Accepted Manuscript Acute Recanalization of a Partially Thrombosed Large Intracranial Aneurysm E. Atallah, MD, E. Valle-Giler, MD, T. Elarjani, MD, N. Chalouhi, MD, S. Tjoumakaris, MD, R.H. Rosenwasser, MD, N. Herial, MD, M.R. Gooch, MD, H. Zarzour, MD, P. Jabbour, MD. PII: S1878-8750(18)30742-3 DOI: 10.1016/j.wneu.2018.04.026 Reference: WNEU 7862 To appear in: World Neurosurgery Received Date: 6 March 2018 Revised Date: 3 April 2018 Accepted Date: 4 April 2018 Please cite this article as: Atallah E, Valle-Giler E, Elarjani T, Chalouhi N, Tjoumakaris S, Rosenwasser R, Herial N, Gooch M, Zarzour H, Jabbour P, Acute Recanalization of a Partially Thrombosed Large Intracranial Aneurysm, World Neurosurgery (2018), doi: 10.1016/j.wneu.2018.04.026. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1 ACCEPTED MANUSCRIPT Acute Recanalization of a Partially Thrombosed Large Intracranial Aneurysm Atallah E. MD, Valle-Giler E, MD, Elarjani T, MD, Chalouhi N, MD, Tjoumakaris S, P, MD. 1 RI PT MD, Rosenwasser RH, MD, Herial N, MD, Gooch MR, MD, Zarzour H, MD, Jabbour SC Department of Neurological Surgery, Thomas Jefferson University Hospitals and Jefferson Hospital for Neurosciences, Philadelphia, PA 2 Department of Neurological Surgery, University of Washington, Seattle, Washington 3 Department of Neurological Surgery, Ochsner Medical Center, New Orleans, LA Corresponding author: M AN U - Pascal Jabbour, MD, Professor and Director Division of Neurovascular Surgery and Endovascular Neurosurgery, Department of Neurological Surgery, Thomas Jefferson University Hospital, 901 Walnut street 3rd Floor, Philadelphia PA 19107, T:2159557000 F:2155037038 Email:pascal.jabbour@jefferson.edu EP TE D - Elias Atallah, MD:1 elias.atallah@jefferson.edu - Turki Elarjani, MD:2 telarjani@gmail.com - Edison Valle-Giler, MD:3 ediosnpvalle@gmail.com - Chalouhi Nohra, MD:1 nohra.chalouhi@jefferson.edu - Nabeel Herial, MD PhD:1 nabeel.Herial@jefferson.edu - Michael Reid Gooch, MD:1 reid.Gooch@Jefferson.edu - Stavropoula Tjoumakaris, MD:1 stavropoula.tjoumakaris@jefferson.edu - Robert H. Rosenwasser, MD:1 robert.rosenwasser@jefferson.edu - Hekmat Zarzour, MD:1 hekmat.zarzour@Jefferson.edu AC C Word Count: 1089 Acknowledgements: None Statement: the manuscript has not been previously published in whole or in part or submitted elsewhere for review. Ethical approval: All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. Disclosure: Dr. Jabbour is a consultant for Medtronic; Dr. Tjoumakaris is a consultant for Stryker. The other authors have no personal financial or institutional interest in any of the drugs, materials, or devices described in this article. Funding: None 2 ACCEPTED MANUSCRIPT I- Abstract Background: Thrombosed large intracranial aneurysms(TLIAs) are not continuously contemplated as stable lesions. Completely occluded large IAs’ spontaneous RI PT recanalization has been previously described. Case description: We report the case of a middle-aged patient presenting with agitation, acute headache, visual field defects and left hemiparesis. A large thrombosed Posterior Communicating (PCom) artery aneurysm was identified with an SC infarct at the same arterial territory on neuroimaging studies. Digital Subtraction Angiography(DSA), one week later, demonstrated complete recanalization of the TLIA. It was treated endovascularly with coils. Patient returns several days later with headaches explained by quadrigeminal M AN U augmenting system sub-arachnoid hemorrhage(SAH). Repeat DSA showed filling of the coiled aneurysm from the Internal Carotid Artery(ICA) injection. PCom was catheterized and deconstructed. Patient was discharged home with no additional neurological deficits. Conclusions: TLIAs are insidious vascular lesions. They can cause nerve or vessel TE D damage by mass effect only or ischemic stroke by emitting emboli into distal vasculature. We advise close and periodic radiological follow-up for TLIAs. Keywords: Large Aneurysm; Thrombosed Aneurysm Spontaneous Recanalization. AC C Aneurysm EP Running Head: Spontaneous Recanalization of Large Thrombosed Intracranial II- Introduction The natural history of large and giant Intracranial Aneurysms(IA) is illustrated by a sequence of thrombosis, growth and rupture. The incidence of spontaneous thrombosis, partial or complete, of IAs varies depending on its location, size and origin.3 The five-year cumulative rupture rates for patients with anterior circulation 3 ACCEPTED MANUSCRIPT large IAs is 40% and 50% for those in the posterior circulation. Although spontaneous thrombosis of large aneurysms(LA) is very common, complete thrombosis is uncommon, and usually spares the parent vessel. Minimally invasive endovascular detachable coils have been widely used in the embolization of IAs. Nonetheless, longterm recanalization rate of completely occluded aneurysms has been reported between RI PT 20-40%.1,2 Volume-to-neck ratio, peri-aneurysmal hemodynamics, the packing density of embolic material and the degree of LA occlusion, have all been reported as possible predictors of TLIA recanalization.4 SC We present a patient with an acute recanalization of a LA and emphasize on the pathophysiology, risk factors and management of the thrombosed aneurysm located in the posterior circulation; as it can re-canalize, create new thromboembolic Case Report TE D III- M AN U events, and potentially rupture within days of being diagnosed. We discuss the case of a middle-aged patient presenting to our service with agitation, sudden headache, visual field deficits and left hemiparesis. On admission, a Computed Tomography(CT) Scan showed a large partially thrombosed right P1-P2 EP artery aneurysm. A cerebral DSA showed an insignificant filling of the 15x18mm PCom vs P2 artery aneurysm from both the right ICA and left vertebral injections. AC C (Figure.1-2) The patient was taken back to the intensive care unit and was appropriately resuscitated. During his stay, the patient started complaining of visualfield cuts. A brain MRI revealed a contemporary infarction involving a large amount of the expected territory of the right PCA without hemorrhagic conversion and redemonstrated the thrombosed aneurysm. (Figure.3) The patient was kept in the hospital for close supervision to repeat a DSA one week later. The repeat DSA showed a complete recanalization of the aneurysm.(Figure.4) The patient underwent multiple attempts of pipeline embolization device placement, but the outflow of the aneurysm could not be catheterized. The aneurysm was coiled and the PCA inflow was deconstructed. (Figure.5) 4 ACCEPTED MANUSCRIPT The patient was discharged on POD-1, but came back after experiencing worsening headaches over the following 3days. Head CTscans showed perimesencephalic sub-arachnoid hemorrhage(SAH), with left homonymous hemianopsia. (Figure.6) Repeat DSA showed filling of the aneurysm from the right- RI PT ICA.(Figure.6) The PComA was catheterized and deconstructed as well after temporary balloon occlusion to prevent any flow into the aneurysm. No flow was documented from both, anterior and posterior circulations. (Figure.7) The patient was discharged the next day at baseline with a corticosteroid taper to manage the local Discussion M AN U SC peri-aneurysmal edema & inflammation. Large brain aneurysms are commonly identified when they compress a nearby structure and manifest with symptoms of mass effect or when they rupture and TE D subsequently cause a SAH. 3 4 IAs’ spontaneous thrombosis is a well-documented occurrence in the natural history of LAs. It is regarded as an arterial defense mechanism against an impending risk of rupture and subsequent neurologic deterioration. 5 The partially or completely EP TLIAs should be addressed as unstable lesions. LAs are more prone to grow, compress, recanalize or rupture; nevertheless, thrombosis and recanalization of a AC C minority of non-LA has also been described. 6 a- Factors Leading to Large Aneurysm Thrombosis Numerous factors that would influence the occurrence of spontaneous IA thrombus include aneurysm volume-to-neck ratio, relatively small aneurysm neck 7-11, hemodynamic alterations in the parent vessel -such as parent vessel spasm 12, aneurysm age, endothelial injury, and the compression of the parent vessel by the aneurysm. 7,11,13 The angiographic procedure itself with contrast media stasis delivered during angiography has been also linked to spontaneous IA thrombosis. 14 5 ACCEPTED MANUSCRIPT Spontaneous aneurysmal thrombosis cannot be constantly addressed as a safe phenomenon. Whether it was large, giant or not, the natural history of an aneurysm is a dynamic process thought to be governed by delicate balance between thrombogenesis and thrombolysis. Aneurysm thrombosis should be taken carefully RI PT into consideration when discussing LA therapeutic management. b- Large Aneurysm Growth and Recanalization: Contributing Features Factors influencing thrombus growth as -thrombus formation, repetitive intramural hemorrhage, development and evolution of an intra-thrombotic capillary et al.16, portrayed the dynamically changing SC networks, and hemorrhage within the aneurysm- have been described before.8,15 Yasui feature of a thrombosed saccular M AN U aneurysm, they discussed the necessity of recurrent hemorrhage happening at the periphery of the thrombosed portion of the aneurysm that may be instigated by neovascular growth in the aneurysmal wall. They confirmed that the presence of intrathrombotic vascular channels is not essential for the growth of giant thrombosed saccular aneurysm, instead, forces in the distal neck may be sufficient to promote TE D dissection between the old thrombus and the inner wall and introduction of fresh blood. Associated with thrombus growth, is the risk of ischemic stroke, mainly due to stretching or compression of the parent vessel by the growing thrombosed aneurysm15. Usually, conventional angiography may miss or underestimate the size of EP a partially thrombosed aneurysm, hence, performing CT Angiography and/or MRI/MR Angiography neuroimaging -as we did in our patient diagnostic and AC C management protocol- is more sensitive in measuring the volume of partially thrombosed aneurysm. Numagami et al.17 described a similar pathological explanation for the recanalization of an outpouching unclippable intracranial ICA giant aneurysms presenting with mass effect and treated with parent vessel occlusion; they projected 2 apparatuses for recanalization: either via neovascularization within the thrombus or via the dilation of vasa vasorum -where the change in hemodynamics after the occlusion promotes the development of collaterals-. Similarly, Sawada et al.200518 advised that the occlusion of the parent artery may not result in permanent exclusion of the aneurysm from the systemic circulation for postoperative intra-thrombic 6 ACCEPTED MANUSCRIPT rebleeding may occur after proximal parent vessel occlusion. They discussed the prominence of a careful angiographic follow-up of dissecting vertebro-basilar aneurysms even in patients successfully treated with endovascular occlusion of the affected artery and aneurysm. RI PT Additional fundamental analysis reported the participation of molecular proinflammatory enzymes such as Matrix Metalloproteinase-9 (MMP-9) –usually expressed in smooth muscle cells, endothelial cells, and monocytes- in the degradation of collagen at the bordering vascular basement membrane, hence participating not only to the aneurysm formation but to its post-thrombus Bouzeghrane et al.19, noted that aneurysms with low MMP-9 SC repermeabilization.19 messenger Ribo-Nucleic Acid expression are at low risk of recanalization. In fact, the M AN U “endovascular endothelial denudation” prior to aneurysm coiling has been shown to reduce the chances of recanalization, mostly due to removal of endothelial cells that releases MMP-9 after coil deployment. 19,20 Additionally, a study conducted by Luo et al.21 demonstrated that high blood velocity and both high and low wall shear stress play an integral role in aneurysm recanalization, growth and rupture. Aneurysm exclusion through endovascular procedures is highly related to vessel neointima TE D formation and intra-aneurismal thrombosis via coiling and stenting .22 High wall shear stress and high flow velocity at the residual –incompletely coiled- aneurysm’s neck, interrupt the normal coagulation and thrombosis by prompting endothelial EP remodeling, internal elastic lamina degradation, interruption of the natural healing process of the thrombosed aneurysm with subsequent recanalization and growth. On the other hand, in a study of Liu et al.2016, low WSS was correlated with a AC C 12,22,23 significantly higher aneurysm rupture rate: after recanalization, the consequently reduced WSS due to wall remodeling and enlarged aneurysm diameter, leads to endothelial inflammation and apoptosis, and ultimately to the dysfunctional aneurysm’s wall ruptures.21 Furthermore, Grunwald et al.24 prospected the risks of endovascular therapy, of aneurysm recanalization, regrowth and the need for reembolization. They questioned the stability of the occlusion following treatment with detachable coils and the efficacy in providing protection against growth or regrowth of the aneurysm. They noticed a 19.5% recanalization rate in those who underwent initial total occlusion by coiling versus 40% in those who had 80-95% occlusion and confirmed that initial aneurysm occlusion rate or “subtotal initial 7 ACCEPTED MANUSCRIPT coiling” -as they recite it- would modify the intra-aneurysmal hemodynamic forces, hence promoting the growth and even rupture of treated aneurysms, and should be a deciding factor for anticipating recanalization and recurrence. Moreover, Jeon et al. 25 displayed a list of significant additional factors that would participate in late recanalization of coiled giant aneurysms. They concluded that >90% of coiled RI PT aneurysms showing complete occlusion at 6months follow-up are stable; whereas, aneurysms >7mm and bifurcation aneurysms were predisposed to late recanalization. They portrayed an annual rate of late recanalization of 2.37% in un-ruptured versus 6.97% in ruptured IAs; closing henceforth that patients presenting with SAH, are at a SC more prominent risk of recanalization 25. Moreover, with the surfacing PFD devices, the risk of giant aneurysms recanalization and risk of rupture is reduced to its M AN U minimum when deployed alone or when assisted with coiling. c- Implications of Neuroimaging in the Management of Thrombosed Giant Aneurysms MRI/MRA or CT/CTA are fundamental disposable imaging in the diagnosis TE D of TLIAs. The presence of peripheral calcifications with a “target sign” on CT or the detection of an “onion-skin sign” in a pre-contrast MRI with different layers EP intensities suggest the presence of an intraluminal IA thrombus. 26 AC C Conclusion TLIAs are unpredictable lesions, they can precipitate an ischemic stroke via exerting mass effect on the parent vessel or by showering distal emboli. They can recanalize quickly, grow and rupture causing mainly a SAH. We propose a close periodic neuroimaging follow-up of spontaneously TLIAs or non-LIAs. Management plans should be individualized based on clinical and imaging deductions. 8 ACCEPTED MANUSCRIPT References 1. RI PT 2. Cohen JE RG, Umansky F, Spektor S. Thrombosis and recanali- zation of symptomatic nongiant saccular aneurysm. Neurol Res. 2003;25(8):857-859. Whittle IR DN, Besser M. Spontaneous thrombosis in giant intracranial aneurysms. J Neurol Neurosurg Psychiatry. 1982;45(11):1040-1047. Lonjon M, Pennes F, Sedat J, Bataille B. Epidemiology, genetic, natural history and clinical presentation of giant cerebral aneurysms. Neurochirurgie. 2015;61(6):361-365. Juvela S PM, Poussa K. . Natural history of unruptured intracranial aneurysms: probability of and risk factors for aneurysm rupture. J Neurosurg. 2000;93(3):379-387. Chang SD MM, Steinberg GK. 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Figure Legend: Figure.1 (a) Non-Contrast Computed Tomography Imaging, at patient admission, showing a central and rounded hyperdensity (yellow arrow) corresponding to the thrombosed right Posterior Communicating Artery Aneurysm, (b) Digital Subtraction Angiogram (DSA) with normal appearing posterior cerebral circulation 10 ACCEPTED MANUSCRIPT Figure.2 Internal Carotid Artery Digital Subtraction Angiogram (DSA) demonstrating minimal delayed filling (yellow arrow) of the Posterior Communicating Artery (PCom) Aneurym RI PT Figure.3 Diffusion Weighted Imaging Magnetic Resonnence Imaging of the Brain, done after the patient started complainig of visual field cuts, demonstrating a hyperintensity (yellow arrow) at the territory of the Posterior Cerebral Artery and showing the corresponding adjacent thrombosed Posterior Communicating SC Artery (PCom) Aneurysm. Figure.4 a. Internal Carotid Artery Angiogram, one week after the patient’s M AN U Posterior Cerebral Artery territory infarct, demonstrating a complete recanalization (yellow arrow) of the previously thrombosed Posterior Communicating Artery (PCom) Aneurysm, b.c. Right vertebral artery Digital Subtraction Angiogram (DSA) demonstrating the significant filling of the re- TE D canalized PCom aneurysm (yellow arrow). Figure.5 a.b. Left vertebral artery Digital Subtraction Angiogram (DSA) showing the coiled (yellow arrow) Posterior Communicating Artery (PCom) Aneurysm EP after Posterior Cerebral Artery (PCA) inflow deconstruction. Figure.6 (a) Non Contrast Computed Tomography (CT) Scan demonstrating a AC C quadrigeminal system Sub Arachnoid Hemorrhage (SAH) (yellow arrow) three days after Posterior Communicating Artery Aneurysm coiling and Posterior Cerebral Artery inflow deconstruction. (b) Digital Subtraction Angiogram (DSA) with an Internal Carotid Artery catheterization demonstrating the recurrence (red arrow) of the previously coiled aneurysm with loss of protection of the aneurysm dome. Figure.7 Internal Carotid Artery Digital Subtraction Angiogram(DSA) demonstrating the complete isolation of the coiled Posterior Communicating (PCom) Artery Aneruysm with no additional filling (yellow arrow) from the 11 ACCEPTED MANUSCRIPT PCom after its deconstruction subsequent to the newest quadrigeminal Sub AC C EP TE D M AN U SC RI PT Arachnoid Hemorrhage(SAH). AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT AC C EP TE D M AN U SC RI PT ACCEPTED MANUSCRIPT ACCEPTED MANUSCRIPT Highlights: -Spontaneous aneurysmal thrombosis cannot be constantly addressed as a safe phenomenon. -Aneurysm thrombosis should be taken carefully into consideration when discussing large RI PT aneurysm therapeutic management. -Thrombosed large intracranial aneurysms are unpredictable lesions, they can precipitate an ischemic stroke via exerting mass effect on the parent vessel or by showering distal emboli. AC C EP TE D M AN U SC -Management plans should be individualized based on clinical and imaging deductions. ACCEPTED MANUSCRIPT Abbreviations: TLIA: Thrombosed Large Intracranial Aneurysm RI PT IA: Intracranial Aneurysm LA: Large Aneurysms DSA: Digital Subtracted Angiography SC SAH: Sub-arachnoide Hemorrhage ICA: Internal Carotid Artery MRI: Magnetic Resonance Imaging AC C EP TE D MMP-9: Matrix Metalloproteinase-9 M AN U CT: Computed Tomography