A Case of Development and Rapid Increase in the Microbleeds after Pipeline Placement for an Intracranial Unruptured Aneurysm

Abstract

Flow diverter stents are used for the treatment of intracranial aneurysms and require long-term antiplatelet therapy, which has been associated with complications such as intracranial hemorrhage. We encountered a case in which rapid increases in the size and number of cerebral microbleeds were observed shortly after flow diverter stent placement. It is known that microthrombosis within a stent can occur after flow diverter stent placement, and this microthrombosis is thought to cause cerebral microbleeds. The patient was a 77-year-old man who underwent flow diverter stent placement for an unruptured intracranial aneurysm. Postoperatively, he developed disorientation and limb paralysis, with magnetic resonance imaging showing diffuse cerebral infarction but no hemorrhagic lesions. Subsequent imaging revealed numerous cerebral microbleeds that were not present earlier and progressively worsened despite dual antiplatelet therapy and blood pressure management. Adjustments to medications, including delaying aspirin and adding antihypertensives, were made. Sodium ozagrel was introduced but later discontinued due to further increases in cerebral microbleeds. At 30 days post-surgery, imaging showed stabilization. By 3 months, residual cerebral microbleeds remained without further progression, and the patient had a modified Rankin scale score of 1. By adjusting antiplatelet medication and controlling blood pressure, it was possible to somewhat manage cerebral hemorrhage. Even when antiplatelet medications are maintained within the optimal therapeutic range, there remains a risk of cerebral hemorrhage. This risk must be carefully considered, and appropriate adjustments to antiplatelet therapy are essential during the perioperative period.

Introduction

Recently, physicians have increasingly performed neuroimaging as part of general physical examinations and the evaluation of minor symptoms. With advancements in these procedures, the detection of unruptured intracranial aneurysms has steadily increased.¹⁾ The introduction of the flow diverter stent (FDS), an endovascular technique used to treat intracranial aneurysms by reconstructing the parent vessel, represents a paradigm shift in unruptured intracranial aneurysm management. However, FDS placement requires long-term antiplatelet therapy, which has been associated with complications, including intracranial hemorrhage in 2.2%-7.5% of cases.²⁾

Cerebral microbleeds (CMBs) are hemosiderin deposits within macrophages caused by bleeding-prone microangiopathy. They appear as dot-like hypointense signals on gradient echo magnetic resonance imaging (MRI).³⁾ The presence of CMBs is widely considered a risk factor for future cerebral hemorrhage and may also be associated with delayed intracerebral hemorrhage.^4,5)

This report discusses a case involving the development and rapid increase of CMBs following FDS placement for an unruptured internal carotid artery aneurysm.

Case Report

The patient was a 77-year-old man with a history of hypertension. A detailed examination for brainstem infarction revealed an unruptured anterior communicating artery aneurysm and a left internal carotid artery aneurysm (Fig. 1). After initiating dual antiplatelet therapy (DAPT) with aspirin (100 mg) and prasugrel (3.75 mg), stent-assisted coil embolization was performed on the unruptured anterior communicating artery aneurysm. One month later, a Pipeline Flex (Medtronic Inc., Dublin, Ireland) was placed for the unruptured left internal carotid artery aneurysm. VerifyNow measurements prior to Pipeline Flex placement were P2Y12 Reaction Units (PRU) 96 and Aspirin Reaction Units (ARU) 385. The treatment was completed without notable complications (Fig. 1). However, the patient developed disorientation and right-sided upper and lower limb paralysis the day after Pipeline Flex placement. Brain MRI revealed diffuse cerebral infarction, considered a postoperative change, but no obvious hemorrhagic lesions were detected (Fig. 2B). Arterial spin labeling showed increased blood flow predominantly in the left hemisphere, suggesting nonconvulsive status epilepticus, for which antiepileptic drugs were initiated. Despite treatment, there was no improvement in symptoms. Four days post-surgery, MRI revealed numerous CMBs that had not been observed before the endovascular treatment (Fig. 2D). The patient continued on DAPT, but an increase in the size and number of CMBs was noted 7 days post-surgery (Fig. 2E). Although PRU and ARU values were 167 and 562, respectively, indicating no excessive inhibition of platelet function, aspirin was discontinued. Additionally, an antihypertensive drug was added to address persistent systolic blood pressure around 150 mmHg. Fourteen days post-surgery, cerebral infarction was observed in the left anterior cerebral artery territory, prompting the addition of sodium ozagrel. However, further CMB progression was observed 3 days later, leading to the discontinuation of sodium ozagrel. By 30 days post-surgery, no additional deterioration was observed on imaging (Fig. 2F). At 3 months post-treatment, MRI showed residual CMBs, but no further increase was noted (modified Rankin scale 1).

Figure 1.

Aneurysm treatment.

We performed SACE for the unruptured anterior communicating artery aneurysm, and one month later, Pipeline Flex placement was performed on the unruptured left internal carotid artery aneurysm.

A: pre-surgery.

B: just after SACE.

C: pre-surgery.

D: just after Pipeline Flex placement.

The white arrowhead is pointing to Pipeline Flex.

SACE: stent-assisted coil embolization

Figure 2.

Increase in CMBs.

The increase in CMBs was demonstrated through a comparison of the same slice of MRI T2 images.

A: before SACE.

B: SACE concluded without any apparent complications.

C: Acute cerebral infarction was observed on DWI the day after placement of FDS.

D: 4 days after surgery.

E: 7 days after surgery.

F: 30 days after surgery.

CMB: cerebral microbleed; DWI: Diffusion weighted imaging; FDS: flow diverter stent; MRI: magnetic resonance imaging; SACE: stent-assisted coil embolization

Written informed consent was obtained from the patients.

Discussion

Cerebral microbleeds are commonly associated with clinical conditions such as stroke and Alzheimer's disease and are known to pose a risk of intracerebral hemorrhage. CMBs are generally reported to result from hemorrhagic changes following microinfarctions, as well as blood leakage caused by an impaired blood-brain barrier and neurovascular unit due to hypertensive microangiopathy and amyloid angiopathy.^3,6) They have been reported in approximately 5.0% of the general adult population,⁷⁾ but it is not clearly understood how long it takes for CMBs to appear. In this case, new CMBs were detected on MRI on post-FDS therapy day 4. Given that preoperative MRI did not reveal any preexisting dementia or CMBs (Fig. 2A), and the patient had a history of hypertension, it seems unlikely that the appearance of the CMBs was due to amyloid angiopathy or chronic hypertension. Postoperative MRI showed scattered ischemic strokes in the left cerebral hemisphere (Fig. 2C), supporting the ischemic origin of the CMBs,⁸⁾ more likely caused by an ischemic mechanism related to thrombosis within the FDS.

It is known that large cerebral infarctions and higher National Institutes of Health Stroke Scale scores are associated with an increased risk of hemorrhagic infarction.⁹⁾ In contrast, hemorrhagic transformation occurs in only 1.5% of infarctions smaller than 2 cm, with a reported median onset of 6 days after the initial stroke.¹⁰⁾ Although hemorrhagic transformation following lacunar infarction has not been previously reported, in this case, microinfarctions were observed prior to the appearance of cerebral microbleeds, and their contribution to the development of microbleeds cannot be ruled out. In addition to CMBs, delayed ipsilateral remote parenchymal hematoma could occur as a potential complication of FDS treatment.¹¹⁾ Although certain mechanisms remain unclear, hemorrhagic transformation of an ischemic lesion, flow modification of intracerebral blood flow by FDS, and DAPT could be proposed as mechanisms of the remote parenchymal hematoma.¹²⁾ Therefore, these mechanisms could also be associated with the development of the CMBs. The temporal difference in the hemorrhagic transformation of microinfarctions may have manifested as an increase in the number of CMBs.

Dual antiplatelet therapy is often required before and after placing a flow diverter, but there is a possibility that DAPT contributed to the development and increase in CMBs. In this case, aspirin and prasugrel were used, and although the VerifyNow results were within the optimal therapeutic range pre- and post-operation, there is still a reported 8.9% risk of intracranial hemorrhage under these conditions.¹³⁾ Additionally, the use of prasugrel, known to significantly increase bleeding complications compared to clopidogrel in the cardiovascular context, cannot be ruled out as a contributing factor to the increase in the size and number of CMBs. Additionally, the use of prasugrel, known to significantly increase bleeding complications compared to clopidogrel in the cardiovascular context,¹⁴⁾ cannot be ruled out as a contributing factor to the increase in the size and number of CMBs. Although it is a single-facility report, 37.6% of patients undergoing endovascular treatment for unruptured cerebral aneurysms developed CMBs.¹⁵⁾ This suggests that ischemic complications due to intra-stent thrombosis are relatively common with FDS placement. Therefore, it is necessary to continue investigating potential factors in the occurrence of CMBs that cannot be monitored by ARU or PRU.

After the appearance of CMBs, DAPT was switched to single antiplatelet therapy, but the patient also developed new cerebral infarctions, complicating the management of antiplatelet therapy. The present case underscores the need for individualized approaches and further study into the factors contributing to increases in CMBs.

Conclusion

We experienced a sudden increase in CMBs that could occur during DAPT for flow diverter placement, regardless of whether antiplatelet agents were within the optimal therapeutic range. Therefore, careful management of antiplatelet agents was warranted after FDS placement for an unruptured intracranial aneurysm.

Authors Contributions

Yoshimasa Fukui: Writing - original draft, Investigation. Hidetoshi Matsukawa: Writing - original draft, Investigation. Kiyoshi Kazekawa: Writing - review & editing. Masahiro Yasaka: Writing - review & editing. Kosei Maruyama: Writing - review & editing. Takashi Fujii: Writing - review & editing. Kosuke Takigawa: Writing - review & editing. Noriaki Tashiro: Writing - review & editing. Yoshiya Hashiguchi: Writing - review & editing. Hiroshi Aikawa: Writing - review & editing. Yoshinori Go: Writing - review & editing.

Conflicts of Interest Disclosure

Hidetoshi Matsukawa received a lecture fee from Daiichi-Sankyo and Stryker and a consulting services fee from B. Braun.