Delayed rupture of intracranial aneurysms after placement of intra-luminal flow diverter

Abstract

Background

Though flow diverter is a safe and efficient modality, some patients can experience delayed aneurysmal rupture. The mechanism of delayed rupture is still obscure to us.

Methods

We performed a systematic search in the PubMed database for patients with delayed rupture of intracranial aneurysms after flow diverter placement.

Results

A total of 36 articles reporting on 60 patients were included in the final analysis. Of the 49 patients with description of presenting symptoms, six (12.2%) patients were incidentally diagnosed, 39 (87.8%) patients were admitted for aneurysmal rupture or mass effect. Multiple flow diverters were used in 38.3% (18/47) of the patients. Coil assistance was applied in 13.0% (7/54) of the patients. Delayed aneurysmal rupture led to intracranial hemorrhage or carotid–cavernous sinus fistula (CCF) in 76.8% (43/56) and 23.2% (13/56) of the patients, respectively. Of the 55 patients with description of outcome, 14 (25.5%) patients achieved good recovery, one (1.8%) patient was severely disabled, 40 (72.7%) patients died. All of the patients in the CCF group survived and experienced good recovery.

Conclusion

Increased intra-aneurysmal pressure, destabilization of the aneurysm wall by intra-aneurysmal thrombus, persistent residual intra-aneurysmal flow, characteristics of the specific aneurysm, and mechanical injury by the flow diverter might conjointly contribute to the final delayed rupture. There has been no established preventive measure to decrease the incidence of delayed rupture yet. The treatment and outcome depend on the presentation of delayed rupture. Patients presenting with aneurysm-related intracranial hemorrhage have a dismal outcome. Those presenting with CCFs usually have a satisfactory recovery.

Introduction

Intra-luminal flow diverter has been demonstrated to be a groundbreaking innovation in the treatment of intracranial aneurysms. It has shifted the treatment concept in endovascular management of intracranial aneurysms from direct coiling to blood flow diverting.¹,² The indications and off-label use of flow diverter have been continuously expanding, which range from giant to small, proximal to peripheral, anterior circulation to posterior circulation, unruptured to ruptured and saccular to non-saccular (fusiform/dissecting, pseudo and blood blister) aneurysms.^3–8 Though flow diverter is a considerably safe and efficient modality, in rare circumstances, some patients can experience delayed aneurysmal rupture.⁹,¹⁰ However, the mechanism of delayed rupture is still obscure to us. To our knowledge, systematic review of delayed aneurysmal rupture after flow diverter placement is lacking. In this study, we perform a systematic literature review on this specific entity.

Methods

On 21 August 2019, we performed a systematic search in the PubMed database for patients with delayed rupture of intracranial aneurysms after flow diverter placement. The searching strategy was as follows: (flow diverter[Title/Abstract]) OR flow diversion[Title/Abstract]) OR flow diverting device[Title/Abstract]) OR pipeline[Title/Abstract]) OR pipeline flex[Title/Abstract]) OR surpass[Title/Abstract]) OR surpass streamline[Title/Abstract]) OR fred[Title/Abstract]) OR silk[Title/Abstract]) OR leo[Title/Abstract]) OR pipeline shield[Title/Abstract]) OR tubridge[Title/Abstract]) OR p64[Title/Abstract]) AND aneurysm[Title/Abstract]. The inclusion criteria for the identified articles were: 1) full text could be obtained or 2) sufficient data could be obtained from the abstract if the full text is inaccessible. Studies without sufficient description of the demographic, clinical and radiological data of the individual patient were excluded from the final analysis. In order to identify potentially missed articles, manual searching of the reference lists of the included articles was also performed. Modified Rankin Scale (mRS) was used for outcome assessment. A mRS score ≤ 3 was defined as good recovery. With respect to the criteria of delayed aneurysmal rupture, the following two points must be fulfilled: 1) rupture of the treated aneurysm after placement of the flow diverter, 2) demonstration of no contrast extravasation on the last angiogram before termination of the procedure.

Results

General information

The PubMed search identified 1334 records, of which 1257 were excluded based on title and abstract screening. Forty-three records were further excluded after reading the full text. We manually searched the reference lists of the remaining 34 articles and two additional articles were further identified. Finally, 36 articles reporting on 60 patients were included in the final analysis (Table 1).⁸,^11–45 The flowchart of searching strategy is illustrated in Figure 1. The patients were aged from 29 to 86 (55.31 ± 13.98) (n = 42) years, with a male to female ratio of 1:3 (11:33).

Table 1.

Clinical data of the patients with delayed aneurysmal rupture after flow diverter treatment.

No.	First author/year	Age/sex	Presenting symptom	Aneurysm characteristics					Antithrombotic regimen	Intraoperative details		Immediate flow alteration	Immediate post-procedural complication	Partial formation of thrombus after FD	Interval to rupture	Findings after rupture	Further treatment	Speculated mechanism of rupture	Autopsy and finding	Outcome (mRS)
				Ruptured or unruptured	Location	Morphology	Intra-aneurysmal thrombosis	Size (mm)		Type and number of FDs	Coils assisting
1	Byrne/201011	NA/NM	NA/NM	Unruptured	MCA	Fusiform	NA/NM	24	Clopidogrel and aspirin before and after treatment, heparin during treatment, warfarin and aspirin after ceasing clopidogrel	Silk	No	NA/NM	No	Yes	Six months	Acute hemorrhage, aneurysm enlargement	Surgical bypass	Warfarin	NA/NM	Death
2	Mustafa/201012	39/F	Hemifacial pain	Unruptured	ICA–cavernous	Fusiform	No	17.6	300 mg Plavix before treatment, Plavix and aspirin after treatment	One Silk (4 mm×35 mm)	No	Significant stagnation of contrast within aneurysm	No	Yes	Two weeks	CCF	TVE of CCF with coils	Unknown	NA/NM	0
3	Lubicz/201013	71/F	Bitemporal hemianopsia	Unruptured	ICA–ophthalmic	Saccular	No	28	Systemic heparinization for 24 h. Aspirin and clopidogrel before treatment and continued for 3–6 months (aspirin 160 mg/day, clopidogrel 75 mg/day)	One Silk (4 mm×30 mm)	No	Significant flow reduction	No	NA/NM	13 days	Massive SAH, stent migration	NA/NM	Migration into sac	NA/NM	Death
4	Turowski/201114	69/F	Incidental	Unruptured	ICA–ophthalmic	Saccular	No	18.2	Aspirin 100 mg/day and clopidogrel 75 mg/day for five days before treatment, and the same regimen after treatment	One Silk (4mm×30 mm)	No	Significant contrast stasis	No	Yes	20 days	Extensive SAH	NA/NM	Unknown	NA/NM	Death
5	Kulcsár/201115	50/M	Acute severe headache	Unruptured	ICA–supraclinoid	Saccular	Yes	21	Aspirin and clopidogrel before treatment and continue for 2–3 months after FD placement	One Silk	Yes	Stagnation of contrast within aneurysm	Thromboembolism	Yes	Two days	SAH and ICH	NA/NM	Unknown	NA/NM	Good recovery
6		74/F	Incidental	Unruptured	ICA–cavernous	Saccular	NA/NM	20	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	One Silk	No	Stagnation of contrast within aneurysm	No	Yes	Three days	CCF	PAO	Unknown	NA/NM	NA/NM
7		44/F	Incidental	Unruptured	ICA–ophthalmic	Saccular	No	18	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	One Silk	No	Inertia-driven inflow jet, stagnation of contrast within aneurysm	No	Yes	Five days	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
8		45/F	Visual loss	Unruptured	ICA–ophthalmic	Fusiform	NA/NM	20	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	One Silk	No	Stagnation of contrast within aneurysm	No	Yes	Five days	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
9		70/M	Bilateral visual deficit	Unruptured	ICA–supraclinoid	Fusiform	No	34	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	Two Leo, one Silk	No	Persisting inflow jet, stagnation of contrast within aneurysm	Thromboembolism	Yes	12 days	Diffuse SAH	NA/NM	Unknown	Mural thinning and necrosis, loss of fibrous tissue and medial smooth muscle	Death
10		54/M	Visual problems	Unruptured	Basilar trunk	Fusiform	No	17	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	One Leo, two Silk	No	Significant contrast stasis	No	Yes	18 days	Diffuse SAH	NA/NM	Unknown	Mural thinning and necrosis, loss of fibrous tissue and medial smooth muscle	Death
11		69/F	Acute severe headache	Unruptured	ICA–ophthalmic	Saccular	NA/NM	15	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	One Silk	No	Stagnation of contrast within aneurysm	Thromboembolism	Yes	20 days	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
12		69/M	Diplopia, headache, unsteadiness	Unruptured	Basilar trunk	Fusiform	NA/NM	25	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	One Leo, two Silk	No	Stagnation of contrast within aneurysm	No	Yes	28 days	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
13		49/F	Visual deficit	Unruptured	ICA–supraclinoid	Saccular	NA/NM	25	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement	One Silk	No	Stagnation of contrast within aneurysm	No	Yes	48 days	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
14		48/F	Diplopia	Unruptured	ICA–cavernous	Saccular	NA/NM	24	Aspirin and clopidogrel before treatment and continue for 2-3 months after FD placement, aspirin till rupture	One Silk	No	Stagnation of contrast within aneurysm	No	Yes	110 days	CCF	PAO	Unknown	NA/NM	NA/NM
15		66/F	Visual deficit	Unruptured	ICA–supraclinoid	Saccular	NA/NM	18	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement, aspirin until rupture	One Silk	No	Stagnation of contrast within aneurysm	Thromboembolism	Yes	135 days	Diffuse SAH	NA/NM	Unknown	NA/NM	Severe disability
16		67/F	Brainstem symptom	Unruptured	Basilar trunk	Fusiform	NA/NM	31	Aspirin and clopidogrel before treatment and continued for 2–3 months after FD placement, aspirin until rupture	One Leo, one Silk	No	Stagnation of contrast within aneurysm	No	Yes	150 days	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
17	Cebral/201116	62/F	NA/NM	Unruptured	ICA–supraclinoid	Saccular	No	26	NA/NM	One Pipeline	No	Significant contrast stasis	NA/NM	NA/NM	Four days	NA/NM	NA/NM	Unknown	NA/NM	NA/NM
18		60/F	NA/NM	Unruptured	ICA–ophthalmic	Saccular	No	38	NA/NM	Two Pipeline	No	Significant contrast stasis	NA/NM	NA/NM	Seven days	NA/NM	NA/NM	Unknown	NA/NM	NA/NM
19	Chow/201217	NA/NM/F	Impairment of ambulation and swallowing	Unruptured	VA	Saccular	No	23	Aspirin and clopidogrel before and after treatment, heparin during procedure	One Pipeline (4mm×20 mm)	No	Significant contrast stasis	No	Yes	20 days	SAH and ICH	NA/NM	Unknown	Mural necrosis	Death
20	Kan/201218	50/F	Vision loss	Unruptured	ICA–ophthalmic	Saccular	No	22.46	Aspirin (325 mg/day) and clopidogrel (75 mg/day) before treatment, aspirin and clopidogrel after treatment	Three Pipeline (4mm×18mm, 4.25mm×16mm, 4.25mm×14 mm)	No	Significant contrast stasis	No	NA/NM	Six days	SAH and ICH	NA/NM	Unknown	NA/NM	Death
21	Cirillo/2012 19	NA/NM/M	NA/NM	Unruptured	Basilar artery	Saccular	No	>25	Ticlopidine (twice/day) and aspirin (300 mg/day) for before (four days) and after treatment, heparin and aspirin during procedure	One Silk (5.5mm×60 mm)	No	Significant contrast stasis	Acute hydrocephalus	Yes	One week	ICH and IVH	NA/NM	Unknown	NA/NM	Death
22	Siddiqui/201220	42/M	Hemiparesis, facial weakness	Unruptured	Basilar artery	Fusiform	No	35.6	Aspirin and clopidogrel before treatment, heparin during procedure, eptifibatide after treatment	Three Pipeline (4 mm× 20mm, 4 mm× 12mm, 3.75mm ×12 mm)	No	Intra-aneurysmal flow is evident	Dysarthria, hemiparesis	NA/NM	One day	SAH and brainstem hemorrhage	NA/NM	Unknown	NA/NM	Death
23		42/F	Vertigo, ataxia	Unruptured	Basilar artery	Fusiform	No	37.1	Aspirin and clopidogrel before treatment, eptifibatide after treatment	Three Pipeline (4 mm× 18mm, 4 mm× 12mm, 3.75mm ×16 mm)	Yes	Significant contrast stasis	Hemiparesis	Yes	Nine weeks	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
24	Velioglu/201221	37/F	NA/NM	Unruptured	ICA terminus	Saccular	No	23	Aspirin (100–300 mg/day) and clopidogrel (75 mg/day) before and after treatment, heparin during procedure	Leo, Silk	Yes	Slow flow in sac	Hemiparesis	Yes	Three days	SAH and diffuse brain edema	NA/NM	Unknown	NA/NM	Death
25		47/F	CN III palsy	Unruptured	ICA–ophthalmic	Saccular	No	20	Aspirin (100–300 mg/day) and clopidogrel (75 mg/day) before and after treatment, heparin during procedure	Silk	No	Slow flow in sac	No	Yes	Five days	SAH and diffuse brain edema	NA/NM	Unknown	NA/NM	Death
26		40/F	Mass effect	Unruptured	ICA–ophthalmic	Saccular	No	18	Aspirin (100–300 mg/day) and clopidogrel (75 mg/day) before and after treatment, heparin during procedure	Silk, Leo	No	Significant slow flow in sac	Intra-stent thrombosis	Yes	Five days	SAH and infarction	One additional Silk	Unknown	NA/NM	2
27		35/M	CN III palsy	Unruptured	ICA–supraclinoid	Fusiform	No	50	Aspirin (100–300 mg/day) and clopidogrel (75 mg/day) before and after treatment, heparin during procedure	Three Leo, two Silk	No	Slow flow in sac	No	Yes	30 days	ICH and IVH	NA/NM	Unknown	NA/NM	Death
28		40/F	Headache and ophthalmic symptoms	Unruptured	ICA–ophthalmic	Saccular	No	50	Aspirin (100–300 mg/day) and clopidogrel (75 mg/day) before and after treatment, heparin during procedure	Silk	No	Significant slow flow in sac	No	NA/NM	25 days	SAH	NA/NM	Unknown	NA/NM	Death
29	McAuliffe/201222	56/F	SAH	Ruptured	ICA–superior hypophyseal	Saccular	No	21	Loading dose aspirin (300 mg) and clopidogrel (600 mg) before treatment, heparin during procedure, aspirin and clopidogrel after treatment	Three Pipeline	No	Significant contrast stasis without discernible inflow jet	No	Yes	Eight days	SAH, aneurysm refilling with a new rupture point locule	One additional Pipeline	Unknown	NA/NM	Death
30	Colby/201323	NA/NM	NA/NM	Unruptured	ICA–ophthalmic	Saccular	No	3	Aspirin (325 mg/day) and clopidogrel (75 mg/day) for seven days before treatment, heparin during procedure	One Pipeline (4mm×16 mm)	No	Persistent filling of contrast	No	No	5 h	Diffuse SAH	NA/NM	Unknown	SAH from the aneurysm	Death
31	Darsaut et al./201324	69/F	Paraesthesias, hemiparesis	Unruptured	ICA–cavernous	Saccular	No	60	Aspirin (325 mg/day) and clopidogrel (75 mg/day) for seven days before treatment, aspirin and clopidogrel after treatment	Two Silk	No	Significant contrast stasis	Dysphasia, hemiparesis	Yes	One day	ICH	NA/NM	Unknown	Neutrophils infiltration	Death
32	Chalouhi/201325	46/F	Homonymous hemianopsia	Unruptured	ICA–supraclinoid	Saccular	No	28	Aspirin and clopidogrel before treatment	One Pipeline (4.25mm×30 mm)	No	Significant contrast stasis	Pipeline migration into sac	Yes	Three days	Extensive SAH, stent migration	Ventriculostomy, PAO with coils and Onyx	Pipeline migration into sac	NA/NM	Death
33	Toma/201326	60/F	Brainstem compression	Unruptured	VA	Saccular	No	25	Aspirin and clopidogrel before (300 mg/day) and after (75 mg/day) treatment, heparin for 5 days after treatment	Three Pipeline	No	Significant contrast stasis	No	Yes	One week	Extensive SAH and IVH	NA/NM	Unknown	NA/NM	Death
34		42/F	NA/NM	Unruptured	ICA–ophthalmic	Saccular	NA/NM	29	Aspirin and clopidogrel before (300 mg/day) and after (75 mg/day) treatment, heparin for five days after treatment	NA/NM	NA/NM	Significant contrast stasis	NA/NM	Yes	Four days	NA/NM	NA/NM	Unknown	NA/NM	Death
35		38/F	NA/NM	Unruptured	Basilar artery	Saccular	NA/NM	38	Aspirin and clopidogrel before (300 mg/day) and after (75 mg/day) treatment, heparin for five days after treatment	NA/NM	NA/NM	Significant contrast stasis	NA/NM	Yes	20 days	NA/NM	NA/NM	Unknown	NA/NM	Death
36	Kuzmik/201327	48/NA/NM	Nausea and vomiting	Unruptured	ICA–paraclinoid	Saccular	No	19	Heparin for 48 h after treatment and then aspirin and clopidogrel	Two Silk	No	Minimal residual neck filling	No	Yes	One week	Extensive SAH, partial recanalization of aneurysm	NA/NM	Unknown	NA/NM	Death
37	Piano/201328	66/F	NA/NM	Unruptured	Basilar artery	Saccular	No	>25	Aspirin and ticlopidine before (3–7 days) and after treatment	Pipeline	No	Significant contrast stasis without discernible inflow jet	No	Yes	Three weeks	SAH	NA/NM	Unknown	NA/NM	Death
38	Cruz/201329	NM	SAH	Ruptured	ICA–supraclinoid	Saccular	No	>25	Aspirin (325 mg) and clopidogrel (600 mg) before treatment, heparin during procedure, aspirin and clopidogrel after treatment	One Pipeline	Yes	Significant contrast stasis	No	NA/NM	Within 24 h	SAH	NA/NM	Unknown	NA/NM	Death
39	Chitale/2014 30	54/F	Headache	Unruptured	ICA–paraclinoid	Saccular	Yes	5.5	NA/NM	Pipeline	No	Significant contrast stasis	No	NA/NM	Within 1 h	Diffuse SAH	Ventriculostomy	Unknown	NA/NM	Death
40	Briganti/201531	41/F	Visual loss, ophthalmoplegia	Unruptured	ICA–supraclinoid	Saccular	No	35	Aspirin (150 mg) and clopidogrel (75 mg) before (five days) treatment, heparin during procedure	Two Pipeline	Yes	Significant contrast stasis	No	NA/NM	12 h	Diffuse SAH	NA/NM	Unknown	NA/NM	Death
41	Ikeda/201532	67/F	Decreased eye vision	Unruptured	ICA–supraclinoid, ICA–paraclinoid	Saccular	No	16	Aspirin (100 mg/day, 14 days), clopidogrel (75 mg/day, 14 days), and cilostazol (200 mg/day, two days) before and after treatment, heparin during procedure	One Pipeline (3.75mm×18 mm)	No	Significant contrast stasis	No	Yes	34 days	SAH	No	Unknown	Macrophage infiltration and wall degeneration	Death
42	Nerva/201533	30s/NA/NM	Headache and confusion	Ruptured	ICA–supraclinoid	BBA	No	5	Loading dosage aspirin (325 mg) and clopidogrel (75 mg) before treatment, heparin during procedure	One Pipeline	No	Contrast extravasation, without contrast stasis in the aneurysm	No	No	Five days	SAH and ICH	One additional Pipeline	Unknown	NA/NM	Death
43	Lin/201534	Middle-aged/NA/NM	Headache and diplopia	Unruptured	ICA–cavernous	Saccular	No	10	Aspirin (325 mg/day) and clopidogrel (75 mg/day) for before (seven days) and after treatment	One Pipeline (5mm×18 mm)	No	Significant contrast stasis without inflow jet	No	NA/NM	Six weeks	CCF	TVE of the aneurysm sac and CS with coils	Unknown	NA/NM	0
44		Middle-aged/NA/NM	CN III palsy	Unruptured	ICA–cavernous	Saccular	No	17	Aspirin (325 mg/day) and clopidogrel (75 mg/day) before (seven days) and after treatment	One Pipeline (4.5mm×20 mm)	No	Significant contrast stasis	No	NA/NM	Three days	CCF	TVE of the aneurysm sac and CS with coils	Unknown	NA/NM	0
45	Fox/201535	Elderly/M	Gait ataxia, hyperflexia	Unruptured	Basilar artery	Saccular	NA/NM	27	Dual antiplatelets before and after treatment	One Pipeline	No	Significant contrast stasis	No	Yes	One week	SAH	NA/NM	Unknown	Organized thrombosis, linear tear	Death
46	Mazur/201636	29/M	Headache	Ruptured	ICA-supraclinoid	BBA	No	4.3	Abciximab during procedure, aspirin and clopidogrel after treatment	One Pipeline (5mm×14 mm)	No	Without significant contrast stasis	No	Yes	Nine days	SAH and ICH	One additional Pipeline	Unknown	NA/NM	Death
47	Raychev/201637	Middle-aged/NA/NM	Hemiparesis and CN III palsy	Unruptured	ICA–PcomA	Saccular	NA/NM	>25	Aspirin (325 mg/day) and clopidogrel (75 mg/day) before treatment	One Pipeline	No	Significant contrast stagnation	No	NA/NM	Five months	SAH and ICH	Sacrifice of ICA	Unknown	NA/NM	NA/NM
48	Roy/201738	NA/NM	Incidental	Unruptured	ICA–cavernous	Saccular	NA/NM	17.4	NA/NM	Pipeline	NA/NM	NA/NM	NA/NM	NA/NM	11 days	CCF	ICA sacrifice	Unknown	NA/NM	0
49		NA/NM	Incidental	Unruptured	ICA–cavernous	Saccular	NA/NM	14.5	NA/NM	Pipeline	NA/NM	NA/NM	NA/NM	NA/NM	11 days	CCF	ICA sacrifice	Unknown	NA/NM	1
50		NA/NM	Incidental	Unruptured	ICA–cavernous	Saccular	NA/NM	31	NA/NM	Pipeline	NA/NM	NA/NM	NA/NM	NA/NM	Three days	CCF	ICA sacrifice	Unknown	NA/NM	0
51		Elderly patient/NA/NM	CN IV palsy	Unruptured	ICA–cavernous	Saccular	No	19	Aspirin and clopidogrel before treatment	One Pipeline	No	Significant contrast stasis	No	NA/NM	Six days	CCF	ICA sacrifice	Unknown	NA/NM	1
52		Elderly patient/NA/NM	CN III palsy	Unruptured	ICA–cavernous	Saccular	No	18.8	Aspirin and clopidogrel before treatment	One Pipeline	No	Significant contrast stasis	No	NA/NM	Six days	CCF	ICA sacrifice	Unknown	NA/NM	0
53	Oishi/201839	86/F	CN III palsy	Unruptured	ICA–cavernous	Saccular	No	20	Aspirin 105 mg/day and clopidogrel 50 mg/day for before (10 days) and after treatment, heparin during procedure	Three Pipeline (4.5mm×30mm, 4.75mm×30mm, 5mm×30 mm)	No	Significant contrast stasis	No	NA/NM	Six weeks	CCF	TVE of the aneurysm sac and CS with coils	Unknown	NA/NM	0
54	Hampton/201840	NA/NM	Headache, hemianopsia	Unruptured	ICA terminus	Saccular	No	35	Aspirin 75 mg/day and clopidogrel 75 mg/day for one week before treatment, heparin, aspirin and clopidogrel after treatment	One Pipeline (2.75mm ×20 mm)	No	Significant contrast stasis	No	Yes	Five days	SAH and IVH	NA/NM	Unknown	NA/NM	Death
55	Sami/20188	Young/NA/NM	NA/NM	Unruptured	ICA–cavernous	Pseudoaneurysm	No	6	Aspirin 325 mg/day and clopidogrel 75 mg/day before (one week) and after treatment, heparin during procedure	One Pipeline	No	Significant contrast stasis	No	Yes	One week	CCF	One additional Pipeline	Unknown	NA/NM	0
56	Nakae/201841	81/F	Diplopia	Unruptured	ICA–cavernous	Saccular	No	18	Aspirin 100 mg/day and clopidogrel 75 mg/day before treatment, heparin during procedure	One Pipeline (4.75 mm×25 mm)	No	Significant contrast stasis	No	NA/NM	10 days	SAH, CCF	TVE of the aneurysm sac and CS with coils	Unknown	NA/NM	1
57	Bhogal/201842	62/M	Progressive cognitive decline	Unruptured	MCA bifurcation	Dissecting	Yes	28	Aspirin 100 mg/day and clopidogrel 75 mg/day before (one week) and after treatment, heparin during procedure	One Pipeline at first admission, a second Pipeline six months later	No	Significant contrast stasis	No	Yes	Eight months	ICH	Decompressive craniectomy	Unknown	NA/NM	Death
58	Griessenauer/201943	69/F	SAH	Ruptured	VA	Dissecting	NA/NM	8	Loading dose of aspirin (650 mg) and clopidogrel (600 mg) before treatment, heparin during procedure, aspirin and clopidogrel after treatment	Pipeline	NA/NM	NA/NM	NA/NM	NA/NM	The same day	SAH	NA/NM	Unknown	NA/NM	Death
59	Piano/201944	70/M	NA/NM	Unruptured	Basilar trunk	Dissecting	NA/NM	> 25	Dual antiplatelet medication before and after treatment	One FRED	Yes	NA/NM	NA/NM	NA/NM	35 days	SAH	NA/NM	Unknown	NA/NM	Death
60	Sirakov/201945	NA/NM	Mass effect	Unruptured	ICA–ophthalmic	Saccular	No	> 25	Aspirin 100 mg/day and clopidogrel 75 mg/day before (≥3 days) and after treatment, heparin during procedure	One p64	Yes	Significant contrast stasis	No	NA/NM	Nine days	ICH	Conservative	Unknown	NA/NM	3

BBA: blood blister aneurysm; CCF: carotid-cavernous fistula; CN: cranial nerve; CS: cavernous sinus; F: female; FD: flow diverter; ICA: internal carotid artery; ICH: intracerebral hemorrhage; IVH: intraventricular hemorrhage; M: male; MCA: middle cerebral artery; mRS: modified Rankin Scale; NA/NM: not applicable/not mentioned; PAO: parent artery occlusion; PcomA: posterior communicating artery; SAH: subarachnoid hemorrhage; TVE: transvenous embolization; VA: vertebral artery

Figure 1.

Flow chart of the searching strategy.

Before flow diverter placement

Of the 49 patients with description of presenting symptoms, six (12.2%) patients were incidentally diagnosed, five (10.2%) patients were admitted for aneurysmal rupture, two (4.1%) patients presented with non-subarachnoid hemorrhage-related headache and 36 (73.5%) patients presented with symptoms of mass effect by the responsible aneurysm. The treated aneurysms were unruptured in 91.7% (55/60) of the patients. The intracranial locations of the aneurysms were at middle cerebral artery, internal carotid artery (ICA) terminus, ICA-posterior communicating artery, ICA-supraclinoid segment, ICA-paraclinoid segment, ICA-superior hypophyseal segment, ICA-ophthalmic segment, ICA-cavernous sinus segment, basilar artery, vertebral artery in two (3.3%), two (3.3%), one (1.7%), 12 (20%), two (3.3%), one (1.7%), 13 (21.7%), 14 (23.3%), 10 (16.7%) and three (5%) patients, respectively (Figure 2(a)). The morphologies were blood blister aneurysm, pseudoaneurysm, fusiform/dissecting aneurysm, saccular aneurysm in two (3.3%), one (1.7%), 13 (21.7%) and 44 (73.3%) patients, respectively (Figure 2(b)). Three (6.8%, 3/44) aneurysms were demonstrated to be partially thrombosed before flow diverter placement. The sizes of the aneurysms were <5 mm, 5–10 mm, >10–≤25 mm, and >25 mm in two (3.3%), five (8.3%), 29 (48.3%) and 24 (40%) patients, respectively (Figure 2(c)).

Figure 2.

Statistical diagrams of the ruptured aneurysms after flow diversion.

(a) Intracranial location of the delayed ruptured aneurysms. (b) Morphology of the delayed ruptured aneurysms. (c) Maximal size of the delayed ruptured aneurysms. (d) The interval from successful deployment of flow diverter to delayed aneurysmal rupture.

CS: cavernous sinus; ICA: internal carotid artery; MCA: middle cerebral artery; PcomA: posterior communicating artery; BBA: blood blister aneurysm; D: day; M: month; W: week

Peri-flow diverter placement

As for the type of flow diverters used, FRED, Silk, p64 and Pipeline were solely used in one (1.7%, 1/58), 17 (29.3%, 17/58), one (1.7%, 1/58) and 32 (55.2%, 32/58) patients, respectively. Different flow diverters were conjointly used in 12.1% (7/58) of the patients. Multiple flow diverters were used in 38.3% (18/47) of the patients. Coil assistance was applied in 13.0% (7/54) of the patients. Immediate intra-aneurysmal contrast stagnation was demonstrated in 92.6% (50/54) of the patients. Other procedure-related complications occurred in 21.6% (11/51) of the patients immediately after flow diverter placement.

Outcome of flow diverter placement

Before post-procedural rupture, formation of intra-aneurysmal thrombus was demonstrated in 97.3% (36/37) of the patients after flow diverter placement. With respect to the timeline of delayed rupture, 11.7% (7/60) of the patients experienced aneurysmal rupture in 1 day post flow diverter placement, 38.3% (23/60) of the patients between the second day and first week, 30% (18/60) of the patients between the second week and first month, 10% (6/60) of the patients between the second and third month, 8.3% (5/60) of the patients between the third and sixth month and 1.7% (1/60) of the patients beyond the sixth month, respectively (Figure 2(d)). Delayed aneurysmal rupture led to intracranial hemorrhage and carotid–cavernous sinus fistula (CCF) in 76.8% (43/56) and 23.2% (13/56) of the patients, respectively. In the patients with intracranial hemorrhage after delayed aneurysmal rupture, only four (9.5%, 4/42) survived following further treatment. However, all of the patients with CCF survived and experienced good recovery. The definite cause of delayed rupture was identified in two (3.3%, 2/60) patients as flow diverter migration. Of the 55 patients with description of outcome, 14 (25.5%) patients achieved good recovery, one (1.8%) patient was severely disabled, 40 (72.7%) patients died.

Antithrombotic regimen

Preoperative antiplatelet regimen could be identified in 54 patients, of whom two (3.7%) received single antiplatelet agent (including one receiving abciximab), 51 (94.4%) received dual antiplatelet agents and one (1.9%) received triple antiplatelet agents. No patient received preoperative anticoagulation agent. Postoperatively, antithrombotic regimen could be identified in 46 patients, of whom six experienced aneurysmal rupture during receiving single antiplatelet agents (13.0%, including one receiving additional anticoagulation agent), 39 during receiving dual antiplatelet agents (84.8%, including two receiving additional anticoagulation agent), one (2.2%) during receiving triple antiplatelet agents.

Discussion

Mechanism of delayed rupture

Flow diverter has become a more and more popular option, especially for the treatment of complex intracranial aneurysms. Some illustrative cases suited for flow diverter placement are presented in Figure 3. Delayed aneurysmal rupture is a severe complication after flow diverter placement, which could lead to a catastrophic consequence (Figure 4). The reported incidence varies greatly between different centers. In a single-center study of the 44 patients with cavernous carotid aneurysms treated with Pipeline, 11.4% (5/44) of the patients developed delayed CCF.³⁸ However, in another international multi-center retrospective study of intracranial aneurysms treated with Pipeline, the reported incidence of delayed rupture was 0.6% (5/793).⁹ The mechanism is still unknown. According to the past studies, several factors might conjointly contribute to this severe consequence.

Figure 3.

Illustrative cases suitable for flow diverter placement.

(a) and (b) Multiple aneurysms at the paraclinoid segment of internal carotid artery. Large or giant aneurysm at the cavernous (c) and ophthalmic (d) segment. Large (e) and giant (f) aneurysms at the vertebra-basilar artery.

Figure 4.

Illustrative case of delayed aneurysmal rupture after flow diverter placement.

A 39-year-old woman is admitted for visual deterioration of the left eye. (a) Angiogram of the left ICA in AP view shows a giant aneurysm at the left ophthalmic segment of ICA. (b) X-ray after placement of a 3.5mm × 30mm Pipeline Flex shows stagnation of the contrast agent in the aneurysm. (c) Angiogram of the left ICA in AP view shows successful obliteration of the aneurysm after introducing several coils. (d) The patient experiences a sudden decline in mental state one day after flow diverter placement. Computed tomography shows extensive subarachnoid hemorrhage due to delayed aneurysmal rupture.

AP: anteroposterior; ICA: internal carotid artery

First, flow diverter placement leads to increased intra-aneurysmal pressure. Compared with the successfully occluded aneurysms, delayed ruptured aneurysms endure more intra-saccular pressure after flow diverter placement by computational hemodynamic analysis.¹⁶ This phenomenon can be explained in two possible ways. On one hand, successful deployment of the flow diverter stent could eliminate the pre-existing proximal stenosis of the parent artery. Though it is not the aim, reduction in proximal stenosis leads to reduced proximal resistance and subsequent increased pressure in the aneurysm segment. On the other hand, placement of flow diverter results in an increased resistance in the aneurysm segment of the parent artery, which would cause reduction in distal vascular resistance and increase in systemic blood pressure by complex autoregulation to maintain blood flow. The intra-aneurysmal pressure would increase with the increase in flow rate.

Second, though a key step in permanent aneurysm repair, intra-aneurysmal thrombus formation following flow diverter placement could also provoke a cascade of local inflammation and autolysis, leading to delayed aneurysm rupture.¹⁵,¹⁷,³² This process is a known source of protease secretion that can weaken the aneurysmal wall.³⁵ Due to the destabilization of the aneurysm wall by intra-aneurysmal thrombus, any residual filling of the aneurysm sac after flow diverter deployment may have the potential for causing subsequent rupture.³²,⁴⁶ This deduction is based on clinical observation and postmortem histopathological investigations of the ruptured cases and previous study of abdominal aortic aneurysms with intra-luminal thrombus.¹⁷ In this study, before post-procedural rupture, partial formation of intra-aneurysmal thrombus was demonstrated in 97.3% (36/37) of the patients after flow diverter placement. However, it is still a mystery why intra-aneurysmal thrombosis may result in permanent cure in some patients but trigger autolysis and future rupture in other patients.

Other risk factors of delayed rupture include: 1) large and giant aneurysm; 2) symptomatic aneurysms; 3) saccular aneurysm with an aspect ratio of > 1.6; 4) delayed flow diverter migration into the aneurysm sac; 5) mechanical injury by flow diverter.¹³,¹⁵,²⁵,³⁵ In this study, we found that 88.8% and 97.8% of the aneurysms experiencing delayed rupture were large/giant and symptomatic aneurysms, respectively. In addition, delayed flow diverter migration into the aneurysm sac was also identified in two patients, which accounts for a rare cause of delayed aneurysm rupture.¹³,²⁵ Linear tear of the aneurysm wall was identified in one patient during autopsy.³⁵ Histopathological examination showed that the aneurysmal wall was extremely thin and microfissures were also noted. No inflammatory cells were detected within the wall and thrombus. Hence, in view of the aforementioned reasons, mechanical stretch was considered the cause of delayed rupture in this patient. Besides, due to the disruption in all layers of aneurysm wall, blood blister aneurysm or pseudoaneurysm is at higher risk of delayed rupture.³³,³⁶ Antithrombotic regimen might present another factor in delayed aneurysmal rupture. However, on one hand, the antithrombotic regimen varies greatly among different institutions with regard to the dosage, duration and agent selection. On the other hand, no study with large sample size focusing on antithrombotic regimen on delayed aneurysmal rupture has been published. Statistical analysis with regard to the antithrombotic regimen on delayed aneurysmal rupture could not be conducted at present. Of note, there were three patients who experienced delayed aneurysmal rupture during receiving single antiplatelet after ceasing the previous dual antiplatelet regimen.¹⁵ Hence, the effect of antiplatelet regimen on aneurysmal rupture is a complicated issue to be investigated. Flow diverter coated with antithrombotic shield presented to be a new technology in the treatment of intracranial aneurysms.⁴⁷,⁴⁸ As patients using flow diverter with shield technology adopt only single antiplatelet regimen, the risk of delayed aneurysmal rupture might be lower in theory. However, its effectiveness and safety need to be verified by further study.

Preventive measures

As was demonstrated by our study, delayed rupture meant a catastrophic event to most of the afflicted patients. Preventive measures to avoid this fatal complication are of great importance. Regrettably, to our knowledge, there has been no well-established suggestion to prevent delayed aneurysm rupture after flow diverter placement. All of the available measures are based on the speculated mechanism of delayed rupture. As hemodynamic study has demonstrated increased intra-aneurysmal pressure after flow diverter placement, some authors advocated careful post-procedural blood pressure control.¹⁶,³² However, no comparative study on blood control in reducing delayed aneurysm rupture has ever been published until now. The effectiveness is to be verified. To achieve complete and stabilized aneurysm thrombosis and early isolation from the blood flow, coil assistance or multiple stent-in-stent flow diverters were also suggested.¹⁵,¹⁶,³²,⁴⁹ But, according to our study, multiple flow diverters were used in 38.3% (18/47) of the patients who experienced delayed rupture. Coil assistance was applied in 13.0% (7/54) of the patients. Of note, multiple stent-in-stent flow diverters carry the risk of branch artery occlusion. To stabilize the already thrombosed aneurysm after flow diverter placement, some authors proposed reducing the post-procedural dose of antiplatelet agent.³² However, the dose and duration of antiplatelet agent post flow diverter placement has always been a question of debate. With respect to the different brands of flow diverters on the occurrence of delayed aneurysm rupture, no comparative study has ever been reported. In this review, FRED, Silk, p64 and Pipeline were solely used in one (1.7%, 1/58), 17 (29.3%, 17/58), one (1.7%, 1/58) and 32 (55.2%, 32/58) patients, respectively. Different generation of flow diverters might also affect the incidence of post-procedural aneurysm rupture. According to the preliminary reports, the second-generation flow diverters seem safer with regard to the issue of delayed rupture.⁴⁴,^50–52 But, as the second-generation flow diverters were just used in a relatively short period time and a limited population, prospective and comparative study with their first-generation counterparts is needed. Besides, as a majority of the delayed ruptured aneurysms were large/giant and symptomatic ones, the decision of flow diverter treatment should be prudent and under sufficient pre-procedural evaluation.

Treatment and outcome

In general, delayed aneurysm rupture after flow diverter placement can present with acute intracranial bleeding (subarachnoid hemorrhage and/or intracerebral hemorrhage) or CCF. Acute intracranial bleeding always means a fatal event. In our review, only four (9.5%, 4/42) patients survived following further treatment. Because of the rapidity of deterioration in general state, most of the patients in this subgroup have no opportunity for further treatment. Even with aggressive management, most of the cases would also experience inevitable deterioration and death.¹¹,²²,²⁵,³⁰,³⁶ Of note, there was one patient who survived and experienced complete thrombosis of the aneurysm with just conservative management.⁴⁵

Patients presented with CCF after flow diverter placement would experience a relatively more favorable outcome. According to this review, all of the patients with CCF survived and experienced good recovery. The treatment for this subgroup of patients was diverse and included transvenous embolization with coils, placement of an additional flow diverter, and ICA occlusion.⁸,¹²,¹⁵ Due to the higher metal coverage of flow diverter, it is difficult to advance the microcatheter through the flow diverter to the carvernous sinus. And embolization of the cavernous sinus via transarterial approach is always impossible.³⁸,³⁹ Hence, transvenous approach is the preferred route. But attention should be paid to the possibility of cranial nerve palsy by mass effect of coils. If transvenous approach is inaccessible, ICA sacrifice could be considered under prudent evaluation with balloon occlusion test. There was one report that the CCF was successfully treated with an additional flow diverter,⁸ but this case presented with a low-flow CCF. The CCF was gradually occluded in a delayed manner. Hence, the efficacy and safety of placing additional flow diverters warrants further investigation.

Conclusion

Delayed rupture of intracranial aneurysm after flow diverter treatment is a rare but usually fatal complication, the mechanism of which is still obscure to us. Increased intra-aneurysmal pressure, destabilization of the aneurysm wall by intra-aneurysmal thrombus, persistent residual intra-aneurysmal flow, characteristics of the specific aneurysm and mechanical injury by the flow diverter might conjointly contribute to the final delayed rupture. There has been no established preventive measure to decrease the incidence of delayed rupture yet. The proposed existing measures need to be verified by future study. The treatment and outcome depend on the presentation of delayed rupture. Patients presenting with aneurysm-related intracranial hemorrhage have a dismal outcome. Those presenting with CCFs usually have a satisfactory recovery. Flow diverter represents groundbreaking progress in the treatment of intracranial aneurysms, but is not an infallible method. Patients receiving flow diverter treatment should be evaluated individually.

ORCID iDs

Xianli Lv https://orcid.org/0000-0001-8270-8464

Jinlu Yu https://orcid.org/0000-0003-2329-7946