Parent vessel occlusion after Pipeline embolization of cerebral aneurysms of the anterior circulation

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  • 1 Departments of Neurological Surgery and Radiology, Division of Cerebrovascular/Neurointerventional Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois;
  • 2 Departments of Radiology,
  • 3 Neurology, and
  • 4 Neurological Surgery, Bernard and Irene Schwartz Neurointerventional Radiology Section, New York University Langone School of Medicine, New York, New York;
  • 5 Departments of Neurological Surgery and Radiology, Universitätsspital Basel, Switzerland;
  • 6 Department of Neurosurgery, Maimonides Medical Center, Brooklyn, New York; and
  • 7 Department of Neurology, Rochester General Hospital, Rochester, New York
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OBJECTIVE

The Pipeline Embolization Device (PED) is now a well-established option for the treatment of giant or complex aneurysms, especially those arising from the anterior circulation. Considering the purpose of such treatment is to maintain patency of the parent vessel, postembolization occlusion of the parent artery can be regarded as an untoward outcome. Antiplatelet therapy in the posttreatment period is therefore required to minimize such events. Here, the authors present a series of patients with anterior circulation aneurysms treated with the PED who subsequently experienced parent vessel occlusion (PVO).

METHODS

The authors performed a retrospective review of all anterior circulation aneurysms consecutively treated at a single institution with the PED through 2014, identifying those with PVO on follow-up imaging. Aneurysm size and location, number of PEDs used, and follow-up digital subtraction angiography results were recorded. When available, pre- and postembolization platelet function testing results were also recorded.

RESULTS

Among 256 patients with anterior circulation aneurysms treated with the PED, the authors identified 8 who developed PVO after embolization. The mean aneurysm size in this cohort was 22.3 mm, and the number of PEDs used per case ranged from 2 to 10. Six patients were found to have asymptomatic PVO discovered incidentally on routine follow-up imaging between 6 months and 3 years postembolization, 3 of whom had documented “delayed” PVO with prior postembolization angiograms confirming aneurysm occlusion and a patent parent vessel at an earlier time. Two additional patients experienced symptomatic PVO, one of which was associated with early discontinuation of antiplatelet therapy.

CONCLUSIONS

In this large series of anterior circulation aneurysms, the authors report a low incidence of symptomatic PVO, complicating premature discontinuation of postembolization antiplatelet or anticoagulation therapy. Beyond the subacute period, asymptomatic PVO was more common, particularly among complex fusiform or very large–necked aneurysms, highlighting an important phenomenon with the use of PED for the treatment of anterior circulation aneurysms, and suggesting that extended periods of antiplatelet coverage may be required in select complex aneurysms.

ABBREVIATIONS ICA = internal carotid artery; MCA = middle cerebral artery; MPED = minimally porous endoluminal device; PED = Pipeline Embolization Device; PRU = platelet reactivity units; PVO = parent vessel occlusion.

OBJECTIVE

The Pipeline Embolization Device (PED) is now a well-established option for the treatment of giant or complex aneurysms, especially those arising from the anterior circulation. Considering the purpose of such treatment is to maintain patency of the parent vessel, postembolization occlusion of the parent artery can be regarded as an untoward outcome. Antiplatelet therapy in the posttreatment period is therefore required to minimize such events. Here, the authors present a series of patients with anterior circulation aneurysms treated with the PED who subsequently experienced parent vessel occlusion (PVO).

METHODS

The authors performed a retrospective review of all anterior circulation aneurysms consecutively treated at a single institution with the PED through 2014, identifying those with PVO on follow-up imaging. Aneurysm size and location, number of PEDs used, and follow-up digital subtraction angiography results were recorded. When available, pre- and postembolization platelet function testing results were also recorded.

RESULTS

Among 256 patients with anterior circulation aneurysms treated with the PED, the authors identified 8 who developed PVO after embolization. The mean aneurysm size in this cohort was 22.3 mm, and the number of PEDs used per case ranged from 2 to 10. Six patients were found to have asymptomatic PVO discovered incidentally on routine follow-up imaging between 6 months and 3 years postembolization, 3 of whom had documented “delayed” PVO with prior postembolization angiograms confirming aneurysm occlusion and a patent parent vessel at an earlier time. Two additional patients experienced symptomatic PVO, one of which was associated with early discontinuation of antiplatelet therapy.

CONCLUSIONS

In this large series of anterior circulation aneurysms, the authors report a low incidence of symptomatic PVO, complicating premature discontinuation of postembolization antiplatelet or anticoagulation therapy. Beyond the subacute period, asymptomatic PVO was more common, particularly among complex fusiform or very large–necked aneurysms, highlighting an important phenomenon with the use of PED for the treatment of anterior circulation aneurysms, and suggesting that extended periods of antiplatelet coverage may be required in select complex aneurysms.

ABBREVIATIONS ICA = internal carotid artery; MCA = middle cerebral artery; MPED = minimally porous endoluminal device; PED = Pipeline Embolization Device; PRU = platelet reactivity units; PVO = parent vessel occlusion.

The Pipeline Embolization Device (PED; Medtronic) is included in the growing family of minimally porous endoluminal devices (MPEDs) used to treat cerebral aneurysms.8 The combination of hemodynamic changes at the aneurysm–parent vessel interface and subsequent neointimal overgrowth of the aneurysm neck using the implanted construct as scaffolding ultimately leads to reconstruction of a normal parent vessel. Parent vessel occlusion (PVO), however, is a rarely reported and unintended outcome of endoluminal therapy with MPEDs. Two principal mechanisms of PVO have been proposed: 1) progressive neointimal hyperplasia (which is often self-limiting and reversible) leading to critical device-associated stenosis and occlusion,1,12,15 and 2) acute or delayed construct-related thrombosis due to the inherent thrombogenicity of the metallic implant. The latter may be associated with inadequate antiplatelet coverage or resistance to the antiplatelet agents used. In the delayed setting, insufficient endothelialization over the construct may lead to thrombus formation along the persistently exposed metal once antiplatelet coverage is reduced, which is typically done according to a prearranged schedule.23–25 Here, we present a series of patients with anterior circulation aneurysms treated with PED constructs who subsequently developed PVO. Importantly, PVO was asymptomatic and discovered on routine follow-up imaging in the majority of patients, while symptomatic PVO was seen only in 2 patients—one acutely before platelet function testing was performed at our institution and one subacutely, in whom antiplatelet therapy was prematurely discontinued. This series also includes cases of delayed PVO after initial 6-month angiography had shown parent vessel patency.

Methods

This study was approved by the institutional review board of the New York University Langone School of Medicine and conducted in accordance with Health Insurance Portability and Accountability Act (HIPAA) regulations. This institution's prospectively maintained Pipeline database was retrospectively reviewed to identify patients with anterior circulation aneurysms treated with the PED through December 2014 who were subsequently found to have PVO on follow-up imaging. Baseline patient and aneurysm characteristics were collected, as were follow-up examinations and imaging results.

Pipeline Embolization

All embolization procedures were performed under general anesthesia. During the initial experience with Pipeline embolization (Cases 1–6), patients arbitrarily received clopidogrel, 75 mg daily, for 7 days prior to embolization and aspirin, 325 mg daily, for 2 days prior to embolization without pre- or postprocedural platelet function testing. Beginning in June 2011, platelet function testing, using the VerifyNow P2Y12 assay (Accumetrics), became available and was performed on the day of embolization prior to the procedure start as well as daily during a patient's subsequent hospital stay. Since that time (during which patients in Cases 7 and 8 underwent treatment), patients receive aspirin 325 mg and clopidogrel 75 mg daily 5 days pre-procedure. Postprocedure clopidogrel doses were adjusted as necessary to achieve a desirable level of P2Y12 platelet inhibition (50–150 platelet reactivity units [PRU]). Abciximab was administered intravenously during the procedure if the patient was found to have insufficient platelet inhibition. Platelet inhibition testing was not performed after discharge to home from the hospital. At the conclusion of each procedure, patients were started on a continuous low-dose heparin infusion (400–600 U/hr) overnight. Upon discharge, patients were prescribed a minimum of 6 months of dual antiplatelet therapy with aspirin and clopidogrel. Decisions to stop or extend antiplatelet coverage were subsequently based on the results of follow-up angiography.

The number and sizes of PEDs selected were based on the aneurysm size and morphology, the complexity of the aneurysm neck, and presence of adjacent vessels in an attempt to recreate the natural course of the parent vessel. Control angiograms were obtained at the completion of each embolization procedure.

Follow-Up

Catheter angiographic evaluation was scheduled at 6 months, 12 months, 3 years, and 5 years after Pipeline embolization, in line with the established PUFS (Pipeline for Uncoilable or Failed Aneurysms) protocol.1

Statistical Analysis

All statistical analyses were performed using JMP Pro (version 11.0, SAS Institute). Summary statistics were tabulated for baseline characteristics. Univariate analyses were performed using logistic regression with the dichotomous outcome of PVO or non-PVO. Factors that were significantly associated with this dichotomous outcome on univariate analysis were then incorporated into a multivariate analysis using a nominal regression model. Statistical significance was defined as p < 0.05.

Results

During the study period, 256 patients underwent Pipeline embolization of anterior circulation aneurysms. Angiographic follow-up using cerebral angiography, CT angiography, or MR angiography was obtained in 224 of these patients. The overall mean age was 55.6 ± 13.3 years (± SD) and 81% of patients were female. The overall mean maximal aneurysm size was 14.8 ± 9.7 mm, and a median of 2 PEDs were used for treatment (range 1–16 PEDs). Of these patients, we identified 8 who were found to have PVO of the treated aneurysmal segment. Table 1 shows the baseline patient and aneurysm characteristics in the PVO and non-PVO cohort patients with any angiographic follow-up. Table 2 details aneurysm and treatment characteristics in the 8 patients with PVO. Among this group, 4 aneurysms were located in the cavernous internal carotid artery (ICA), 2 in the paraophthalmic ICA,20 and 1 each in the petrous and cervical ICA as well as the middle cerebral artery (MCA) bifurcation. One patient with a paraophthalmic aneurysm had undergone attempted surgical treatment of this aneurysm. The maximal aneurysm diameters ranged from 12.5 to 35.4 mm, with neck widths ranging from 8.5 to 36.1 mm. The number of PEDs deployed per aneurysm ranged from 2 to 10 (Table 2).

TABLE 1.

Baseline patient and aneurysm characteristics

VariableOverallPVONo PVOp Value
No. of patients*2248216
Age ± SD, yrs55.6 ± 13.356.4 ± 13.655.6 ± 13.40.87
Female sex81%88%81%1
Mean max aneurysm diameter ± SD, mm14.8 ± 9.722.3 ± 8.914.5 ± 9.60.049
% of large & giant aneurysms67.9%100%66.7%
Mean max aneurysm neck ± SD, mm8.2 ± 7.713.1 ± 9.48 ± 7.60.15
% of large necks77.2%100%76.4%
Median no. of PEDs used (range)2 (1–16)3.5 (2–10)2 (1–16)0.039
% w/>5 PEDs4.7%25%3.9%

Boldface type indicates statistical significance.

Total number of patients with angiographic follow-up.

Large defined as ≥ 10 and < 25 mm; giant defined as > 25 mm in maximal diameter.

Large neck defined as > 4 mm.

TABLE 2.

Aneurysm and treatment characteristics among patients with PVO

Case No.Age (yrs)Initial Aneurysm PresentationAneurysm Location*SideMax Diameter (mm)Width of Neck (mm)No. of PEDs
172HA & visual deficitParaophthalmicLt17.69.22
270CN III/VI palsies; Horner's syndromeCavernousRt32.512.54
357TIACavernousRt35.49.93
445CN VI palsyCavernousLt28.18.54
561ProptosisCavernousLt2210.23
630HA & facial painPetrousLt2136.110
753HAParaophthalmicRt12.5102
860HAMCA bifurcationRt14.18.56

CN = cranial nerve; HA = headache; TIA = transient ischemic attack.

Based on the system by Shapiro et al.

Two patients in the PVO cohort required balloon angioplasty during embolization. In 1 patient (Case 2), the PED construct was extended into a region of stenosis just proximal to the aneurysm. A balloon was used to dilate this segment after placement of 4 PEDs. In the second patient (Case 4), segmental stenosis of the ICA both proximal and distal to the aneurysm was treated with balloon angioplasty prior to deployment of the PED construct.

P2Y12 platelet function testing became available to us after the first 105 patients in our anterior circulation series and was used routinely during the time the last 2 patients with PVO underwent treatment. One patient (Case 7) had a P2Y12 level of 241 PRU just prior to embolization, for which abciximab was given intraarterially during embolization. Subsequent P2Y12 levels were 291, 254, and 154 PRU on postembolization Days 1, 2, and 3, respectively. She was given aspirin 300 mg the evening of her embolization and then received aspirin 325 mg and clopidogrel 150 mg daily on postembolization Days 1–3 until testing indicated suitable P2Y12 inhibition, following which she was discharged home on a regimen of aspirin 325 mg and clopidogrel 75 mg daily. Another patient (Case 8) had a P2Y12 level of 170 PRU prior to embolization and then 206 PRU the following morning. This patient was given 150 mg of clopidogrel and the P2Y12 level subsequently decreased to 95 PRU later on postembolization Day 1. This patient was discharged home on a regimen of aspirin 325 mg and clopidogrel 75 mg daily. A P2Y12 level 1 month later was 3 PRU, for which clopidogrel was decreased to 75 mg every other day. A P2Y12 level at the time of her 6-month follow-up was 206 PRU. At 6-month follow-up angiography, the treated aneurysm was found to be occluded, so clopidogrel was then discontinued.

Two patients were found to have symptomatic PVO in the immediate-to-early postembolization period. One patient (Case 1) developed sudden-onset right hemiparesis and aphasia several hours after Pipeline embolization. An emergency angiogram demonstrated PVO (Fig. 1), and a mechanical thrombectomy and thrombolysis was performed to recanalize the ICA. Despite this, the patient suffered a left frontal infarct (Fig. 1). Of note, this patient's postembolization heparin infusion had been stopped just 2 hours after his embolization in response to anecdotal case reports of intraparenchymal hemorrhage after Pipeline embolization. This patient's antiplatelet status was not determined. The second patient with symptomatic PVO (Case 3) self-discontinued antiplatelet medications approximately 1 week postembolization, and subsequently presented to an outside hospital with a nondominant parietal lobe stroke 6 weeks after embolization. CT angiography at that time demonstrated PVO.

FIG. 1.
FIG. 1.

Case 1. Case example of a 72-year-old male presenting with headache and visual complaints who was found to have a large right paraophthalmic ICA aneurysm (A and B). The neck of the aneurysm measured 17.6 mm with a dome of 9.2 mm. The patient underwent Pipeline embolization using 2 telescoping PEDs. He remained neurologically stable on completion of the procedure. Several hours later, the patient developed right hemiplegia and aphasia. An emergency cerebral angiogram was obtained, which demonstrated occlusion of the left ICA just past the ophthalmic artery (E). Mechanical thrombectomy and thrombolysis was performed to recanalize his left ICA but the patient developed a left frontal infarct. A: Preembolization digital subtraction (DS) angiogram of the left ICA in the lateral projection, showing a giant paraophthalmic segment aneurysm. B: 3D rotational angiography of the left ICA further characterizing the aneurysm's broad neck. C and D: Immediate postembolization angiograms of the left ICA in native (C) and unsubtracted (D) views showing the Pipeline construct and contrast stagnation within the aneurysm sac. E: Postembolization DS angiogram obtained after the patient developed right hemiplegia, showing occlusion of the left ICA just above the ophthalmic artery. F: Right ICA DS angiogram showing inadequate cross-filling through the anterior communicating artery. G: Postthrombectomy/thrombolysis DS angiogram of the left ICA showing restored flow through the ICA. Note the significantly reduced filling of the aneurysm compared with the immediate postembolization DS angiogram (*). H: Noncontrast head CT scan obtained 3 days after the patient's embolization and parent vessel occlusion, demonstrating cortical and subcortical infarction within the left frontal lobe.

In the 6 patients with asymptomatic PVO (Cases 2 and 4–8, Figs. 2 and 3), follow-up angiography was available at 6 months postembolization in all but 1 patient (Table 3). Complete occlusion of the target aneurysm at 6 months was documented in all 5 patients with angiograms, with PVO also found in 2 patients (Cases 4 and 5), and greater than 50% in-stent stenosis in a third patient (Case 8). The other 4 patients (3 with open parent arteries on the 6-month angiogram and 1 without 6-month angiography) were found to have PVO at 12-month, 18-month, or 3-year angiographic follow-up (Table 3). Two patients (Cases 3 and 5) also underwent 5-year angiographic follow-up that demonstrated persistent parent vessel and aneurysm occlusions. Among the patients with delayed ICA occlusion, all showed collateral supply to the occluded ICA territory through the circle of Willis—via the anterior communicating artery (all 6 patients) and the ipsilateral posterior communicating artery (4 patients). Two patients had additional collateral support through external carotid artery reconstitution of the ipsilateral ophthalmic artery. The one patient with an MCA occlusion showed leptomeningeal collateralization from the ipsilateral anterior and posterior cerebral arteries.

FIG. 2.
FIG. 2.

Case 2. Case example of a 70-year-old female presenting with cranial nerve III and VI palsies of the right eye who was found to have a giant right cavernous ICA aneurysm. The neck of the aneurysm measured 12 mm with a dome of 32 mm. The patient underwent Pipeline embolization using 4 telescoping PEDs. Due to vessel stenosis within the proximal ICA, balloon dilation was performed during embolization. A: Preembolization DS angiogram of the right ICA in a left anterior oblique projection showing a giant cavernous segment ICA aneurysm. The region of ICA stenosis proximal to the aneurysm can be seen. B and C: Immediate postembolization angiogram of the right ICA in native (B) and subtracted (C) views showing stagnation of contrast within the aneurysm sac. D: Six-month follow-up DS angiogram of the right ICA showing complete occlusion of the aneurysm with only minimal intimal hyperplasia within the Pipeline construct. E: One-year follow-up DS angiogram of the right common carotid artery (CCA) showing complete occlusion of the proximal right ICA. F and G: Five-year follow-up DS angiogram of the right CCA (F) and left ICA (G) showing persistent complete occlusion of the right ICA with collateral filling of the right hemisphere through the anterior communicating artery.

FIG. 3.
FIG. 3.

Case 6. Case example of a 30-year-old female presenting with headache and left facial pain who was found to have a giant left petrous ICA aneurysm with a 36-mm neck and 21-mm dome. Pipeline embolization with 10 telescoping PEDs was performed. A: Preembolization DS angiogram showing a large left petrous ICA aneurysm. B: Immediate postembolization control DS angiogram showing contrast stagnation within the aneurysm dome. C and D: Six-month (not shown) and 1-year (C, unsubtracted; and D, subtracted) follow-up DS angiograms both show complete aneurysm occlusion with only minimal intimal hyperplasia within the Pipeline construct. E: Three-year follow-up DS angiogram of the left CCA showing complete occlusion of the left ICA with persistent complete aneurysm occlusion. F–H: Three-year follow-up DS angiogram of the right ICA (F), left vertebral artery (G), and left external carotid artery (H) showing collateral filling of the left hemisphere through the anterior communicating artery (F), posterior communicating arteries (G), and the left ophthalmic artery via multiple branches of the left external carotid artery (H).

TABLE 3.

Angiographic outcomes

Case No.6 Mos12 Mos18 Mos3 Yrs
AneurysmParent VesselAneurysmParent VesselAneurysmParent VesselAneurysmParent Vessel
1NANANANANANANANA
2Complete occlusionOpenComplete occlusionComplete occlusionNANAComplete occlusionComplete occlusion
3NANANANANANANANA
4Complete occlusionComplete occlusionNANANANAComplete occlusionComplete occlusion
5Complete occlusionComplete occlusionNANANANAComplete occlusionComplete occlusion
6Complete occlusionOpenComplete occlusionOpenNANAComplete occlusionComplete occlusion
7NANANANAComplete occlusionComplete occlusionNANA
8Complete occlusion>50% in-stent stenosisComplete occlusionComplete occlusionNANANANA

NA = not available.

At the time of angiographic follow-up confirming delayed PVO, no patient had new permanent neurological deficits. One patient (Case 5) reported a mild headache within days after the embolization procedure that was treated initially with steroids. This headache persisted for several months. Another patient (Case 6) reported several days of headache approximately 1 week prior to a 3-year angiographic follow-up, which revealed an interval PVO. No other patient reported unusual headaches or other symptoms prior to the delayed discovery of their PVO.

To further evaluate the natural history of in-stent stenosis among our population of anterior circulation aneurysms treated with PED, we assessed the presence of in-stent stenosis among patients with serial angiographic follow-up. Of the 248 patients in our series without PVO, 199 (80.2%) underwent angiography at 6 months and 121 of these patients had additional angiographic follow-up after 6 months. Twelve additional patients underwent initial follow-up studies at 10–18 months posttreatment. Among patients with follow-up angiography, nonocclusive in-stent stenosis was seen at 6 months in 10 patients (8.3%), 9 of whom had minimal (< 25%) stenosis. The final patient had approximately 70% stenosis at 6 months. These stenoses resolved on serial angiography in all 10 of these patients. Progressive in-stent stenosis was documented in 2 additional patients: one with a cluster of supraclinoid ICA aneurysms in whom focal in-stent stenosis of 25% was seen at 3 years and worsened to 40% vessel diameter compromise on a 5-year catheter angiogram, and a second patient with a long dysplastic cavernous/supraclinoid segment aneurysm found to have a new focal segment of device-related stenosis approximating 60% vessel narrowing 18 months after embolization. In addition to the patient in Case 3, dual antiplatelet therapy was stopped before 6 months in only 3 patients in our overall anterior circulation series due to nonneurological bleeding. None of these 3 patients experienced PVO.

Univariate logistic regression analysis among the 224 patients with angiographic follow-up identified maximal aneurysm size (p = 0.049) and number of PEDs used (p = 0.039) as factors significantly associated with parent vessel occlusion. Subsequent multivariate logistic regression analysis incorporating these 2 factors failed to show any significance.

Discussion

The development of MPEDs such as the PED has resulted in a paradigm shift in the treatment of cerebral aneurysms. The benefits of flow diversion over traditional coiling methods include the ability to embolize an aneurysm without entering the aneurysm sac and reconstruction of the parent vessel, particularly in large or complex neck aneurysms, which can result in stable and definitive aneurysm occlusion. Untoward outcomes including hemorrhagic and ischemic complications have been extensively described.17,21 In this report, we present 8 cases of PVO after treatment of anterior circulation aneurysms with the PED, 6 of which were asymptomatic and discovered only on routine follow-up imaging, highlighting an unusual but important phenomenon. In each of these 6 asymptomatic patients, the goal of complete aneurysm occlusion was achieved, albeit coupled with unanticipated PVO.

Cases of both acute and delayed (3–23 months) PVO after Pipeline embolization have been reported (Table 4). We identified 9 previously reported cases in the literature of asymptomatic PVO after Pipeline embolization of aneurysms that were typically found on routine follow-up imaging.4,10,17–19,25 All such asymptomatic cases in which the aneurysm location was reported involved the anterior circulation (ICA or MCA). In contrast, all but 1 case involving the posterior circulation were fatal or significantly morbid.

TABLE 4.

Reports of parent vessel occlusion after Pipeline embolization

Authors & YearNo. of PatientsAneurysm LocationAneurysm TypeTime to PVOPresentationAntiplatelet AgentsTreatmentOutcome
Fiorella et al., 20101VADissecting23 mosVisual deficitClopidogrel stopped at 18 mosRestarted dual antiplatelet then converted to warfarinProgressed to fatal basilar thrombosis over 5 mos despite warfarin
Klisch et al., 20111VBLarge, fusiform∼12 mosHAClopidogrel stopped after 12-mo angiogram showed complete aneurysm occlusionSteroids for HANeurologically intact
1VBLarge, fusiform∼12 mosComaClopidogrel stopped after 12-mo angiogram showed complete aneurysm occlusionIV & IA thrombolysis & mechanical thrombectomyFatal
Puffer et al., 20121Paraclinoid ICANR6 mosAsymptomatic, routine FUNRNoneAsymptomatic
Chitale et al., 20121MCADissecting140 daysAsymptomaticNRNoneAsymptomatic
Lanzino et al., 20121ICANR6 mosAsymptomatic, routine FUNRNRAsymptomatic
Siddiqui et al., 20121MCAGiant6 hrsLeft MCA syndromeNRAttempted mechanical revascularization; eptifibatide dripFull recovery
Meckel et al., 20131VBGiant fusiform11.5 mosPosterior circulation infarctsHad stopped clopidogrel 2 wks prior to PVO based on angiogram showing largely thrombosed aneurysmIV & IA thrombolysis, mechanical thrombectomy, posterior fossa decompressionFatal
Chalouhi et al., 20131MCALarge5 mosHemiplegiaNRNoneHemiplegia
Szikora et al., 2010; Szikora et al., 20131ICAGiant fusiform3 mosHemiparesisPatient prematurely stopped clopidogrelNonePermanent hemiparesis
1ICANR2 daysTransient hemiparesisPatient had not taken antiplatelet medications prior to procedure; also had occlusion during PED procedure treated w/tirofibanNo treatment due to good collateralsRecanalized spontaneously; associated w/partial refilling of treated aneurysm
O'Kelly et al., 20132ICANR7 & 12 mosNRNRNoneNo permanent neurological deficits
Park et al., 20156NRNRNR4 asymptomatic; 2 strokesNRNR4 asymptomatic; 2 fatal
Zanaty et al., 20141M1 MCANRNRNRPatient stopped antiplateletsNRmRS Score 3
1M3 MCADissecting6 mosAsymptomatic, routine FUNRNoneAsymptomatic
Puffer et al., 20141ICANRNRAsymptomatic, routine FUNRNoneAsymptomatic
Toth et al., 20151VBGiant, thrombosed4.5 mosComaPatient stopped antiplatelets 4.5 mos after treatmentNonemRS Score 5

FU = follow-up; IA = intraarterial; IV = intravenous; mRS = modified Rankin Scale; NR = not reported; VA = vertebral artery; VB = vertebrobasilar.

The causes of PVO in our series were not confidently identified. Several factors can contribute to occlusion of the parent vessel after MPED therapy, including the intrinsic thrombogenicity of the endoluminal construct, the effectiveness of antiplatelet therapy (suitable dosing and drug resistance), the coagulopathic disposition of the patient, the degree of stenosis affecting the parent vessel, and the equilibrium of blood flow through the parent vessel construct—particularly in relation to competitive inflows through alternative collateral sources. Cases of delayed PVO in the literature have been reported to occur soon after discontinuation of clopidogrel, either as prescribed by the treating physicians based on medical necessity or follow-up imaging6,9,13 or when self-discontinued by patients,23–25 as occurred with 1 patient in our series. In reported cases following medically prescribed or scheduled discontinuation of antiplatelet medication, PVO has commonly occurred months after embolization. On the other hand, examples in the literature of occlusion following self-discontinuation are usually discovered earlier after embolization.

Due to the small number of occlusions, no statistical association with aneurysm morphology or number of devices could be demonstrated in this series. However, all aneurysms in this series of patients experiencing PVO were large or giant (mean maximal diameter 25.8 mm) with complex morphology, similar to those lesions treated in the PUFS trial1 that led to FDA clearance of the PED. In our practice, we typically use multiple overlapping devices to treat larger saccular aneurysms, aneurysms with broad necks, or fusiform aneurysms. It is not known how the crossing profile (thickness) or length of a Pipeline construct might affect intimal hyperplasia but it is possible that both factors are associated with an increased thrombogenic disposition.11 Similarly, longer constructs (particularly those used in the treatment of fusiform aneurysms) likely require more time to complete over-endothelialization, possibly necessitating longer courses of dual antiplatelet therapy to prevent device-related thrombosis. In our current practice, patients with longer Pipeline constructs are maintained on dual antiplatelet therapy for longer periods of time (typically 12–24 months). Collateral flow through the circle of Willis and, in some cases, the external carotid artery prevented ischemic symptoms in the asymptomatic patients. One could hypothesize that robust collateral potential may reduce the demand for flow through the endoluminal construct, particularly if antegrade flow through the construct becomes compromised by intimal hyperplasia, device-related thrombosis, or both. Preclinical studies would be needed to test such a hypothesis.

The phenomenon of in-stent stenosis and intimal hyperplasia after flow diversion is not well understood. Intimal hyperplasia is associated with several molecular pathways14 and has been demonstrated to occur in a significant number of patients treated with flow diversion on 6-month follow-up angiography.5,7 This angiographic finding, however, typically resolves spontaneously.5,7 In our series, the demonstration of normal angiograms at 6–12 months in 2 of the PVO patients argues against a necessarily progressive course of worsening intimal hyperplasia leading to PVO.

Delayed PVO was documented in 3 patients in this series (Cases 2, 6, and 8) who had 6-month angiograms showing a patent parent vessel but were subsequently found to have complete PVO on 12-month (Cases 2 and 8) or 3-year (Case 6) follow-up angiograms. The patients in Cases 2 and 6 had only minimal intimal hyperplasia at 6 months while the patient in Case 8 had greater than 50% in-stent stenosis. It is not clear how soon after Pipeline embolization the remaining cases occurred since these occlusions were discovered on the first follow-up angiogram after embolization. These observations are in agreement with similar findings of several large series, in which development of delayed intimal hyperplasia was not observed.1,2,12,15

We acknowledge limitations to this study. First and foremost, while all patients were prescribed dual antiplatelet therapy for at least the first 6 months after Pipeline embolization, our practice of managing dual antiplatelet therapy changed over time and was not well documented after the initial follow-up angiogram. Although many centers prescribe shorter durations of dual antiplatelet therapy after flow diversion, it is possible that longer durations may be warranted in given situations as discussed above. Second, PVO is overall a rare phenomenon after Pipeline embolization, so it is difficult to make definitive statements about its etiology. We hope that this study serves to highlight this phenomenon, especially that of asymptomatic PVO, so that future prospective studies of flow diversion can better characterize the factors associated with PVO.

Conclusions

PVO after Pipeline embolization of anterior circulation aneurysms occurs with a low frequency and can remain asymptomatic in patients who are adequately treated with dual antiplatelet medications, leading to successful embolization. Further studies are needed to determine the underlying mechanisms behind PVO.

Disclosures

Drs. Shapiro, Becske, and Nelson report that they are consultants for Medtronic.

Author Contributions

Conception and design: Potts. Acquisition of data: Potts. Analysis and interpretation of data: Potts, Shapiro, Zumofen, Raz, Nossek, DeSousa, Becske, Riina. Drafting the article: Potts, Shapiro, Nelson. Critically revising the article: all authors. Reviewed submitted version of manuscript: Potts, Zumofen, Raz, Nossek, DeSousa, Becske, Riina, Nelson. Approved the final version of the manuscript on behalf of all authors: Potts. Statistical analysis: Potts. Study supervision: Nelson.

References

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    • Export Citation
  • 6

    Fiorella D, Hsu D, Woo HH, Tarr RW, Nelson PK: Very late thrombosis of a Pipeline embolization device construct.. Neurosurgery 67:3 Suppl Operative onsE313onsE314, 2010

    • Search Google Scholar
    • Export Citation
  • 7

    John S, Bain MD, Hui FK, Hussain MS, Masaryk TJ, Rasmussen PA, : Long-term follow-up of in-stent stenosis after Pipeline flow diversion treatment of intracranial aneurysms. Neurosurgery 78:862867, 2016

    • Search Google Scholar
    • Export Citation
  • 8

    Kallmes DF, Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ: A new endoluminal, flow-disrupting device for treatment of saccular aneurysms. Stroke 38:23462352, 2007

    • Search Google Scholar
    • Export Citation
  • 9

    Klisch J, Turk A, Turner R, Woo HH, Fiorella D: Very late thrombosis of flow-diverting constructs after the treatment of large fusiform posterior circulation aneurysms. AJNR Am J Neuroradiol 32:627632, 2011

    • Search Google Scholar
    • Export Citation
  • 10

    Lanzino G, Crobeddu E, Cloft HJ, Hanel R, Kallmes DF: Efficacy and safety of flow diversion for paraclinoid aneurysms: a matched-pair analysis compared with standard endovascular approaches. AJNR Am J Neuroradiol 33:21582161, 2012

    • Search Google Scholar
    • Export Citation
  • 11

    Lüscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, : Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 115:10511058, 2007

    • Search Google Scholar
    • Export Citation
  • 12

    Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, : Curative endovascular reconstruction of cerebral aneurysms with the Pipeline embolization device: the Buenos Aires experience.. Neurosurgery 64:632643, N6, 2009

    • Search Google Scholar
    • Export Citation
  • 13

    Meckel S, McAuliffe W, Fiorella D, Taschner CA, Phatouros C, Phillips TJ, : Endovascular treatment of complex aneurysms at the vertebrobasilar junction with flow-diverting stents: initial experience. Neurosurgery 73:386394, 2013

    • Search Google Scholar
    • Export Citation
  • 14

    Mills B, Robb T, Larson DF: Intimal hyperplasia: slow but deadly. Perfusion 27:520528, 2012

  • 15

    Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D: The Pipeline embolization device for the intracranial treatment of aneurysms trial. AJNR Am J Neuroradiol 32:3440, 2011

    • Search Google Scholar
    • Export Citation
  • 16

    O'Kelly CJ, Spears J, Chow M, Wong J, Boulton M, Weill A, : Canadian experience with the Pipeline embolization device for repair of unruptured intracranial aneurysms. AJNR Am J Neuroradiol 34:381387, 2013

    • Search Google Scholar
    • Export Citation
  • 17

    Park MS, Albuquerque FC, Nanaszko M, Sanborn MR, Moon K, Abla AA, : Critical assessment of complications associated with use of the Pipeline embolization device. J Neurointerv Surg 7:652659, 2015

    • Search Google Scholar
    • Export Citation
  • 18

    Puffer RC, Piano M, Lanzino G, Valvassori L, Kallmes DF, Quilici L, : Treatment of cavernous sinus aneurysms with flow diversion: results in 44 patients. AJNR Am J Neuroradiol 35:948951, 2014

    • Search Google Scholar
    • Export Citation
  • 19

    Puffer RC, Kallmes DF, Cloft HJ, Lanzino G: Patency of the ophthalmic artery after flow diversion treatment of paraclinoid aneurysms. J Neurosurg 116:892896, 2012

    • Search Google Scholar
    • Export Citation
  • 20

    Shapiro M, Becske T, Riina HA, Raz E, Zumofen D, Jafar JJ, : Toward an endovascular internal carotid artery classification system. AJNR Am J Neuroradiol 35:230236, 2014

    • Search Google Scholar
    • Export Citation
  • 21

    Siddiqui AH, Kan P, Abla AA, Hopkins LN, Levy EI: Complications after treatment with Pipeline embolization for giant distal intracranial aneurysms with or without coil embolization. Neurosurgery 71:E509E513, 2012

    • Search Google Scholar
    • Export Citation
  • 22

    Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, : Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the Budapest experience with the Pipeline embolization device. AJNR Am J Neuroradiol 31:11391147, 2010

    • Search Google Scholar
    • Export Citation
  • 23

    Szikora I, Marosfoi M, Salomváry B, Berentei Z, Gubucz I: Resolution of mass effect and compression symptoms following endoluminal flow diversion for the treatment of intracranial aneurysms. AJNR Am J Neuroradiol 34:935939, 2013

    • Search Google Scholar
    • Export Citation
  • 24

    Toth G, Bain M, Hussain MS, Moskowitz S, Masaryk T, Rasmussen P, : Posterior circulation flow diversion: a single-center experience and literature review. J Neurointerv Surg 7:574583, 2015

    • Search Google Scholar
    • Export Citation
  • 25

    Zanaty M, Chalouhi N, Tjoumakaris SI, Gonzalez LF, Rosenwasser R, Jabbour P: Flow diversion for complex middle cerebral artery aneurysms. Neuroradiology 56:381387, 2014

    • Search Google Scholar
    • Export Citation

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Contributor Notes

Correspondence Matthew B. Potts, Departments of Neurological Surgery and Radiology, Division of Cerebrovascular/Neurointerventional Surgery, Northwestern University Feinberg School of Medicine, 676 N St. Clair St., Ste. 2210, Chicago, IL 60611. email: mpotts@nm.org.

INCLUDE WHEN CITING Published online January 6, 2017; DOI: 10.3171/2016.9.JNS152638.

Disclosures Drs. Shapiro, Becske, and Nelson report that they are consultants for Medtronic.

  • View in gallery

    Case 1. Case example of a 72-year-old male presenting with headache and visual complaints who was found to have a large right paraophthalmic ICA aneurysm (A and B). The neck of the aneurysm measured 17.6 mm with a dome of 9.2 mm. The patient underwent Pipeline embolization using 2 telescoping PEDs. He remained neurologically stable on completion of the procedure. Several hours later, the patient developed right hemiplegia and aphasia. An emergency cerebral angiogram was obtained, which demonstrated occlusion of the left ICA just past the ophthalmic artery (E). Mechanical thrombectomy and thrombolysis was performed to recanalize his left ICA but the patient developed a left frontal infarct. A: Preembolization digital subtraction (DS) angiogram of the left ICA in the lateral projection, showing a giant paraophthalmic segment aneurysm. B: 3D rotational angiography of the left ICA further characterizing the aneurysm's broad neck. C and D: Immediate postembolization angiograms of the left ICA in native (C) and unsubtracted (D) views showing the Pipeline construct and contrast stagnation within the aneurysm sac. E: Postembolization DS angiogram obtained after the patient developed right hemiplegia, showing occlusion of the left ICA just above the ophthalmic artery. F: Right ICA DS angiogram showing inadequate cross-filling through the anterior communicating artery. G: Postthrombectomy/thrombolysis DS angiogram of the left ICA showing restored flow through the ICA. Note the significantly reduced filling of the aneurysm compared with the immediate postembolization DS angiogram (*). H: Noncontrast head CT scan obtained 3 days after the patient's embolization and parent vessel occlusion, demonstrating cortical and subcortical infarction within the left frontal lobe.

  • View in gallery

    Case 2. Case example of a 70-year-old female presenting with cranial nerve III and VI palsies of the right eye who was found to have a giant right cavernous ICA aneurysm. The neck of the aneurysm measured 12 mm with a dome of 32 mm. The patient underwent Pipeline embolization using 4 telescoping PEDs. Due to vessel stenosis within the proximal ICA, balloon dilation was performed during embolization. A: Preembolization DS angiogram of the right ICA in a left anterior oblique projection showing a giant cavernous segment ICA aneurysm. The region of ICA stenosis proximal to the aneurysm can be seen. B and C: Immediate postembolization angiogram of the right ICA in native (B) and subtracted (C) views showing stagnation of contrast within the aneurysm sac. D: Six-month follow-up DS angiogram of the right ICA showing complete occlusion of the aneurysm with only minimal intimal hyperplasia within the Pipeline construct. E: One-year follow-up DS angiogram of the right common carotid artery (CCA) showing complete occlusion of the proximal right ICA. F and G: Five-year follow-up DS angiogram of the right CCA (F) and left ICA (G) showing persistent complete occlusion of the right ICA with collateral filling of the right hemisphere through the anterior communicating artery.

  • View in gallery

    Case 6. Case example of a 30-year-old female presenting with headache and left facial pain who was found to have a giant left petrous ICA aneurysm with a 36-mm neck and 21-mm dome. Pipeline embolization with 10 telescoping PEDs was performed. A: Preembolization DS angiogram showing a large left petrous ICA aneurysm. B: Immediate postembolization control DS angiogram showing contrast stagnation within the aneurysm dome. C and D: Six-month (not shown) and 1-year (C, unsubtracted; and D, subtracted) follow-up DS angiograms both show complete aneurysm occlusion with only minimal intimal hyperplasia within the Pipeline construct. E: Three-year follow-up DS angiogram of the left CCA showing complete occlusion of the left ICA with persistent complete aneurysm occlusion. F–H: Three-year follow-up DS angiogram of the right ICA (F), left vertebral artery (G), and left external carotid artery (H) showing collateral filling of the left hemisphere through the anterior communicating artery (F), posterior communicating arteries (G), and the left ophthalmic artery via multiple branches of the left external carotid artery (H).

  • 1

    Becske T, Kallmes DF, Saatci I, McDougall CG, Szikora I, Lanzino G, : Pipeline for uncoilable or failed aneurysms: results from a multicenter clinical trial. Radiology 267:858868, 2013

    • Search Google Scholar
    • Export Citation
  • 2

    Becske T, Potts MB, Shapiro M, Kallmes DF, Brinjikji W, Saatci I, : Pipeline for uncoilable or failed aneurysms: 3-year follow-up results.. J Neurosurg [epub ahead of print October 14, 2016. DOI: 10.3171/20156.JNS15311]

    • Search Google Scholar
    • Export Citation
  • 3

    Chalouhi N, Satti SR, Tjoumakaris S, Dumont AS, Gonzalez LF, Rosenwasser R, : Delayed migration of a Pipeline embolization device.. Neurosurgery 72:2 Suppl Operative ons229ons234, 2013

    • Search Google Scholar
    • Export Citation
  • 4

    Chitale R, Gonzalez LF, Randazzo C, Dumont AS, Tjoumakaris S, Rosenwasser R, : Single center experience with Pipeline stent: feasibility, technique, and complications. Neurosurgery 71:679691, 2012

    • Search Google Scholar
    • Export Citation
  • 5

    Cohen JE, Gomori JM, Moscovici S, Leker RR, Itshayek E: Delayed complications after flow-diverter stenting: reactive in-stent stenosis and creeping stents. J Clin Neurosci 21:11161122, 2014

    • Search Google Scholar
    • Export Citation
  • 6

    Fiorella D, Hsu D, Woo HH, Tarr RW, Nelson PK: Very late thrombosis of a Pipeline embolization device construct.. Neurosurgery 67:3 Suppl Operative onsE313onsE314, 2010

    • Search Google Scholar
    • Export Citation
  • 7

    John S, Bain MD, Hui FK, Hussain MS, Masaryk TJ, Rasmussen PA, : Long-term follow-up of in-stent stenosis after Pipeline flow diversion treatment of intracranial aneurysms. Neurosurgery 78:862867, 2016

    • Search Google Scholar
    • Export Citation
  • 8

    Kallmes DF, Ding YH, Dai D, Kadirvel R, Lewis DA, Cloft HJ: A new endoluminal, flow-disrupting device for treatment of saccular aneurysms. Stroke 38:23462352, 2007

    • Search Google Scholar
    • Export Citation
  • 9

    Klisch J, Turk A, Turner R, Woo HH, Fiorella D: Very late thrombosis of flow-diverting constructs after the treatment of large fusiform posterior circulation aneurysms. AJNR Am J Neuroradiol 32:627632, 2011

    • Search Google Scholar
    • Export Citation
  • 10

    Lanzino G, Crobeddu E, Cloft HJ, Hanel R, Kallmes DF: Efficacy and safety of flow diversion for paraclinoid aneurysms: a matched-pair analysis compared with standard endovascular approaches. AJNR Am J Neuroradiol 33:21582161, 2012

    • Search Google Scholar
    • Export Citation
  • 11

    Lüscher TF, Steffel J, Eberli FR, Joner M, Nakazawa G, Tanner FC, : Drug-eluting stent and coronary thrombosis: biological mechanisms and clinical implications. Circulation 115:10511058, 2007

    • Search Google Scholar
    • Export Citation
  • 12

    Lylyk P, Miranda C, Ceratto R, Ferrario A, Scrivano E, Luna HR, : Curative endovascular reconstruction of cerebral aneurysms with the Pipeline embolization device: the Buenos Aires experience.. Neurosurgery 64:632643, N6, 2009

    • Search Google Scholar
    • Export Citation
  • 13

    Meckel S, McAuliffe W, Fiorella D, Taschner CA, Phatouros C, Phillips TJ, : Endovascular treatment of complex aneurysms at the vertebrobasilar junction with flow-diverting stents: initial experience. Neurosurgery 73:386394, 2013

    • Search Google Scholar
    • Export Citation
  • 14

    Mills B, Robb T, Larson DF: Intimal hyperplasia: slow but deadly. Perfusion 27:520528, 2012

  • 15

    Nelson PK, Lylyk P, Szikora I, Wetzel SG, Wanke I, Fiorella D: The Pipeline embolization device for the intracranial treatment of aneurysms trial. AJNR Am J Neuroradiol 32:3440, 2011

    • Search Google Scholar
    • Export Citation
  • 16

    O'Kelly CJ, Spears J, Chow M, Wong J, Boulton M, Weill A, : Canadian experience with the Pipeline embolization device for repair of unruptured intracranial aneurysms. AJNR Am J Neuroradiol 34:381387, 2013

    • Search Google Scholar
    • Export Citation
  • 17

    Park MS, Albuquerque FC, Nanaszko M, Sanborn MR, Moon K, Abla AA, : Critical assessment of complications associated with use of the Pipeline embolization device. J Neurointerv Surg 7:652659, 2015

    • Search Google Scholar
    • Export Citation
  • 18

    Puffer RC, Piano M, Lanzino G, Valvassori L, Kallmes DF, Quilici L, : Treatment of cavernous sinus aneurysms with flow diversion: results in 44 patients. AJNR Am J Neuroradiol 35:948951, 2014

    • Search Google Scholar
    • Export Citation
  • 19

    Puffer RC, Kallmes DF, Cloft HJ, Lanzino G: Patency of the ophthalmic artery after flow diversion treatment of paraclinoid aneurysms. J Neurosurg 116:892896, 2012

    • Search Google Scholar
    • Export Citation
  • 20

    Shapiro M, Becske T, Riina HA, Raz E, Zumofen D, Jafar JJ, : Toward an endovascular internal carotid artery classification system. AJNR Am J Neuroradiol 35:230236, 2014

    • Search Google Scholar
    • Export Citation
  • 21

    Siddiqui AH, Kan P, Abla AA, Hopkins LN, Levy EI: Complications after treatment with Pipeline embolization for giant distal intracranial aneurysms with or without coil embolization. Neurosurgery 71:E509E513, 2012

    • Search Google Scholar
    • Export Citation
  • 22

    Szikora I, Berentei Z, Kulcsar Z, Marosfoi M, Vajda ZS, Lee W, : Treatment of intracranial aneurysms by functional reconstruction of the parent artery: the Budapest experience with the Pipeline embolization device. AJNR Am J Neuroradiol 31:11391147, 2010

    • Search Google Scholar
    • Export Citation
  • 23

    Szikora I, Marosfoi M, Salomváry B, Berentei Z, Gubucz I: Resolution of mass effect and compression symptoms following endoluminal flow diversion for the treatment of intracranial aneurysms. AJNR Am J Neuroradiol 34:935939, 2013

    • Search Google Scholar
    • Export Citation
  • 24

    Toth G, Bain M, Hussain MS, Moskowitz S, Masaryk T, Rasmussen P, : Posterior circulation flow diversion: a single-center experience and literature review. J Neurointerv Surg 7:574583, 2015

    • Search Google Scholar
    • Export Citation
  • 25

    Zanaty M, Chalouhi N, Tjoumakaris SI, Gonzalez LF, Rosenwasser R, Jabbour P: Flow diversion for complex middle cerebral artery aneurysms. Neuroradiology 56:381387, 2014

    • Search Google Scholar
    • Export Citation

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