Safety of Endovascular Treatment for Concomitant Unruptured Intracranial Aneurysms and Cerebral Vascular Stenosis

Background To evaluate the safety of endovascular therapy for concomitant unruptured intracranial aneurysms (UIAs) and cerebral vascular stenosis. Methods Patients between January to August 2019 were retrospectively reviewed at our institution. Concomitant UIA and cerebral vascular stenosis patients underwent endovascular treatment were included. The demographics and clinical information were collected. Patients were divided into 4 groups according to lesions that was treated (aneurysm, stenosis, both lesions in a single session or in separated sessions). Patients were divided into another 2 groups based on locations of aneurysm and stenosis (ipsilateral and non-ipsilateral). The demographics and clinical data were compared among groups. Results A total of 105 (4.9%) cases have concomitant UIA and cerebral vascular stenosis. Eighty-one patients underwent endovascular treatment for the stenosis(n=18), aneurysm(n=41) or both lesions (one session=10; separated sessions n=12). Seven (8.6%) patients experienced procedural related complications, including 1 (1.2%) hemorrhagic and 6 (7.4%) ischemic types. In terms of procedures, 4 (6.3%) complications is related with UIA embolization, 2(5.0%) related with intracranial stenosis angioplasty. Complication rate of patients underwent intracranial angioplasty and aneurysm embolization simultaneously is much higher (20%) than that of the other groups (5.6%-8.3%). Patients with ipsilateral lesions also had higher complication rate (11.1%) than non-ipsilateral patients (6.7%). Follow-up (74 patients, mean=6.5months) result showed good clinical outcome in 70 (94.6%) patients. Conclusions Simultaneous treatment for concomitant UIA and extracranial stenosis may not pose additional risks. Ipsilateral lesions and single session procedure for intracranial stenosis and UIA are potential risk factors for periprocedural complications.


Abstract
Background To evaluate the safety of endovascular therapy for concomitant unruptured intracranial aneurysms (UIAs) and cerebral vascular stenosis. Methods Patients between January to August 2019 were retrospectively reviewed at our institution. Concomitant UIA and cerebral vascular stenosis patients underwent endovascular treatment were included. The demographics and clinical information were collected. Patients were divided into 4 groups according to lesions that was treated (aneurysm, stenosis, both lesions in a single session or in separated sessions). Patients were divided into another 2 groups based on locations of aneurysm and stenosis (ipsilateral and non-ipsilateral). The demographics and clinical data were compared among groups. Results A total of 105 (4.9%) cases have concomitant UIA and cerebral vascular stenosis. Eighty-one patients underwent endovascular treatment for the stenosis(n=18), aneurysm(n=41) or both lesions (one session=10; separated sessions n=12). Seven (8.6%) patients experienced procedural related complications, including 1 (1.2%) hemorrhagic and 6 (7.4%) ischemic types. In terms of procedures, 4 (6.3%) complications is related with UIA embolization, 2(5.0%) related with intracranial stenosis angioplasty. Complication rate of patients underwent intracranial angioplasty and aneurysm embolization simultaneously is much higher (20%) than that of the other groups (5.6%-8.3%). Patients with ipsilateral lesions also had higher complication rate (11.1%) than non-ipsilateral patients (6.7%). Follow-up (74 patients, mean=6.5months) result showed good clinical outcome in 70 (94.6%) patients. Conclusions Simultaneous treatment for concomitant UIA and extracranial stenosis may not pose additional risks. Ipsilateral lesions and single session procedure for intracranial stenosis and UIA are potential risk factors for periprocedural complications.

Background
Concomitant existence of unruptured intracranial aneurysms (UIAs) and cerebral vascular stenosis are relatively rare lesions supposed to have high treatment risks [1]. Embolization of the UIA may decrease blood perfusion of the brain due to low blood pressure under general anesthesia, which may cause ischemic events. Conversely, angioplasty of the stenosis in patients with UIAs may cause UIA rupture due to hemodynamic changes such as increased blood ow, especially when UIA and stenosis are located ipsilaterally. No consensus currently exists to guide endovascular treatment for this kind of patients.
Many patients with concomitant carotid stenosis and ipsilateral UIA underwent endovascular treatment have been reported. The overall complication rate is not high and clinical outcome turn out to be good [2][3][4][5][6][7]. However, rare authors have reported endovascular treatment results of concomitant UIAs and cerebral vascular stenosis despite location and degree of stenosis, as well as location and morphology characteristics of UIAs. The risk of ischemic stroke secondary to stenosis and the risk of subarachnoid hemorrhage (SAH) secondary to UIA rupture must be evaluated and balanced before treatment [8][9][10]. What is the risk factors for procedural related complications and whether there are any difference between intracranial and extracranial lesions is not known. In the current study, we evaluate the safety of endovascular treatment for concomitant UIAs and cerebral vascular stenosis to solve these questions.

Patients
This study was approved by the ethics committee of our hospital, and all patients provided written informed consent. We retrospectively reviewed patients from January to August 2019 at our institution.
All patients were diagnosed with imaging studies including computed tomography angiography (CTA), magnetic resonance angiography (MRA), and/or DSA. Patients with concomitant UIA and cerebral vascular stenosis were included. Patients demographics, clinical information, procedure details, complications and clinical follow-up results were collected. Patients were excluded from the study if there was no complete information. Patients who were lost to follow-up or without further treatment after diagnosis were eliminated in further analyses. Patients were divided into 4 groups according to lesions that was treated (UIA, stenosis, both lesions in a single session or both lesions in separated sessions).
Patients were divided into another 2 groups based on the relationship between the UIA and stenosis (ipsilateral and non-ipsilateral). The demographics, complications and clinical outcomes were compared among groups.

De nitions of variables
Patients' demographics and clinical data were collected. In the current study, cerebral vascular include intracranial vascular, as well as extracranial segment of common carotid artery (CCA), internal carotid artery (ICA) and vertebral artery (VA). Initial clinical presentations were categorized into speci c ischemic symptoms and non-speci c symptoms. Speci c ischemic symptoms are symptoms directly resulted by relative stenosis, include stenosis related numbness of anybody parts, weakness of limbs, vertigo and slurred speech, etc. Some patients found UIA incidentally when performing routine medical examination (asymptomatic UIA). Non-speci c symptoms include non-speci c headache, dizziness and asymptomatic UIA. The stenosis was strati ed into 4 distinct categories (NASCET criteria) based on degree: mild (< 50%), moderate (50%-70%), severe (70%-99%) and occluded (100%).
The relationship between UIA and stenosis is categorized into two types according to the location: ipsilateral and non-ipsilateral. The former refers to both UIA and stenosis located at left CCA system (left CCA, Left ICA, Left MCA and Left ACA), right CCA system (right CCA, right ICA, right MCA and right ACA) or posterior circulation (Unless UIA and stenosis located at bilateral VAs respectively). For multiple UIAs and/or stenosis, any two lesions located at the same system were categorized into ipsilateral group.
Endovascular embolization status of the UIA was classi ed into complete occlusion, near complete occlusion and partial occlusion according to Raymond Classi cation for intracranial embolization. Pipeline is excepted because ow diverter is not applicable for Raymond classi cation.
Periprocedural complications are categorized into ischemic and hemorrhagic types. Ischemic complication is de ned as any additional neurologic de cits compared with pre-operation and infarctions con rmed by CT/MRI within 30 days after procedure [11]. Hemorrhagic complication is de ned as intracranial hemorrhage (ICH/SAH) happened within 7 days after procedure con rmed by CT [12]. All patients were evaluated with the modi ed Rankin Scale (mRS) before procedure and at last follow-up. mRS 0-2 (independent) is regarded as favorable clinical outcome and mRS ≥ 3 (dependent) is regarded as unfavorable clinical outcome.

UIA embolization and Stenosis angioplasty
There is no consensus for the treatment of concomitant aneurysm and stenosis. Treatment indication for stenosis and UIA is strictly according to the Guidelines from the American Heart Association/American Stroke Association(AHA/ASA) respectively [13,14]. Dual antiplatelet therapy that comprised aspirin (100 mg/day) and clopidogrel (75 mg/day) was initiated at least 5 days before stent implantation. For UIA embolization, all procedures were performed under general anesthesia. A 6-to 8-F sheath was inserted through the femoral artery and a 6-to 8-F guiding catheter was navigated into the internal carotid or the vertebral artery. For ostial ICA, an 8-F guiding catheter was used for all patients. The guiding catheter was ushed via a pressure bag with saline containing 3000U of heparin/500 ml. The microcatheter tip was guided to the desired position using micro-guidewire. The UIA was embolized with coils alone, stent-assisted coils or pipeline with or without coils. For angioplasty, general anesthesia and local anesthesia are adopted for intracranial and extracranial lesions respectively. During the intervention, 3000-4000 IU of heparin was administered, and additional 1000 IU per hour. Angioplasty (balloon angioplasty along or stenting) was done according to the standardized routine form AHA/ASA and our Unit [14]. Before and immediately after the procedure, the neurological function of every patient was evaluated.

Follow-up
All patients received in-person or telephone follow-up. The nal mRS score was based on their functional status at last follow-up.

Statistical analyses
Patients' characteristics were described with frequencies for categorical variables and mean standard deviation for continuous variables. Categorical variables were compared using Fisher exact test or the Pearson χ 2 test. Continuous variables were compared between groups using student's t test or one-way ANOVA. All P values were reported as 2-sided. P < 0.05 was considered signi cant. All statistical analyses were conducted by using SPSS 22.0 (Chicago, IL, USA).

Patients demographics and clinical information
A total 2140 patients were reviewed, and 105(4.9%)patients have concomitant UIAs and cerebral vascular stenosis. Eighty-one patients underwent endovascular treatment and were involved in this study. Age range from 40-82 years old (mean ± standard deviation: 60.2 ± 7.6 years old). Thirty-six (44.4%) patients' initial presentation are speci c ischemic symptoms. Sixty-two patients have 1 UIAs, 14 patients have 2 and 5 patients have more than 3, making a total of 106 UIAs. The maximum diameter of UIA range from 1-20 mm (mean ± SD: 4.47 ± 3.06 mm).  Table 1.

Complications and clinical follow-up
A total of 7 (8.6%) procedural related complications happened, including 1 (1.2%) hemorrhagic and 6 (7.4%) ischemic types. One patient died of SAH after stent assisted embolization of an RVA UIA, accompanied by an BA stenosis (ipsilateral). Among 6 ischemic complications, 1 patient died of LVA occlusion (In-stent thrombosis) after Pipeline implantation for an UIA, non-ipsilateral LICA stenosis at C4 segment and RVA occlusion is exist for this patient. Four patients experienced ischemic complications (2 related with UIA embolization and 2 with angioplasty) and have permanent neurological de cits at last follow-up. Another one patient received ostial ICA angioplasty and ipsilateral MCA UIA embolization during one procedure, and experienced transient ischemic symptoms and completely recovered at discharge. For this patient, we are not sure the complication is caused by UIA embolization or angioplasty, because they are ipsilaterally located and managed at the same session.
In total, in terms of procedures, 4 (6.3%) complications are related with UIA embolization, 2(5.0%) related with intracranial stenosis angioplasty and 1 is not sure. In terms of lesions location, 4(11.1%) complications happened in patients with ipsilateral lesions and 3(6.7%) in non-ipsilateral lesions. The summarized complication occurrence and follow-up result based on different groups are revealed in Table 2 and Table 3. The complication rate of patients under simultaneous treatment of UIA and intracranial stenosis is higher (20% & 5.6%-8.3%). The complication rate of ipsilateral group is also 11.1%, while that of non-ipsilateral group is only 6.7%. Among all the 81 patients, 7(8.6%) were failed to followup, leaving 74 to analyze the clinical outcome. Follow-up period ranges from 3 to 11 months (mean ± SD: 6.5 months

Discussion
In this study, we reviewed consecutive patients in a single center for patients with concomitant UIA and cerebral vascular stenosis. A total 2140 patients were reviewed, and 105 patients have concomitant UIA and cerebral vascular stenosis. Eighty-one patients underwent endovascular therapy for the UIA and/or stenosis. The incidence of concomitant UIA and cerebral vascular stenosis is around 4.9%. The reported incidence of concomitant carotid artery stenosis and UIA ranges between 3% and 5% [8,15]. In this cohort, patients were included if they have any concomitant UIAs and cerebral vascular stenosis, instead of patients only with concomitant carotid artery stenosis and UIA. No consensus has been achieved to guide endovascular treatment of concomitant UIAs and cerebral artery stenosis. Angioplasty may increase the risk of UIA rupture from altered hemodynamics. Embolization of an UIA through untreated stenosis pose additional risks. The mechanical interaction between the access catheters and stenotic plaque may increase the risk of thromboembolic complications [15,16].
Several reports have investigated whether simultaneous carotid artery stenting (CAS) and coil embolization, or multi-staged therapy is better. Simultaneous therapy will decrease the risk of UIA rupture but may increase the risk of thromboembolic complications [5,17,18]. There is a theoretical risk of UIA rupture during and after angioplasty secondary to cerebral hyper perfusion syndrome [8,19]. Alternatively, if management is rst focused on UIA, the patient may subsequently be at risk for perioperative cerebral ischemia as a result of a reduction in perfusion pressure during anesthesia [8,9]. As the safety of endovascular modalities for UIA treatment and carotid stenosis continues to improve, the notion of single-staged treatment has increasing appeal. Cases reports have demonstrated the feasibility of simultaneous single-staged treatment of concomitant carotid stenosis and ipsilateral UIAs [7,17,20,21]. Some authors hold different views. Carotid artery angioplasty in the setting of a concomitant UIA can be performed safely without an increased 30-day or late-term risk of rupture. If indicated, treatment of the UIA can take place after the patient recovers from the carotid procedure [22]. The complication rates of endovascular angioplasty for CAS is around 2.5% [23]. In this study, no complication is related with extracranial stenosis (extracranial segment of CCA ICA and VA) angioplasty, which indicate the safety of same session treatment for concomitant UIA and extracranial stenosis.
The reported overall complications rate of endovascular treatment for intracranial stenosis is around 10%, and the unfavorable clinical outcome rate is around 5% [24][25][26]. The reported complications rate of endovascular treatment for UIAs is 4.9% [27] and unfavorable outcome is around 4.8% [28]. In this cohort, UIA embolization and intracranial stenosis angioplasty related complication is 4 (6.3%) and 2 (5.0%) respectively, and total unfavorable clinical outcome is 4 (5.4%). The judgement of responsible lesion is based on procedures, but we should treat the UIA and stenosis as one entity because they are concomitant. One would be risk factor when we are managing the other and we should treat them as a whole instead of investigating responsible lesions. The complication incidence in this cohort is acceptable compared with reported literatures. Short term clinical follow-up revealed no ischemic and hemorrhagic stroke, indicating that endovascular treatment for concomitant UIA and intracranial stenosis is safe and effective. Due to small sample size and low complication rate, our grouped analyses based on treatment strategy and lesions distribution revealed no statistically signi cant risk factors for procedural related complications, but the complication rate of patients underwent intracranial angioplasty and UIA embolization in a single session is much higher (20%) than that of the other groups (5.6%-8.3%). Patients with ipsilateral lesions also had higher complication rate (11.1%) than nonipsilateral patients (6.7%). Even though there is no statistical signi cance, we think these two factors are inclined to be high risk factors associated with periprocedural complications. Our experience has led us to treat UIA and intracranial stenosis in separated sessions.

Limitations Of The Study
Our study has several limitations. Due to the retrospective and single center property of the current study, the 4.9% incidence of concomitant UIA and cerebral vascular stenosis patients may have some bias. Population based study may be more accurate. Secondly, due to small sample size and low complication incidence, we did not nd any statistically signi cant risk factors for procedural related complications. The inclined risk factors, including single session procedure for both lesions and intracranial lesions, are to be veri ed multicentric trials or registries.

Conclusions
Simultaneous treatment for concomitant UIA and extracranial stenosis may not pose additional risks.
Ipsilateral lesions and single session procedure for intracranial stenosis and UIA are potential risk factors for periprocedural complications. The result of this study needs to be con rmed by further studies.  Single session angioplasty of stenosis and UIA embolization. A patient with mild barylalia for 10 days.
DSA revealed severe stenosis in the left right vertebral artery as well as an ipsilateral aneurysm located at the very distal of the stenosis (a, b). Balloon dilatation was performed successfully for the stenosis(c). The aneurysm was embolized in in the same session (d).