DOI: 10.33962/roneuro-2021-075 The complementary multimodal treatment of recalcitrant cerebral aneurysms. Two centres experience Mohamed Adel Deniwar, Mohamed Kassem, Ashraf Ezzeldin, Jafar J. Jafar Romanian Neurosurgery (2021) XXXV (4): pp. 452-456 DOI: 10.33962/roneuro-2021-076 www.journals.lapub.co.uk/index.php/roneurosurgery The complementary multimodal treatment of recalcitrant cerebral aneurysms. Two centres experience Mohamed Adel Deniwar1, Mohamed Kassem1, Ashraf Ezzeldin1, Jafar J. Jafar2 1 Mansoura University, Faculty of Medicine, EGYPT 2 Langone Medical Center, New York University, USA ABSTRACT Background: The main treatment of cerebral aneurysms is the direct surgical clipping or endovascular coil embolization. However, some cerebral aneurysms that we reviewed in the literature are still not susceptible to a single treatment approach. These aneurysms can be referred to as complex aneurysms. Objective: We aim to report these aneurysms and share our clinical experience with their treatment and diagnosis. Methods: All cases of cerebral aneurysms treated in New York University and in Mansoura University from 2010-2021 were retrospectively reviewed. Results: 18 patients with 21 cerebral aneurysms were treated by combined surgical and endovascular modalities. Aneurysms associated with arteriovenous malformations (AVMs) in 3 patients, associated with vasospasm in 7 patients, and 3 patients had double aneurysms. A total of 18 patients with aneurysms were treated with combined endovascular and microsurgical therapy. Early angiogram (< 1 week) reveled; complete obliteration of 19 aneurysms (90%) out of total 21 aneurysms, residual filling was observed in 2 aneurysms (10%). Late radiological follow up (> 3 months- 2 years) reveled; a stable residual filling in one and the other case underwent retreatment. Conclusions: The recalcitrant or complex cerebral aneurysms can be better referred to as diseases rather than lesions as many clinical and anatomical factors make their treatment difficult. Endovascular and microsurgery could be complementary to each other and create a multimodal approach for treating them. BACKGROUND Direct surgical clipping or endovascular coil embolization is the most common treatment for cerebral aneurysms. (4) Despite significant advancements in microsurgical techniques and equipment, as well as endovascular devices in a parallel direction, some brain aneurysms that we evaluated in the literature are still not susceptible to a single treatment approach. These aneurysms can be referred to as recalcitrant or complex aneurysms. (6,8,10-12,21) We aim to report these challenging aneurysms and share our clinical experience with their treatment and diagnosis. Keywords complex aneurysms, cerebral, multimodal, complementary treatment Corresponding author: Mohamed Adel Deniwar Mansoura University, Faculty of Medicine, Egypt mohameddeniwar@mans.edu.eg Copyright and usage. This is an Open Access article, distributed under the terms of the Creative Commons Attribution Non–Commercial No Derivatives License (https://creativecommons .org/licenses/by-nc-nd/4.0/) which permits non- commercial re-use, distribution, and reproduction in any medium, provided the original work is unaltered and is properly cited. The written permission of the Romanian Society of Neurosurgery must be obtained for commercial re-use or in order to create a derivative work. ISSN online 2344-4959 © Romanian Society of Neurosurgery First published October 2021 by London Academic Publishing www.lapub.co.uk http://www.lapub.co.uk/ 453 The complementary multimodal treatment of recalcitrant cerebral aneurysms METHODOLOGY After IRB approval for both New York University and Mansoura University, all cases of cerebral aneurysms treated in New York University and in Mansoura University from 2010-2021 were retrospectively reviewed. Inclusion criteria Patients proved radiological (CT or MR Angiogram or digital subtraction angiography) to harbor cerebral aneurysms that was treated by both endovascular and open surgery with any of the following criteria: 1. Ruptured or unruptured 2. Single or multiple 3. Giant and/or widely necked aneurysms 4. With or without AVMs 5. With or without vasospasm 6. Compressing or involving origin of adjacent arteries. 7. Aneurysms were primary managed with surgery or endovascular embolization and showed residual or recurrence on follow-up. Exclusion criteria Aneurysms that were treated by one modality only (endovascular or open surgery). Patient demographics, aneurysm characteristics, procedural details, clinical outcome (Glasgow outcome scale) and radiological follow-up were analyzed. The radiological follow-up was achieved using digital subtraction angiography (DSA) and/or magnetic resonance angiography (MRA) and/or CT scan angiography (CTA). RESULTS 18 patients harboring cerebral aneurysms were found to be treated by combined surgical and endovascular modalities. Patient demographics There were 11 females and 7 males. The mean age was 58 years (age range, 40–70 year). Characteristics of aneurysms In total, there were 21 aneurysms in 18 patients. Three patients had aneurysms linked with arteriovenous malformations (AVMs), seven patients had vasospasm, and three patients had double aneurysms (Figure1). Figure 1. Diagram illustrating the included aneurysm cases. Aneurysmal rupture and/or bleeding from associated AVMs were the commonest presentation, in 14 patients. The admission Hunt and Hess (HH) grade distribution of this patient group was as follows: Grade I, II 9 patients; and Grade III or more, 5 patients. The other 4 patients with unruptured aneurysms were as follow: incidentally discovered 1 patient during screening for familial aneurysm; 1 patient presented with third cranial palsy; 1 patient presented with agitation and confusion and another patient with aneurysm associated AVM was presented by convulsions. The mean aneurysm size was 8.5 millimeters (mm). There were 16 small aneurysms (up to 10 mm diameter), and 5 large aneurysms (15–28 mm in diameter). 9 aneurysms had a wide neck (>3mm in width), 6 were saccular in shape and 4 were lobulated. The most common locations of the aneurysms were the posterior communicating artery (PComma) and middle cerebral artery (MCA) and for the AVMs associated with the aneurysms were as follows: 2 cerebellar and 1 temporal. (Table 1) Table 1. Aneurysmal location Parent artery Number (n) PComm 5 MCA 4 AComm 3 ICA –bifurcation- 3 ACA 2 PICA-AICA complex 1 SCA 1 Anterior choridal 1 Ophthalmic 1 PComm, posterior communicating; AComm, anterior communicating; PICA-AICA, posterior inferior cerebellar artery anterior inferior cerebellar artery; SCA, Superior cerebellar artery. 454 Mohamed Adel Deniwar, Mohamed Kassem, Ashraf Ezzeldin, Jafar J. Jafar Treatment techniques A total of 18 patients with aneurysms were treated with combined endovascular and open surgery. 1 case with residual aneurysmal neck following surgical clipping underwent coil embolization. 3 cases with recurrent aneurysm following pervious coil embolization underwent surgical clipping. 3 cases of double aneurysms underwent coil embolization and surgical clipping. 4 cases of AVM flow related aneurysms underwent partial embolization of the nidus and coil embolization of aneurysm followed by surgical resection. 7 cases developed cerebral vasospasm following surgical clipping underwent balloon and pharmaceutical angioplasty. To facilitate surgical clipping: preoperative balloon occlusion test (BTO) and intraoperative DSA was applied in 3 and 7 cases receptively. (Figure 2 and 3) Figure 2. An intraoperative image showing complementary surgical resection of AVM after pervious endovascular onyx embolization of the AVM associated with an aneurysm. A white arrow points to onyx in the nidus. Figure 3. (A): An intraoperative image showing a pervious coiled aneurysm that developed significant recurrence (white arrow points to the coil in the aneurysmal sac). (B): An intraoperative image showing clipping of the same aneurysm in figure 3A with two clips after removal of the coils. Outcome The average radiological and clinical follow-up intervals were 13 and 16 months, respectively. All patients had an early (one week) postoperative radiological follow-up. An early angiography revealed full obliteration of 19 aneurysms (90%) out of a total of 21 aneurysms, with residual filling found in 2 aneurysms (10%), which were followed up on. Late radiological follow up (> 3months- 2 years) was done for the patients on follow-up visits. A stable residual filling in one case and the other underwent retreatment (clipping with intraoperative DSA guidance). (Table 2) Table 2. Summary of the clinical outcome Patients Clinical outcome prior to discharge (< 1 month) (N)* Late outcome (>3 months) Neuro logically intact Same neurol ogical deficit post- manag ement New neurologi cal deficit post- manage ment Individual Aneurysms 17 0 1** No significant change Aneurysms associated with AVMs 2 0 1*** Complete improvement Neurological status factors: Glasgow coma score, motor, cranial nerve and cognitive functions; other psychological and intellectual assessment were not included. * Number of patients. ** 1 patient developed monocular blindness post ophthalmic artery aneurysmal clipping postoperative angiogram revealed patent ophthalmic and orbital branches though ophthalmology consult revealed no optic disc abnormalities, but diagnosis was posterior ischemic neuropathy with poor prognosis. *** 1 patient developed right lower limb weakness grade 4+ and positive Romberg, patient had avulsed PICA during AVM embolization and sacrifice the vertebral artery was done, later developed massive cerebellar infarction later on, however gradual improvement was not noticed during outpatient clinic visits in 6 months. DISCUSSION Complex and recalcitrant aneurysms Many researches had attempted to categorize recalcitrant aneurysms in some way. Hacin-Bey et al., as a combination of anatomical aneurysm variables and clinical factors describe complex aneurysm characteristics. These characteristics are summarized in a table in his study. (8) (See Table 3) 455 The complementary multimodal treatment of recalcitrant cerebral aneurysms Table 3. Hacin-Bey et al. table of features that define recalcitrant or complex aneurysms (7). Aneurysm anatomy (best assessed by 3D aneurysm reconstruction from DSA or CTA data) Clinical features (detailed clinical risk stratification important) Size: large or giant, too small for a clip or coil Clinical grade at presentation: HH_3. Shape: fusiform, serpentine, pseudoaneurysm, dissecting aneurysm. Timing: vasospasm at the time of presentation. Content: filled with thrombus, calcified wall, dysplastic vessel wall. Medical comorbidities: cardiovascular, pulmonary, renal or endocrine comorbidity. Neck: difficult surgical access, broad, calcified, involving perforator vessels, and other branching vessels. Advanced age. Perianeurysmal environmental: aneurysm embedded ineloquent brain tissue, bone, edema, scar from previous surgery. 3D, three dimensional: DSA, digital subtraction angiography: CTA, computed tomography angiography; HH, Hunt and Hess. Used Table from with permission from Wolters Kluwer Health with modifications. The ISAT (International Subarachnoid Aneurysm Trial) requires subjective agreement that an aneurysm might be treated by endovascular or open surgery (5). Many aneurysms, however, did not fit the requirements, such as: 1- patients with life- threatening intracerebral or subdural hematomas; 2- incompatible neck-to-dome ratios; 3-parent artery or branch artery incorporation into the dome; 4- fusiform aneurysms; 5-thrombotic aneurysms; 6- giants; 7-blisters; 8- pseudo/traumatic aneurysms; 9- those with mass effect; and 10-those that had failed repeated endovascular treatment (16,20). Complementary multimodal therapeutic approach Choudhri et al described the Stanford neurosurgical experience with the combination of endovascular and open surgery in 67 cases. The aneurysms in all of the individuals in the study were completely obliterated, with no mortality. (2) The combination method was used to treat a total of 96 aneurysms, according to Lawton et al. The aneurysms were enormous or giant in size in 43% of the cases, and fusiform or dolichoectatic in 34%. In 91 aneurysms, the angiographic obliteration was complete (95%) (15). Chen et al. and Cockroft et al., both had reported the treatment of recalcitrant cerebral aneurysms by surgical reconstruction of aneurysm neck followed by endovascular coiling on a planned concept. Cockroft et al. also reported in his series the initial coil embolization of ruptured basilar tip aneurysm to reduce the risk of rebleeding followed by permanent surgical clipping (1,3). The radiological and clinical out come of this multimodal treatment in these reported studies and our study was favorable. These good results of combing both surgical and endovascular techniques encouraged the evolution of a new treatment modality, which is the hybrid cerebrovascular surgery. Hybrid cerebrovascular surgery era In several subspecialties, hybrid surgery is regarded as a cutting-edge technique. The term "hybrid" refers to a combination of standard surgical and endovascular methods. Actually, it's a multimodal technique that may be done in one session or over a period of time (scheduled). The use of hybrid surgery in the treatment of cardiovascular disorders has ushered in a new era in disease management.(18,19) In the same direction for the cerebrovascular diseases, hybrid operative theatres have been innovated in the neurosurgical institutes in last few years. Between November 2003 and August 2011, Muryma et al. and Kurtia et al. published two case series of patients with intractable complicated cerebrovascular lesions who were treated with a combination strategy (endovascular and surgical). (14,17) Other case reports were documented in the literature too. (5,7,9,13) A furthermore studies are expected be conducted on a larger scale concerning the hybrid cerebrovascular surgery in the nearby future. CONCLUSION The recalcitrant or complex cerebral aneurysms can be better referred to as diseases rather than lesions; of which many clinical factors in add to the anatomical one define their complexity and make their treatment difficult. Endovascular and open surgery could be complementary to each other and create a multimodal or combined approach for treating these aneurysms, and that concept has 456 Mohamed Adel Deniwar, Mohamed Kassem, Ashraf Ezzeldin, Jafar J. Jafar evolved to what known nowadays as the hybrid cerebrovascular surgery. CONTRIBUTORSHIP STATEMENT Mohamed Deniwar, Mohamed Kassem and Ashraf Ezz Eldin designed the study. Mohamed deniwar, Mohamed Kassem, Ashraf Ezz Eldin and Jafar J. Jafar, participated in data extraction, analysis, writing and drafting of the manuscript, Jafar J. Jafar critically revised the manuscript and all authors approved the final version. IRB APPROVAL After IRB approval for both New York University (i14-01394) and Mansoura University (R.21.03.1240), all cases of cerebral aneurysms treated in New York University and in Mansoura University from 2010-2021 were retrospectively reviewed. REFERENCES 1. Chen L, Kato Y, Sano H, Watanabe S, Yoneda M, Hayakawa M, Sadato A, Irie K, Negoro M, Karagiozov KL, Kanno T. Management of complex, surgically intractable intracranial aneurysms: the option for intentional reconstruction of aneurysm neck followed by endovascular coiling. Cerebrovascular Diseases. 2007 Apr 2;23(5-6):381-7. 2. Choudhri O, Mukerji N, Steinberg MD, Gary K. Combined endovascular and microsurgical management of complex cerebral aneurysms. Frontiers in neurology. 2013 Aug 8;4:108. 3. Cockroft KM, Marks MP, Steinberg GK. Planned direct dual-modality treatment of complex broad-necked intracranial aneurysms: four technical case reports. Neurosurgery. 2000 Jan 1;46(1):226-31. 4. Colby GP, Coon AL, Tamargo RJ. Surgical management of aneurysmal subarachnoidal hemorrhage. NeurosurgClin N Am (2010) 21(2): 247–61. 5. Deniwar M, Ambekar S, Elhammady MS. Multimodal management of a complex indirect carotid cavernous fistula. Neurology India. 2015 Jul 1;63(4):606. 6. Greenberg, MS. Handbook of neurosurgery: SAH and Aneurysms. in: 8th ed. Greenberg, Lakeland; 2016 May. 7. Guerrero CA, Raja AI, Naranjo N, Krisht AF. Obliteration of carotid-cavernous fistulas using direct surgical and coil- assisted embolization: technical case report. Neurosurgery. 2006 Feb 1;58(2):E382. 8. Hacein-Bey L, Connolly Jr ES, Mayer SA, Young WL, Pile- Spellman J, Solomon RA. Complex intracranial aneurysms: combined operative and endovascular approaches. Neurosurgery. 1998 Dec 1;43(6):1304-12. 9. Heiroth HJ, Turowski B, Etminan N, Steiger HJ, Hänggi D. Coiling of a carotid cavernous sinus fistula via microsurgical venotomy: recommendation of a combined neurosurgical and endovascular approach. Journal of neurointerventional surgery. 2013 Mar 1; 5(2):e7. 10. Kallmes DF, Hanel R, Lopes D, Boccardi E, Bonafé A, Cekirge S, Fiorella D, Jabbour P, Levy E, McDougall C, Siddiqui A. International retrospective study of the pipeline embolization device: a multicenter aneurysm treatment study. American Journal of Neuroradiology. 2015 Jan 1;36(1):108-15.N. 11. Killory BD, Nakaji P, Gonzales LF, Ponce FA, Wait SD, Spetzler RF. Prospective Evaluation of Surgical Microscope–Integrated Intraoperative Near‐Infrared Indocyanine Green Angiography During Cerebral Arteriovenous Malformation Surgery. Neurosurgery. 2009 Sep 1;65(3):456-62. 12. Kim HK, Hwang SK, Kim SH. Types of thromboembolic complications in coil embolization for intracerebral aneurysms and management. Journal of Korean Neurosurgical Society. 2009 Sep 1;46(3):226-31. 13. Krisht AF, Burson T. Combined pretemporal and endovascular approach to the cavernous sinus for the treatment of carotid-cavernous dural fistulae: technical case report. Neurosurgery. 1999 Feb 1; 44(2):415-8. 14. Kurita H, Takeda R, Ikeda T, Kikkawa Y, Fushihara G, Ooigawa H, Ishihara S. Hybrid cerebrovascular surgery for complex cerebral aneurysms and arteriovenous malformations. Japanese journal of neurosurgery. 2015;24(3):173-9. 15. Lawton MT, Quinones Hinojosa A, Sanai N, Malek JY, Dowd CF. Combined microsurgical and endovascular management of complex intracranial aneurysms. Neurosurgery (2003) 52(2):263–74. 16. Molyneux, Andrew J., et al. "International subarachnoid aneurysm trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised comparison of effects on survival, dependency, seizures, rebleeding, subgroups, and aneurysm occlusion." The Lancet 366.9488 (2005): 809-817. 17. Murayama Y, Arakawa H, Ishibashi T, Kawamura D, Ebara M, Irie K, Takao H, Ikeuchi S, Ogawa T, Kato M, Kajiwara I. Combined surgical and endovascular treatment of complex cerebrovascular diseases in the hybrid operating room. Journal of neurointerventional surgery. 2013 Sep 1;5(5):489-93. 18. Nollert G, Figel A, Bulitta C, Altenbeck F, Hartkens T, Gerhard V. The hybrid operating room. INTECH Open Access Publisher; 2012. 19. Nollert G, Wich S, Hartkens T, Figel A. The Cardiovascular Hybrid Operating Room. InAtlas of Advanced Endoaortic Surgery 2013 (pp. 1-9). Springer London. 20. Origitano TC. Current options in clipping versus coiling of intracranial aneurysms: to clip, to coil, to wait and watch. Neurosurgery Clinics of North America. 2008 Jul 31;19(3):469-76. 21. Terada T, Tsuura M, Matsumoto H, Masuo O, Shintani A, Ryujin Y, Itakura T. Factors Leading to and Treatment of Aneurysmal Perforation during Coil Embolization Analysis of 105 Consecutive Cases. Interventional Neuroradiology. 2003 Mar 1;9(1):21-9.