Neuroradiology (2014) 56:155–161 DOI 10.1007/s00234-013-1302-2

INTERVENTIONAL NEURORADIOLOGY

Delayed ipsilateral parenchymal hemorrhage following treatment of intracranial aneurysms with flow diverter Catherine Tomas & Azzedine Benaissa & Denis Herbreteau & Krzysztof Kadziolka & Laurent Pierot

Received: 13 July 2013 / Accepted: 4 November 2013 / Published online: 17 November 2013 # Springer-Verlag Berlin Heidelberg 2013

Abstract Introduction The use of flow diverters (FDs) has shown promising results, particularly in the treatment of large or complex intracranial aneurysms. However, some complications can occur both during and after FD treatment, including delayed ipsilateral parenchymal hemorrhage (DIPH). The clinical presentation, etiopathogeny, and management of this complication are not well understood. We report a series of four patients with DIPH and discuss the potential mechanisms and modalities of treatment. Methods Four patients treated with FDs and presenting with DIPH were diagnosed in two different centers. Clinical and imaging data were reviewed before and after the procedure. Characteristics of the intraparenchymal hematomas, the modalities of treatment, and clinical course were analyzed. Results Intraparenchymal hemorrhage occurred 1 to 4 days after aneurysm treatment with FDs. All hemorrhages were situated in the ipsilateral hemisphere and were anatomically remote from the treated aneurysm. The four patients were treated with emergency surgery (hematoma evacuation). All patients had a favorable clinical outcome (mRS=1) at midterm evaluation. Follow-up imaging showed good permeability of the FD in all subjects and complete aneurysm occlusion in all patients.

C. Tomas : A. Benaissa : K. Kadziolka : L. Pierot Department of Neuroradiology, Centres Hospitaliers Universitaires de Reims, Reims, France D. Herbreteau Department of Neuroradiology, Centres Hospitaliers Universitaires de Tours, Tours, France L. Pierot (*) Service de Neuroradiologie, Hopital Maison Blanche, 45, rue Cognacq Jay, 51092 Reims Cedex, France e-mail: [email protected]

Conclusion From the literature review, DIPH appears to be more frequent than delayed aneurysm rupture and may be a cause of increasing concern for the use of flow diverters. However, the mechanisms of DIPH are not completely understood. Surgical evacuation of the hematoma seems to be feasible with acceptable safety and good clinical outcomes. Keywords Flow diverter . Intracerebral hemorrhage . Aneurysm . Delayed intracerebral hematoma . Remote intracerebral hemorrhage Abbreviations ASA Acetylsalicylic acid DIPH Delayed ipsilateral parenchymal hemorrhage FD Flow diverter ICA internal carotid artery ICH Intracerebral hemorrhage IA Intracranial aneurysm SAH Subarachnoid hemorrhage

Introduction Endovascular treatment is now the first line of treatment for intracranial aneurysms (IAs) [1–3]. Since the introduction of the Guglielmi detachable coil system (Target Therapeutic/ Boston Scientific, Fremont, CA) in 1991, endovascular treatment of IAs has evolved from balloon or stent-assisted coiling to the use of flow diverters (FDs). When a FD is placed in the parent artery, it redirects blood flow away from the aneurysm and through the parent vessel, thereby promoting aneurysmal thrombosis and serving as a support for neointimal layer regrowth that subsequently covers the FD and the aneurysm neck. Thus, over time, complete aneurysm occlusion is achieved [4]. These devices are indicated for the treatment of large and giant, fusiform, and wide-neck aneurysms.

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Complications such as aneurysm rupture and thromboembolic events can occur after FD treatment. With the increasing use of FD treatment, unexpected complications such as delayed aneurysm rupture have been reported [4–8]. More recently, delayed ipsilateral parenchymal hematoma (DIPH) has also been reported as a potential complication of FD treatment, but very few cases were analyzed [9]. In our series, four patients who were treated with FD presented with DIPH in the postoperative period. Clinical presentation, modalities of treatment, and outcomes were analyzed, and their potential mechanisms were also discussed.

Materials and methods Patient data In the present study, 70 patients harboring 70 IAs were treated with FDs at two centers in France (Reims and Tours). The indications for FD placement were unruptured aneurysms developed in the anterior circulation. Four patients (5.7 %) treated with FDs (two in Reims and two in Tours) who had post-procedure DIPH were studied. Two out of four were treated with FD because of their shape (fusiform); the remaining ones were treated by FD because of aneurysm recanalization after standard treatment. The population studied consisted of three females and one male who were 36, 40, 46, and 61 years in age, respectively. One patient had a known history of hypertension. All subjects had a modified Rankin Scale (mRS) score of 0 before FD treatment. Aneurysm data All of the aneurysms were situated in the internal carotid artery (ICA). Two aneurysms were saccular and two were fusiform. Aneurysm size was between 5 and 16 mm. Two aneurysms had already been treated with coils due to previous rupture. In patient 1, the aneurysm was treated with coils 66 months before treatment with FD. Another patient (patient 2) was previously treated three times: he was first treated with coils at the time of aneurysm rupture retreated at 40 months with additional coiling and again at 21 months after the second treatment with coiling and stenting due to aneurysm recanalization. Eleven months later, the patient was retreated with FD. The two other patients (patient 3 and patient 4) had unruptured aneurysms and were treated with FDs because of the aneurysm shape (fusiform) (Table 1). The decision to treat these aneurysms with FDs was made from multidisciplinary consultation with interventional neuroradiologists and neurosurgeons.

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Procedure All patients were pretreated with clopidogrel (75 mg) 3 to 7 days before FD treatment. No measurement of the platelet response to clopidogrel was performed. For all patients, the treatment was performed under general anesthesia by an experienced interventional neuroradiologist with at least 5 years of experience. 3D reconstruction and 2D working projections were employed to correctly measure the parent artery in order to select the appropriate FD size. Per procedural heparinization associated with a loading dose of 250 mg of aspirin was used in all cases. Transfemoral access was performed with a long 6 F Flexor shuttle introducer (Cook Medical, Bloomington, IN). A coaxial system catheter was used for the stent navigation associating a 6 F-guiding catheter in which a delivery microcatheter was inserted [0.027-in. ID microcatheter Marksman catheter (Covidien, Irvine, CA) for the Pipeline FD; 0.040-in. ID microcatheter Surpass (Stryker Neurovascular, Kalamazoo, MI) for the Surpass FD]. After placement of the microcatheter, the FD was deployed to cover the aneurysm neck. The correct deployment of the FD was controlled by digital subtraction angiography (DSA) and angiographic computed tomography. In all cases, no per procedural or immediate postprocedural complications were observed. No aneurysmal rupture or thromboembolic event was encountered. No perforation of a distal vessel was observed. Post-procedural medication included dual antiplatelet therapy [75 mg/day clopidogrel and 160 mg/day aspirin (ASA)]. No post-procedural heparinization was used. All patients underwent brain imaging by magnetic resonance imaging (MRI) or computed tomography (CT) during their post-procedure hospital stay. The following characteristics of intraparenchymal hemorrhage were reviewed: delay between procedure and bleeding, location, size, clinical signs, and treatment. The clinical course of each patient was evaluated according to the mRS score before FD treatment at 1 and at 3–4 months after the procedure (midterm followup). Midterm imaging follow-up (DSA or CTA) was evaluated 3–4 months after the FD procedure. Aneurysm occlusion was evaluated using a 3-grade scale: (A) complete occlusion, (B) neck remnant, and (C) aneurysm remnant. Parent artery patency was also evaluated as permeable or occluded.

Results Three out of four patients in whom DIPH occurred were treated with Pipeline (one device per patient for patients 1 and 2 and four devices for patient 4) and the remaining one with Surpass (1 device).

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Table 1 Clinical and imaging data Patient 1

Patient 2

Patient 3

Patient 4

Sex Age Hypertension Clinical presentation Aneurysm location

M 36 No SAH ICA

F 40 Yes SAH ICA

F 46 No Fortuitous discovery Cavernous ICA

Aneurysm diameter Aneurysm morphology Previous treatment Time between the two treatment

4/5 mm Saccular Coils 66 months

6, 6/5,4 mm Saccular Coils + stent 11 months

16/13 mm Fusiform NO –

F 61 No Diplopia nerve III paralysis Two aneurysms carotidophthalmic anterior cavernous ICA 10/8 mm Fusiform NO –

Type of flow diverter Number of flow diverters Per procedural complications Anticoagulation treatment

Immediate flow reduction Time to bleed Intraparenchymal hemorrhage location Hematoma size Clinical signs Surgical hematoma

Pipeline 1 No Clopidogrel 75 mg (3 months); ASA 160 mg (1 year) Yes 4 days Frontal IPH 31/50 mm Aphasia Yes

Pipeline 1 No Clopidogrel 75 mg (3 months); ASA 160 mg (1 year) Yes 1 day Frontal IPH + SAH 60/45 mm Hemiparesis Yes

Surpass 1 No Clopidogrel 75 mg (3 months); ASA 160 mg (1 year) Yes 3 days Frontal IPH + SAH 50/46 mm Headaches Yes

Pipeline 4 No Clopidogrel 75 mg (3 months); ASA 160 mg (1 year) Yes 2 days Frontal IPH + SAH 63/20 mm Hemiparesis and mydriasis Yes

Clinical outcomes

Total recovery

Partial recovery and hand paresis

Partial recovery and memory difficulties

Partial recovery, difficulties to talk, and frontal lobe syndrome

Intraparenchymal hemorrhage characteristics The clinical status of all patients remained unchanged immediately after the FD procedure. Patients 1 and 2 did not undergo brain imaging between the end of the procedure and the occurrence of the intracerebral hematoma. Patients 3 and 4 underwent brain imaging (MRI) 1 day after the procedure and showed no post-procedural complications (i.e., no intracranial bleeding or ischemic complications) (Fig. 1). Intraparenchymal hemorrhages occurred in patients 1–4 on days 4, 1, 3, and 2 after the procedure, respectively. The hemorrhages were associated with a subarachnoid hemorrhage (SAH) in three patients, subdural bleeding in one patient, and intraventricular hemorrhage in one patient (Fig. 1). All hemorrhages were anatomically remote from the treated aneurysm. The hematomas were situated in the ipsilateral cerebral hemisphere (frontal region) in all patients. The average size of the greater length was 55.8±6.7 mm (range 50–63, median 55). Hemorrhages were discovered by hemiparesis in two patients (patient 2 and patient 4), aphasia (patient 1), and headache (patient 3) (Table 1). All four patients underwent

emergency surgery because of the mass effect and received platelet transfusion before surgery. A craniotomy was performed for the removal of the intraparenchymal hematoma. At the end of the procedure, no further bleeding was observed in the surgical area. Postoperative treatment with clopidogrel was interrupted, and ASA was maintained to prevent FD thrombosis. Clopidogrel was reintroduced between 7 and 14 days after the procedure. No measurement of the platelet response to clopidogrel was performed. CT controls were performed after the surgery. Clinical course Patient 1 completely recovered from aphasia at the midterm follow-up (mRS=2 at 1 month; mRS=1 at midterm). Patient 2 partially recovered with remaining right hand paresis (mRS= 4 at 1 month; mRS=1 at midterm). Patient 3 complained of periodic memory disturbances, but no focal neurologic disorder was observed (mRS=1 at 1 month and at midterm). Patient 4 experienced a septic shock caused by a urinary infection after surgery and was hospitalized for 43 days in the ICU. He had a discrete frontal lobe syndrome 4 months

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Fig. 1 Pretreatment angiography (a) showing a right fusiform aneurysm associated with a second carotid-ophthalmic aneurysm. Axial FLAIR MR image (b) performed 1 day after the procedure showed no post-procedure complications (no intracranial bleeding or ischemic complications). Two days later, the patient presented hemiparesis and mydriasis. CT (c)

revealed a right frontal hematoma with SAH and subdural hematoma, inducing a mass effect treated by surgical way. CT control was performed after surgery (d). Axial Flair MR image (e) and 3D angiography (f) 4 months after the surgery showed satisfying brain decompression and a complete aneurysm occlusion with no stenosis of the parent artery

after treatment (mRS=4 at 1 month; mRS=1 at midterm) (Table 2).

with FDs, we conducted a retrospective analysis of the frequency, clinical presentation of DIPH, modalities of management, and clinical outcomes.

Imaging follow-up Frequency Angiography was the latest imaging control obtained in three patients (patients 1, 2, and 4). Angiographic imaging was performed 5 months post-procedure for patients 1 and 2 and performed 4 months after FD placement for patient 4. For patient 3, an MRI and CTA were performed 5 months after the procedure because angiography could not be performed due to the agitation of the patient. FDs were permeable in all patients. Complete aneurysm occlusion was obtained in all patients at the midterm follow-up visit.

In our series, DIPH was observed in 4/70 patients (5.7 %). In the large RADAR survey that retrospectively analyzed the rate of aneurysm rupture following FD treatment in 53 centers worldwide, DIPH was observed in 14/720 patients (1.9 %) [10]. In other series, DIPH was observed in 1.1 to 8.5 % [9, 11–13]. The occurrence of DIPH seems to be more frequent than delayed aneurysm rupture. Delayed aneurysm rupture was observed in 14/1,421 patients (1.0 %) in the RADAR survey [10], and Saatci et al. reported a 0.5 % rate of delayed aneurysm rupture (1/191) [11].

Discussion Characteristics of DIPH DIPH has recently emerged as a threatening complication of IA treatment with FDs, but very few cases have been analyzed [9]. Using a database of all patients with aneurysms treated

In our series, DIPH occurred in three out of four patients treated with the Pipeline FD and in one patient treated with

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Table 2 mRS, 3-grades scale, and stent patency

Patient 1

Patient 2

Patient 3

Patient 4

mRS initial mRS at 1 month mRS at midterm 3-grade scale before treatment 3-grades scale after treatment (midterm evaluation)

0 2 1 C A

0 4 1 C A

0 1 1 – A

0 4 1 – A

Permeability of flow diverter after treatment

Yes

Yes

Yes

Yes

the Surpass FD. All cases of DIPH reported by Cruz et al. were with the same FD (Pipeline). This is probably due to the fact that the Pipeline FD is more commonly used. DIPH occurred a few days after treatment (between 1 and 4 days after the procedure). Similarly, in the Cruz et al. study, DIPH occurred a few days after the procedure (between 1 and 6 days) [9]. However, in the PUFS trial, DIPH occurred as late as 14 days after FD treatment [12]. In both our series and in Cruz et al., all aneurysms were located in the anterior circulation and varied in size (4 to 16 mm in our study; 5 to 21 mm in the Cruz et al. study). In addition, the hematomas described in both series had similar characteristics (i.e., remote from the treated aneurysm and on the ipsilateral side). In our series, hematomas were associated with SAH in three out four patients (with subdural bleeding in one patient) and with intraventricular hemorrhage in one patient (Fig. 1).

does not appear to be related to the aneurysm size on the contrary to delayed aneurysm rupture (Table 1) [9]. Dual-agent antiaggregation regimen and cardiovascular risk factor

The mechanism of DIPH remains unclear. Three hypotheses can be proposed to explain the occurrence of remote ipsilateral parenchymal hematoma after the flow diversion procedure.

Other factors can also promote bleeding. Several series have shown an increased risk of bleeding events in patients with cerebrovascular or cardiovascular disease on dual antiplatelet therapy compared to those on single antiplatelet therapy [15, 16]. Dual antiplatelet therapy can also increase the hematoma volume in case of bleeding leading to acute cerebral deterioration of the intracerebral hemorrhage (ICH) and likelihood for a surgical hematoma evacuation [17]. Secondly, hypertension is a firmly established risk factor for intracerebral hemorrhage in the general population and even more so in patients with intracerebral aneurysms [18]. Toyoda et al. demonstrated that an increased blood pressure while taking antithrombotic medication was positively associated with the development of an intracranial hemorrhage [19]. One of our patients was known to be hypertensive, highlighting the increased risk of intracerebral bleeding over the general population.

Hemorrhagic transformation of an ischemic lesion

Intraparenchymal hematoma in FDs versus stents

DIPH can be the result of hemorrhagic transformation of an ischemic lesion. This can either be due to thromboembolic events during the diagnostic phase of treatment or distal microemboli consecutive to intrastent thrombosis and foreign bodies [14]. However, no ischemic lesion was observed on the postoperative MRI performed before bleeding in two patients in our series.

Hemorrhagic complications are less frequent after stentassisted coiling than after FD treatment. As previously analyzed, DIPH is observed in 1.1 to 8.5 % of patients treated with FDs [9–13]. In a literature survey by Shapiro et al., hemorrhagic complications were observed in 2.2 % of patients, which was considered comparable to the rate observed with standard coiling [20]. However, these hemorrhagic complications were not precisely described, and some complications were probably not really DIPH.

Etiology and pathogenesis

Flow modifications Cebral et al. hypothesized that FD use not only modifies intraaneurysm flow but also intracerebral blood flow [6]. Cruz et al. indicated that treatment of anterior circulation aneurysms using FDs could change the blood pressure waveform inducing a larger pulse pressure that increases the pressure transmitted to the aneurysm and the distal cerebral arteries leading to hemorrhagic complications (aneurysm rupture and intraparenchymal hemorrhage) [9]. This type of complication

Management of DIPH Etiology and pathogenesis for DIPH has not been clearly identified. As a consequence, no real prevention of this complication is currently feasible. The optimal dual antiplatelet treatment (medications, dose, and duration) has to be precisely defined, and further studies are needed on this topic.

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Curative treatment of DIPH is based on surgery in the case of compressive hematoma. Neurosurgeons are often reluctant to perform this type of surgery because of the high risk of massive bleeding during the procedure on patients under dual antiplatelet therapy. In the series by Cruz et al., the four patients with DIPH did not have surgery, and two of them had unfavorable outcomes (mRS scores, 4 and 6). All patients in our series had surgical evacuation of the hematoma (after platelet transfusion) with good midterm clinical outcomes (mRS=1 for all four patients) [6]. The overall good clinical outcomes seen in our series suggest that emergency surgery after platelet transfusion is a good treatment option in the case of compressive hematomas. The management of antiplatelet treatment after surgery is critical. On the one hand, continuation of antiplatelet treatment can be associated with rebleeding in the surgical area. On the other hand, the risk of FD thrombosis is high if no antiplatelet treatment is given. For our patients, single antiplatelet treatment with aspirin was started the day after surgery, and no bleeding was observed in the surgical area. Limitations This study is retrospective, and large prospective series are certainly needed to precisely determine the frequency of this complication as well as pathogenesis and treatment. The evaluation of the antiplatelet response is lacking. However, few studies have evaluated the interest of testing clopidogrel resistance in neuro-interventional practice. An association has been described between clopidogrel hyperresponse and hemorrhagic complications, as well as between clopidogrel resistance and thromboembolic complications [21, 22]. An important variability has been shown between these tests that are difficult to be used in daily practice [23, 24] In summary, the frequency of DIPH is not precisely defined but is likely between 1.1 and 8.5 %. Based on our experience and reports from the literature, DIPH appears to be more frequent than delayed aneurysm rupture after FD treatment. The pathogenesis of DIPH still remains unclear but is probably multifactorial, combining hemorrhagic transformation of ischemic lesions, flow modifications, and dual antiplatelet treatment. Further studies are certainly necessary to optimize antiplatelet treatment after FD treatment, taking into account the relative risks of thromboembolic events and DIPH. Surgical evacuation also seems to improve the clinical outcomes of patients with DIPH. Acknowledgments We thank the Covidien Neurovascular Clinical and Scientific Communications Team. We gratefully acknowledge the contribution of Rachel Castro, MPH, in manuscript preparation. Conflict of interest LP consults for Codman, Covidien, Microvention, Penumbra and Sequent.

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