 3-5) or bMM (n = 113; 51 women; mean age, 64.8; median NIHSS score, 3; interquartile range [IQR], 2-4). The rate of asymptomatic ICH was lower in bMM (4.6% vs 17.5%; P = .002), while the rate of 3-month FI (after imputation of missing follow-up evaluations) was lower in MT (77.4% vs 88.5%; P = .02). The 2 groups did not differ in any other efficacy or safety outcomes. In multivariable analyses, MT was associated with higher odds of asymptomatic ICH (odds ratio [OR], 11.07; 95% CI, 1.31-93.53; P = .03). In the meta-analysis of 4 studies (843 patients), MT was associated with higher odds of symptomatic ICH in unadjusted analyses (OR, 5.52; 95% CI, 1.91-15.49; P = .002; I2 = 0%). This association did not retain its significance in adjusted analyses including 2 studies (OR, 2.06; 95% CI, 0.49-8.63; P = .32; I2 = 0%). The meta-analysis did not document any other independent associations between treatment groups and safety or efficacy outcomes.

This multicenter study coupled with the meta-analysis suggests similar outcomes of MT and bMM in patients with stroke with mELVO, but no conclusions about treatment effect can be made. The clinical equipoise can further be resolved by a randomized clinical trial 9).


The treatment of large vessel occlusion (LVO) with mechanical thrombectomy (MT) is feasible and safe. MT is standard of care in treating acute ischemic stroke due to LVO 10).

Mechanical thrombectomy utilizing combined manual aspiration with a stent retriever is an effective and safe strategy for endovascular recanalization of large vessel occlusions presenting within the context of acute ischemic stroke (AIS). 11).

However, when difficult anatomy is encountered in which the reperfusion catheter cannot be positioned well, the outcomes can be less than optimal.

Mechanical thrombectomy case series.

A 45-year-old male had a type A aortic dissection that presented with sudden onset neck pain and cold sweating. Aortic valve resuspension, proximal anastomosis of the ascending aortic graft, partial aortic arch graft replacement, and innominate artery reimplantation was performed. After the aortic surgery, left limb weakness was noted in the intensive care unit. Computed tomography angiography of the brain showed right common carotid artery (CCA) occlusion up to the internal carotid artery (ICA). The right CCA was exposed and directly punctured. A thrombus was successfully removed, and a total of 5 stents were deployed to treat the ICA and CCA dissection. Angiography showed a final TICI 3 result, and the patient had excellent clinically recovery.

Acute mechanical thrombectomy through open direct neck puncture due to an acute type A aortic dissection and concurrent CCA dissection and occlusion is an effective and optimal method 12).


1)

Giles JA, Vellimana AK, Adeoye OM. Endovascular Treatment of Acute Stroke. Curr Neurol Neurosci Rep. 2022 Jan 31. doi: 10.1007/s11910-022-01168-9. Epub ahead of print. PMID: 35098425.
2)

Kulcsar Z, Bonvin C, Pereira VM, Altrichter S, Yilmaz H, Lovblad KO, Sztajzel R, Rufenacht DA. Penumbra system: a novel mechanical thrombectomy device for large-vessel occlusions in acute stroke. AJNR Am J Neuroradiol. 2010; 31:628–633
3)

The penumbra pivotal stroke trial: safety and effectiveness of a new generation of mechanical devices for clot removal in intracranial large vessel occlusive disease. Stroke. 2009; 40:2761–2768
4)

Psychogios MN, Kreusch A, Wasser K, Mohr A, Gro- schel K, Knauth M. Recanalization of large intracra- nial vessels using the penumbra system: a single- center experience. AJNR Am J Neuroradiol. 2012; 33:1488–1493
5)

de Havenon A, Petersen N, Sultan-Qurraie A, Alexander M, Yaghi S, Park M, Grandhi R, Mistry E. Blood Pressure Management Before, During, and After Endovascular Thrombectomy for Acute Ischemic Stroke. Semin Neurol. 2021 Jan 20. doi: 10.1055/s-0040-1722721. Epub ahead of print. PMID: 33472269.
6)

Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the Early Management of Patients With Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke. 2018; 49:e46–e110
7)

DiBiasio EL, Jayaraman MV, Goyal M, Yaghi S, Tung E, Hidlay DT, Tung GA, Baird GL, McTaggart RA. Dismantling the ability of CT and MRI to identify the target mismatch profile in patients with anterior circulation large vessel occlusion beyond six hours from symptom onset. Emerg Radiol. 2019 Mar 31. doi: 10.1007/s10140-019-01686-z. [Epub ahead of print] PubMed PMID: 30929145.
8)

Sarraj A, Hassan AE, Grotta J, Sitton C, Cutter G, Cai C, Chen PR, Imam B, Pujara D, Arora A, Reddy S, Parsha K, Riascos RF, Vora N, Abraham M, Edgell R, Hellinger F, Haussen DC, Blackburn S, Kamal H, Barreto AD, Martin-Schild S, Lansberg M, Gupta R, Savitz S, Albers GW. Optimizing Patient Selection for Endovascular Treatment in Acute Ischemic Stroke (SELECT): A Prospective, Multicenter Cohort Study of Imaging Selection. Ann Neurol. 2020 Mar;87(3):419-433. doi: 10.1002/ana.25669. Epub 2020 Jan 21. Erratum in: Ann Neurol. 2020 Nov;88(5):1056-1057. PMID: 31916270.
9)

Goyal N, Tsivgoulis G, Malhotra K, Ishfaq MF, Pandhi A, Frohler MT, Spiotta AM, Anadani M, Psychogios M, Maus V, Siddiqui A, Waqas M, Schellinger PD, Groen M, Krogias C, Richter D, Saqqur M, Garcia-Bermejo P, Mokin M, Leker R, Cohen JE, Katsanos AH, Magoufis G, Psychogios K, Lioutas V, VanNostrand M, Sharma VK, Paciaroni M, Rentzos A, Shoirah H, Mocco J, Nickele C, Inoa V, Hoit D, Elijovich L, Alexandrov AV, Arthur AS. Medical Management vs Mechanical Thrombectomy for Mild Strokes: An International Multicenter Study and Systematic Review and Meta-analysis. JAMA Neurol. 2019 Sep 23. doi: 10.1001/jamaneurol.2019.3112. [Epub ahead of print] PubMed PMID: 31545353.
10)

Samaniego EA, Roa JA, Limaye K, Adams HP Jr. Mechanical Thrombectomy: Emerging Technologies and Techniques. J Stroke Cerebrovasc Dis. 2018 Jun 27. pii: S1052-3057(18)30265-9. doi: 10.1016/j.jstrokecerebrovasdis.2018.05.025. [Epub ahead of print] Review. PubMed PMID: 29960666.
11)

Humphries W, Hoit D, Doss VT, Elijovich L, Frei D, Loy D, Dooley G, Turk AS, Chaudry I, Turner R, Mocco J, Morone P, Fiorella DA, Siddiqui A, Mokin M, Arthur AS. Distal aspiration with retrievable stent assisted thrombectomy for the treatment of acute ischemic stroke. J Neurointerv Surg. 2014 Jan 24. doi: 10.1136/neurintsurg-2013-010986. [Epub ahead of print] PubMed PMID: 24463439.
12)

Lin CM, Chang CH, Chen SW, Huang YH, Yi-Chou Wang A, Chen CC. Direct Neck Exposure for Rescue Endovascular Mechanical Thrombectomy in a Patient with Acute Common Carotid Occlusion Concurrent with Type A Aortic Dissection. World Neurosurg. 2019 Jan 28. pii: S1878-8750(19)30179-2. doi: 10.1016/j.wneu.2019.01.081. [Epub ahead of print] PubMed PMID: 30703603.

Artery of Percheron occlusion

Artery of Percheron occlusion

One uncommon type of ischemic stroke is occlusion of the artery of Percheron (AOP) leading to infarction of the paramedian thalami and mesencephalon.

Artery of Percheron (AOP) occlusion is a rare cause of ischemic stroke characterized by bilateral para-median thalamic infarcts. It usually presents with altered mental status, hyper-somnolence, and ocular movement disorders with associated hemiplegia or hemisensory loss.

There are several variants of thalamic blood supply, and identifying the potential presence and infarction of an AOP is important in the diagnosis and treatment of ischemic strokes affecting the thalami and mesencephalon, especially because of the unusual and variable presentation of these forms of ischemic strokes.


An elderly patient was found unconscious at home. CT of the head without contrast was unremarkable, while CT angiography of the head and neck revealed a subocclusive thrombus on the pre communicating (P1) segment of the left posterior cerebral artery (PCA). MRI brain revealed bilateral regions of diffusion restriction in the paramedian thalami and bilateral medial mesencephalon. Initial angiography confirmed the presence of a subocclusive thrombus in the P1 segment of the left PCA. Thrombectomy was performed achieving recanalization of the left PCA and reperfusion of bilateral thalami via a visualized artery of Percheron. Postoperatively, the patient was kept on a daily dose of 325 mg of aspirin. The patient did not improve neurologically. A follow-up MRI brain showed diffusion restriction in the left occipital lobe and petechial hemorrhages in the bilateral thalami. The family eventually opted for palliative measures, and the patient expired on day 14 of admission due to acute respiratory failure from palliative extubating 1).


A 58-year-old woman with an AOP infarct and indicates the importance of recognizing an AOP infarct early despite its clinical variations in order to treat the stroke in a timely fashion. This short review also includes a discussion of imaging modalities in such cases and clinical differential diagnoses to consider with management strategies 2).


A case of cardio-embolic AOP infarction in a 72-year-old man with sepsis and new-onset atrial fibrillation. Early diagnosis is challenging, but diffuse-weighted magnetic resonance imaging demonstrates the lesion in the acute setting. Anticoagulation therapy was started and patient’s mental status gradually improved 3).


1)

Elsayed S, Al Balushi A, Schupper A, Shoirah H. Artery of Percheron occlusion with first-pass recanalisation of the first segment of posterior cerebral artery. BMJ Case Rep. 2021 Apr 21;14(4):e237968. doi: 10.1136/bcr-2020-237968. PMID: 33883107.
2)

Kichloo A, Jamal SM, Zain EA, Wani F, Vipparala N. Artery of Percheron Infarction: A Short Review. J Investig Med High Impact Case Rep. 2019 Jan-Dec;7:2324709619867355. doi: 10.1177/2324709619867355. PMID: 31394937; PMCID: PMC6689919.
3)

Goico A, Mikesell T. Artery of Percheron infarction: a rare cause of somnolence in a patient with sepsis and atrial fibrillation. Oxf Med Case Reports. 2018 Jul 5;2018(7):omy032. doi: 10.1093/omcr/omy032. PMID: 30740230; PMCID: PMC6363084.

Middle cerebral artery occlusion

Middle cerebral artery occlusion

Middle cerebral artery stenosis may lead to a middle cerebral artery stroke via three mechanisms:

(1) deep lacunar infarcts that develop when the exiting branch of the lenticulostriate artery is trapped within the thromboatheroma

(2) development of atheromatous ulceration with thrombosis and subsequent distal embolization

(3) hemispheric hypoperfusion caused by significant MCA obstruction and inadequate collateralization

Clinical

Complications

see Malignant middle cerebral artery territory infarction.


In these patients the clinical presentation usually starts with focal signs and progresses with a decline of consciousness until brainstem dysfunction is evident.

A shift of the ischemic tissue rather than intracranial hypertension is the most likely responsible for the initial decrease in consciousness 1) 2).

Several other satellite reactions are involved in an inexorable pathogenetic cascade, including disturbances of microvascular tone, endothelial cell swelling, and activation of platelets, leucocytes, and coagulation 3).

Diagnosis

Imaging studies are the mainstay for identification of people at higher risk for malignant infarction among the ischemic stroke population.

Perfusion computed tomography

Perfusion computed tomography of the brain is routinely performed for first and later controls. The earliest warning signs for developing malignant infarction include involvement of an area larger than 50% of the MCA territory and an infarct extending also to the anterior or posterior cerebral artery territories. A midline shift >10 mm, effacement of subarachnoid spaces, and attenuation of corticomedullary differentiation are also related to higher risk of severe deterioration 4), but they usually occur later, when a malignant syndrome is already in progress. The intravenous injection of contrast medium with elaboration of its distribution (perfusion-CT) entails higher diagnostic accuracy of ischemic areas and an even earlier detection of patients at higher risk. A drop in cerebral perfusion of more 66% is related to a likely malignant evolution 5).

Magnetic resonance imaging

Magnetic resonance imaging is another helpful exam, which in ischemic stroke can be used for prognostic purposes within few hours of clinical onset. Its sensitivity is higher than CT and it is more likely to show changes at earlier time points than CT scan. On diffusion weighted images (DWI) an ischemic area of at least 145 mL strongly predicts a massive cerebral infarction 6) 7).

It is straightforward that at final stages the pressure inside the skull of patients with large cerebral infarction is probably high. Anyway, a pressure increase limited to the infarcted and immediately adjacent areas could happen, leading to neurological worsening and even death despite no spread of intracranial hypertension 8).

Undisputed poor prognosis predictors as CT uncal herniation and anisocoria sometimes occur without an overall ICP raise is detected 9).

The measurement may also be influenced by the device used (solid-state or fluid-filled) as well as by its location (subdural, intraparenchymal, intraventricular; ipsilateral or contralateral to ischemia) 10).

Treatment

see Middle cerebral artery occlusion treatment.

Outcome

Malignant evolution is more common in younger patients 11).

Despite optimal medical management this condition may lead to death in 70–80% of cases 12) 13).

The criteria for surgical indication mean a selection of patients who likely will have less postoperative disabilities. Living with a severe neurological impairment may appear more acceptable in some cultures, and inhumane in others. A recent review anyway concluded that the vast majority of operated patients do not regret having undergone surgery 14).

The natural history of middle cerebral artery occlusion MCA occlusion has become increasingly important since the surgical option of EC/IC bypass surgery has been available.

The clinical course of 24 patients with angiographically-demonstrated occlusion of the MCA artery was reviewed. Eight patients presented with a major disabling stroke and five of these died during the acute phase of this ischemic event. The remaining 19 patients were followed for a mean of 54.2 months. There were five deaths in follow-up and two of these were due to subsequent strokes. Fourteen patients manifested a benign course: one of these had a further minor stroke and four had TIAs. Altogether, 3 strokes occurred during the follow-up period (2 fatal, 1 minor) and all were in the territory of the artery known to be occluded. Of those patients who survived their presenting ischemic event, 12 (63%) remained completely functional in terms of activities of daily living. MCA occlusion does not necessarily carry a poor prognosis with medial therapy alone and the role of bypass surgery hopefully will be clarified by the ongoing clinically randomized trial 15).

Case series

Encephaloduroarteriosynangiosis (EDAS) as a form of indirect revascularization has been recently proposed as a potentially promising alternative for patients with intracranial atherosclerotic disease (ICAD). The object of a study was to compare the prognostic roles between isolated EDAS and medical therapy in patients with atherosclerotic middle cerebral artery occlusion (MCAO).

From January 2014 to June 2017, 125 patients with atherosclerotic MCAO were enrolled in this prospective nonrandomized controlled cohort study. Patients who underwent EDAS (n = 60) were compared with those treated medically (n = 65). Early and late adverse events and functional outcomes including memory ability were compared between groups.

During 23.7 months of mean follow-up, rates of adverse events, including ischemic events in the territory of the qualifying middle cerebral artery (MCA), and death from any causes, were not significantly different in patients treated with EDAS and with medical therapy (6.7% vs. 12.3%; p=0.285). Landmark analyses revealed that at initial 6-month follow-up, there was no significant difference for adverse event rates, while the opposite finding was demonstrated for the subsequent period (EDAS 1/57 [1.7%] vs. medical management 7/64 [10.9%]; p=0.024). And the P value for the interaction between time (first 6 months vs. subsequent period) was 0.044. No significant differences were found with the respect to neural function status and cognitive ability.

In the long-term, isolated EDAS can be considered effective and safe for patients with atherosclerotic MCAO, whereas it may need additional medical therapy support in the short-term 16).

Case reports

A 69-year-old with right hemiparesis and global aphasia. Perfusion computed tomography imaging revealed ischemic penumbra in the middle cerebral artery territory. Angiography showed left middle cerebral artery occlusion. Mechanical thrombectomy with one pass was performed, and successful recanalization was obtained. Embolic material was retrieved; it contained tumor fragments with atypical keratinizing squamous cell carcinoma. Contrast computed tomography imaging indicated tumor invasion into the superior vena cava, and contrast transcranial Doppler indicated the presence of a right-to-left shunt after the Valsalva maneuver. They diagnosed the patient with acute ischemic stroke of large vessel occlusion due to venous invasion of esophageal carcinoma via a right-to-left shunt. This is the first case of embolic occlusion resulting from an extracardiac tumor via a right-to-left shunt. Contrast transcranial Doppler potentially detects right-to-left shunts in patients who cannot undergo transesophageal echocardiography 17).

References

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Kasner SE, Demchuk AM, Berrouschot J, et al. Predictors of fatal brain edema in massive hemispheric ischemic stroke. Stroke. 2001;32(9):2117–2123.
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Poca MA, Benejam B, Sahuquillo J, et al. Monitoring intracranial pressure in patients with malignant middle cerebral artery infarction: is it useful? Journal of Neurosurgery. 2010;112(3):648–657.
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Carhuapoma JR, Qureshi AI, Bhardwaj A, Williams MA. Interhemispheric intracranial pressure gradients in massive cerebral infarction. Journal of Neurosurgical Anesthesiology. 2002;14(4):299–303.
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Wijdicks EFM, Diringer MN. Middle cerebral artery territory infarction and early brain swelling: progression and effect of age on outcome. Mayo Clinic Proceedings. 1998;73(9):829–836.
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Rahme R, Zuccarello M, Kleindorfer D, et al. Decompressive hemicraniectomy for malignant middle cerebral artery territory infarction: is lifeworth living? Journal of Neurosurgery. 2012;117(4):749–754.
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Moulin DE, Lo R, Chiang J, Barnett HJ. Prognosis in middle cerebral artery occlusion. Stroke. 1985 Mar-Apr;16(2):282-4. PubMed PMID: 3975967.
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Zhang Q, Li Y, Tong H, Wu X, Wang Y, Ge W, He C, Liu R, Yu S. Comparison of therapeutic efficacy between isolated encephaloduroarteriosynangiosis and medical treatment in patients with atherosclerotic middle cerebral artery occlusion. World Neurosurg. 2018 Jun 20. pii: S1878-8750(18)31272-5. doi: 10.1016/j.wneu.2018.06.057. [Epub ahead of print] PubMed PMID: 29935318.
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Araki S, Maekawa K, Kobayashi K, Sano T, Yabana T, Shibata M, Miya F. Tumor Embolism Through Right-to-Left Shunt Due to Venous Invasion of Esophageal Carcinoma. J Stroke Cerebrovasc Dis. 2020 Sep 30;29(12):105352. doi: 10.1016/j.jstrokecerebrovasdis.2020.105352. Epub ahead of print. PMID: 33010722.
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