Fatal intracranial hemorrhage after carotid artery stenting: Three case reports and a literature review.

INTRODUCTION: We herein describe three patients who developed fatal intracranial hemorrhage (ICH) after carotid artery stenting (CAS).Case Presentation: We retrospectively reviewed 126 patients who underwent CAS from January 2016 to December 2018 and identified 3 patients (2.4%) (all male, mean age of 59 years) who developed ICH after CAS. Two of them developed left basal ganglia hemorrhage with extension into the ventricle and subarachnoid space, and the third patient developed primary ventricular bleeding. One hemorrhage occurred immediately after CAS, whereas the other two occurred 3 hours and 8 hours after the procedure, respectively. The mean stenosis of the treated carotid arteries was 91%. All three hemorrhages were fatal, and the mean time from hemorrhage to death was 50 hours.
CONCLUSION: ICH is a potentially fatal complication of CAS and often occurs several hours after the procedure. Headache, vomiting, and consciousness disorders are the most common symptoms of ICH. Careful screening to identify high-risk patients and strict management of perioperative blood pressure are important to prevent this complication.

Introduction

Carotid artery stenting (CAS) is widely performed for primary and secondary stroke prevention in patients with carotid stenosis. The use of emboli-prevention devices has markedly reduced the incidence of ischemic stroke following CAS. Intracranial hemorrhage (ICH) is a relatively rare but potentially fatal complication of CAS, occurring in 0.36% to 6.67% of patients after CAS, and its mortality rate is about 75%.[1] We retrospectively reviewed 126 patients who underwent CAS from January 2016 to December 2018 and identified 3 patients (2.4%) who developed fatal ICH after CAS.

Case reports

Case 1

A 67-year-old man was admitted to our hospital with recurrent transient ischemic attacks, including right lower extremity weakness, that had occurred six times during the 2 months prior to admission. He had a history of hypertension, hypercholesterolemia, and coronary heart disease. Moderate to severe stenosis was found in the bilateral internal carotid arteries (ICAs) by computed tomography (CT) angiography at another hospital (images not shown). The patient was referred to our hospital for CAS. His preoperative blood pressure ranged from 130/60 to 140/80 mmHg. He was pretreated with aspirin at 100 mg/day and clopidogrel at 75 mg/day for 1 week before CAS, which was performed by a femoral approach under local anesthesia. Intravenous heparin was administered with a bolus of 50 U/kg and additional half doses as needed, and the heparin was not reversed at completion of the procedure. The stenosis ratio was computed according to the North American Symptomatic Carotid Endarterectomy Trial (NASCET).[2] Digital subtraction angiography (DSA) confirmed 95% stenosis of the left ICA (Figure 1(a)) and poor intracranial circulation (Figure 1(e)). The right ICA also had 75% stenosis, and DSA of the intracerebral circulation revealed occlusion of the right ICA after the ophthalmic artery (Figure 1(d)). The bilateral vertebral arteries were severely stenosed, and neither posterior communicating artery was patent (Figure 1(c)). After pre-dilation (6 atm) using a Ryujin balloon (2.5 × 30 mm; Terumo Corporation, Tokyo, Japan), a Spider filter (diameter of 6.0 mm; Medtronic, Minneapolis, MN, USA) was deployed in the high cervical ICA. The stenosis was pre-dilated (8 atm) again with a Viatrac balloon (5.5 × 30 mm; Abbott Laboratories, Chicago, IL, USA) and then stented with a tapered self-expanding stent (Acculink, 7–10 × 40 mm; Abbott Laboratories) (Figure 1(b)). After the procedure, the intracranial circulation of the left ICA was greatly improved (Figure 1(f)). However, irritability, irresponsiveness, and projectile vomiting were observed 10 minutes after the operation, and the blood pressure increased to 186/98 mmHg. Emergency CT revealed left basal ganglia and intraventricular hemorrhage and extensive subarachnoid hemorrhage (Figure 1(g)). Urapidil, protamine, and mannitol were immediately administered for blood pressure control, heparin neutralization, and dehydration. Shortly thereafter, the patient developed a coma accompanied by anisocoria and a dulled pupillary light reflex. Therefore, the diagnosis of cerebral hernia was considered. The patient’s blood pressure gradually decreased after emergency tracheal intubation, trepanation, and drainage of the hematoma. A catheter was placed into the left carotid artery to identify the source of the hemorrhage, and DSA showed speckled extravasation of contrast agent at the small branches of the middle cerebral artery (MCA) (Figure 1(h), (i)). The patient died 40 hours after CAS.

Figure 1.

Case 1: Intraoperative DSA and CT images after intracranial hemorrhage.

(a). DSA of the left CCA confirmed string-stenosis of the left proximal ICA with delayed filling of the ICA compared with the ECA. (b) After carotid artery stenting (Acculink, 7–10 × 40 mm), no residual stenosis of the left ICA was present. (c) DSA showed stenosed bilateral vertebral arteries. (d) Intracerebral DSA revealed occlusion of the right ICA after the ophthalmic artery. (e) Poor intracranial circulation of the left hemisphere. (f) Improved blood flow of the ACA and MCA after left ICA stenting. (g) Ten minutes following the operation, the patient became dysphoric and rapidly unconscious. CT showed extensive hemorrhage in the left basal ganglia with extension into the lateral ventricles, lateral fissure, and subarachnoid. (h) DSA of the left CCA demonstrated contrast medium extravasation mainly from the branches of the MCA (arrows). (i) Masked image showed pooling of contrast medium (arrows).

DSA, digital subtraction angiography; CT, computed tomography; ICA, internal carotid artery; ECA, external carotid artery; CCA, common carotid artery; MCA, middle cerebral artery; ACA, anterior cerebral artery.

Case 2

A 60-year-old man was admitted to our hospital with a 3-year history of intermittent dizziness. His blood pressure was 100/70 and 150/70 mmHg in the left and right upper limb, respectively. No overt abnormalities were noted on neurological physical examination. The patient had a history of hypertension, coronary heart disease, hyperlipidemia, and stenosis of the bilateral iliac and femoral arteries. We speculated that the patient might have left subclavian artery (SCA) stenosis or occlusion; therefore, direct angiography was performed. Imaging revealed an occluded left SCA (Figure 2(a)) and 50%, 60%, and 80% stenosis of the right vertebral artery, right ICA (Figure 2(c)), and left ICA (Figure 2(d)), respectively. No aneurysm or malformation was found in the intracranial arteries (Figure 2(f)). An 8-Fr Envoy guiding catheter (Codman Neuro/DePuy Synthes, Warsaw, IN, USA) was placed in 3-cm proximity to the left carotid bifurcation, followed by insertion of an Angioguard emboli-prevention device (Cordis, Santa Clara, CA, USA) into the C2 segment of the left ICA. A Precise stent (9 × 40 mm; Cordis) was then placed after pre-dilation (7 atm) by a Submarine Rapido balloon (6.0 × 30 mm; Medtronic). The left ICA stenosis vanished after the procedure (Figure 2(e)). The 8-Fr Envoy guiding catheter was placed at the proximal end of the left SCA stump, and a 0.035-inch guidewire was used to recanalize the occluded left SCA. After placement of an Express LD stent (8 × 37 mm; Boston Scientific, Marlborough, MA, USA) at the stenosed segment of the left SCA, the distal SCA and axillary artery were patent, although the vertebral artery was still invisible (Figure 2(b)). The patient complained of dizziness, headache, and irritability 3 hours after the operation, and physical examination showed that his limb movement was symmetrical. An emergency CT scan indicated extensive intraventricular hemorrhage (Figure 2(g)–(i)), and 250 mL of mannitol for dehydration was administered before emergency bilateral ventricle drainage under local anesthesia. Frequent vomiting occurred 4 hours after the operation followed by coma with an increase in the blood pressure to 216/74 mmHg even after administration of mannitol and urapidil. The patient died 28 hours after the CAS operation.

Figure 2.

Case 2: Intraoperative DSA and CT images after intracranial hemorrhage.

(a) DSA revealed the occluded left subclavian artery. (b) After recanalization and stenting (Express LD, 8 × 37 mm), the left subclavian artery and axillary artery showed good contrast medium perfusion, but the vertebral artery was still absent. (c) DSA of the right common carotid artery showed 60% stenosis of the ICA. (d) DSA of the left common carotid artery showed 80% focal stenosis of the proximal ICA. (e) The stenosis disappeared after stenting (Precise, 9 × 40 mm). (f) The preoperative DSA of the left intracranial circulation was normal. (g)–(i) Three hours after the operation, the patient developed dizziness, headache, and dysphoria. Brain CT showed extensive bleeding in the primary cerebral ventricles.

DSA, digital subtraction angiography; CT, computed tomography; ICA, internal carotid artery.

Case 3

A 50-year-old man was transferred to our hospital with a 2-month history of frequent episodes of right hemiparesis. The most recent attack had occurred 6 days previously, and he had since experienced persistent right lower extremity weakness (grade 4 muscle strength, National Institutes of Health Stroke Scale score of 2). Magnetic resonance imaging revealed a cerebral watershed infarction of the left centrum semiovale. The patient had a history of hypertension, diabetes, coronary disease, and hyperlipidemia. DSA had been performed 4 years previously following complaints of repeated dizziness, revealing 90% stenosis of the right ICA (Figure 3(a)), 60% stenosis of the left ICA, and occlusion of the right vertebral artery. A Precise stent (9 × 40 mm; Cordis) was introduced into the right ICA (Figure 3(b)) at that time. At the current presentation, the imaging examination revealed that the stenosis of the left ICA was obviously more serious than that 4 years previously (99% vs. 60%, respectively) (Figure 3(c)), and severe stenoses were also found in the left vertebral artery (Figure 3(e)) and M1 segment of the left MCA (Figure 3(g)). After pre-expansion (6 atm) by a Ryujin balloon (2.5 × 20 mm; Terumo Corporation), an Accunet 5.5-mm emboli-prevention device (Abbott Laboratories) was placed at the C2 segment of the left ICA. The stenosis was expanded again (8 atm) by a Viatrac balloon (4.0 × 30 mm; Abbott Laboratories) followed by insertion of an Acculink stent (6–8 × 40 mm; Abbott Laboratories). After the procedure, about 30% residual stenosis remained, and a third expansion (8 atm) was performed with the Viatrac balloon (4.0 × 30 mm) (8 atm). Finally, the stenosis disappeared (Figure 3(d)). Meanwhile, the intracranial circulation had significantly improved compared with the pre-stenting status (Figure 3(h)). We subsequently corrected the left vertebral artery stenosis using an Express SD stent (6 × 14 mm; Boston Scientific) (Figure 3(f)). Sudden headache, projectile vomiting, and right hemiplegia developed 8 hours after the operation, and the blood pressure increased to 200/110 mmHg. Emergency CT revealed extensive hemorrhage in the left basal ganglia rupturing into the lateral ventricle (Figure 3(i)). The patient died 4 days later despite the performance of decompressive craniectomy and hematoma removal immediately after development of the ICH. In this case, increased oxidative stress was responsible for a cerebral infarction, hemodynamic impairment, or a left MCA perforator stroke. In the treatment of all lesions similar to those in Case 3, reactive oxygen species are the specific indicators. In the present case, it was very difficult to control the blood pressure after CAS in tandem lesions. We anticipate the development of valuable strategies for such cases in the foreseeable future.

Figure 3.

Case 3: Most recent MRI, DSA of 4 years previously and current presentation, and CT images after intracranial hemorrhage.

(a) Brain MRI showed a watershed infarction in the left centrum semiovale. (b)–(e) Four years previously. (b) Preoperative angiogram showed 90% stenosis at the origin of the right ICA. (c) Post-intervention (Precise, 9 × 40 mm) image showed correct placement of the stent and good recanalization of the right ICA. (d) Sixty percent stenosis at the origin of the left ICA. (e) DSA of the right subclavian artery revealed occlusion of the vertebral artery at its origin. (f) Preoperative image showed a near occlusive lesion of the left ICA with delayed filling of the ICA compared with the ECA. (g) CAS (Acculink, 6–8 × 40 mm) eliminated the stenosis of the left ICA, resulting in improved blood flow. (h) DSA of the left subclavian artery showed 80% stenosis at the origin of the vertebral artery. (i) No residual stenosis of the left vertebral artery was present after stenting (Express SD, 6 × 14 mm). (j) DSA showed severe M1 stenosis and poor intracranial circulation. (k) Post-stenting angiogram showed significantly increased blood flow of the left intracranial circulation compared with the pre-CAS flow. (l) Eight hours post-procedure, the patient developed headache, vomiting, and right hemiplegia. An urgent CT scan showed a large left basal ganglia hemorrhage with intraventricular extension. The patient died 4 days after decompressive craniectomy.

MRI, magnetic resonance imaging; DSA, digital subtraction angiography; CT, computed tomography; ICA, internal carotid artery; ECA, external carotid artery; CAS, carotid artery stenting.

Ethics statement

Ethical approval was given by the Zhejiang Greentown Cardiovascular Hospital. All patients provided written informed consent.

Discussion

Carotid angioplasty and CAS are important procedures for the treatment of carotid artery stenosis, and their efficacy and safety have been widely accepted. The incidence of ICH as a complication after CAS is relatively low (about 0.7% as reported in the literature), but it has high mortality and disability rates.

CAS-associated ICH has been described in several reports[3-18] (Table 1), but fatal ICH was first reported by McCabe et al.[3] in 1999. A pooled analysis indicated that in 70% of cases, the ICH occurred within 24 hours after CAS.[1] The data in Table 1 suggest that most cases of ICH following CAS develop within 10 hours after the procedure. One of our three patients developed ICH immediately after the procedure and the other two developed ICH within 3 and 8 hours, respectively, consistent with previous studies (Table 1). The typical symptoms of ICH include ipsilateral headache, nausea, vomiting, and focal seizures.

Table 1.

CAS-associated ICH (studies published from 1999 to 2013).

Authors		Published year	Cases of CAS, n	Cases of ICH, n	Incidence of ICH	Outcome	Mortality	Time from end of CAS to ICH	Mean stenosis of treated artery
McCabe et al.[3]		1999	No record	1		Death	100%	6 hours	95%
Morrish et al.[4]		2000	90	4	4.4%	Death (n = 3)Disability (n = 1)	75%	Immediate (n = 1) Mean of 2.8 days (n = 3)	95%
Al-Mubarak et al.[6]		2001	No record	1		Death	100%	Immediate	90%
Abou-Chebl et al.[7]		2004	450	3	0.67%	Death (n = 2) Disability (n = 1)	66.7%	10 hours	95.60%
Friedman et al.[8]		2004	No record	1		Death	100%	45 minutes	>90%
Krajickova et al.[9]		2005	No record	1		Death	100%	2 hours	>90%
Buhk et al.10		2006	No record	1		Death	100%	30 minutes	95%
Przewlocki et al.[11]		2007	No record	1		Total recovery	0%	2 hours	95%
Ogasawara et al.[12]		2007	CAS(n = 2898)	21	0.72%	Death (n = 7)	26%	1.7 days	93%
			CEA(n = 1596)	6	0.38%		10.7 days	88.80%
Takayama et al.[13]		2007	No record	1		Severe disability	0%	Immediate	>95%
Timaran et al.[14]		2009	13,093	19	0.15%	Death (n = 5)	26.3%	No record	No record
Grunwald et al.[15]		2009	417	3	0.72%	All independent	0%	8–10 hours	>90%
Tan and Phatouros16		2009	170	3	1.76%	Death (n = 1) Disability (n = 2)	33.3%	<6 hours	94%
Xu et al.[17]		2009	832	10	1.20%	Death (n = 4) Disability (n = 2) Total recovery (n = 4)	40%	6.1 hours	95%
McDonald et al.[18]		2011	13,884	116	0.84%	Death (n = 43)	37%	No record	No record
Present series			126	3	2.4%	All deaths	100%	Immediate (n = 1) 3 hours (n = 1) 8 hours (n = 1)	91%

CAS, carotid artery stenting; ICH, intracranial hemorrhage; CEA, carotid endarterectomy

Incidence and outcome of ICH

Single-photon emission CT is an intuitive and noninvasive functional imaging technique. It shows both morphological changes and pathophysiologic changes in blood flow, biochemistry, and metabolism. In general, this technique can be used to measure blood flow. The brain accounts for 2% to 3% of the body weight but requires 15% to 20% of cardiac output. Cerebral blood flow (CBF) is the amount of blood flow per 100 g of brain tissue per unit time. The CBF value of normal people in a quiet state differs among the measuring methods used. In quiet conditions, a young man of average size has global CBF of 700 to 770 mL/min, or about 50 to 55 mL/100 g/min. When the average hemispheric CBF is reduced to 25 to 30 mL/100 g/min, mental confusion and even loss of consciousness may occur. The critical CBF for neurologic decline is about 18 mL/100 g/min. The cerebral blood supply through the ICA accounts for about four-fifths of the total CBF, and that through the vertebral artery accounts for about one-fifth. The pressure difference between the carotid artery and the MCA is almost equal to that between the vertebral artery and the basilar ring, suggesting that the blood flow and circulation time of the left and right hemispheres, carotid system, and vertebral artery system are different in normal subjects. The blood circulation of the brain is not only abundant in quantity but also rapid in supply. The time required for blood to enter the cranial cavity from the artery and reach the venous sinus is only 4 to 8 s. The blood flow velocity of the vertebrobasilar system is lower than that of the internal carotid system.

Kang et al.[1] reported that the incidence of CAS-associated ICH varied from 0.36% to 6.67% in a pooled analysis of the English literature published from 1996 to 2005. According to the reports in which the total number of CAS procedures was documented, 41 cases of ICH occurred among 3719 carotid angioplasties (incidence of 1.1%). The subgroup analysis indicated that ICH occurred in 0.63% of patients in studies consisting of >100 cases and in 2.69% of case series consisting of <100 cases. Three of 126 patients undergoing CAS died of ICH in the current study (incidence of 2.4%), which is consistent with the above-mentioned subgroup of <100 patients. The incidence of ICH was significantly higher in studies with small sample sizes than in those with large numbers of cases (Table 1), demonstrating that rich experience may reduce the possibility of ICH after CAS. Although the incidence of CAS-associated ICH varies greatly, the prognosis is strikingly similar with high mortality and disability rates. In one study, the risk of death was 30-fold higher for patients with than without ICH (odds ratio, 29.83, P < 0.0001).[18] Kang et al.[1] reported a mortality rate of 75% in their pooled analysis of 53 patients with CAS-associated ICH. The mortality rate ranged from 26% to 100% in other reports.[3,4,6-10,12,14,16-18] In the present study, all three patients with ICH died (mortality rate of 100%).

Etiology and pathogenesis of ICH

The etiology and pathogenesis of CAS-associated ICH are complex. The most popular viewpoint is that ICH is attributed to impaired autoregulation of CBF. Severe carotid disease results in compensatory dilation of cerebral vessels distal to the stenosis. This is part of the normal autoregulatory response to maintain adequate CBF. As a result of chronic dilation, the vessels lose their ability to autoregulate vascular resistance in response to changes in blood pressure. The sudden restoration of normal CBF to the chronically hypoperfused brain results in edema, capillary breakthrough, and eventual macroscopic hemorrhages.[20],[21] Distal cerebral embolization and subsequent ICH in areas of infarction may increase the risk of acute ICH after CAS. Several observational studies have demonstrated that atherosclerotic fragments are released from carotid plaques during virtually all CAS procedures and that a high proportion of stented carotid lesions continue to release embolic material after the procedure.[22],[23] During CAS, balloon inflation and stent placement are responsible for direct stimulation of the carotid baroreceptors, which may cause hemodynamic depression. Cerebral ischemia secondary to hemodynamic depression may result in severe endothelial injury, thereby increasing the risk of ICH.[24] Buhk et al.[10] considered that the pathophysiologic mechanism of ICH might be associated with rupture of small perforating arteries in the basal ganglia, similar to hemorrhage induced by hypertension. This theory was additionally supported by Pfefferkorn et al.,[5] who measured hemodynamic parameters during the CAS procedure, and by Friedman et al.,[8] who reported a case of fatal thalamic hemorrhage following CAS that occurred in a vascular territory unlikely to be supplied by the treated artery. In the third case of the current report, the infarction was located in the centrum semiovale, whereas ICH in the basal ganglia could be explained by this theory. Krajickova et al.[9] described a patient who died of simple intraventricular hemorrhage, similar to the second case in the present report. The authors speculated that such patients might have a choroid plexus vascular malformation undetectable by DSA.[9] With respect to the cause of bleeding in the right lateral fissure in the first case of the present report, we speculate that the massive hemorrhage in the left basal ganglia entered the left ventricle and subsequently the right ventricle, after which it further entered the sulci of the brain surface, including the lateral fissure.

Risk factors for ICH

The most important risk factor for ICH following CAS is the presence of high-level stenosis of the treated artery. The mean stenosis of the operated arteries was 91% in our report, which is similar to previous reports (Table 1). Other risk factors include severe stenosis or occlusion of the contralateral ICA, poor intracranial collateral flow, perioperative hypertension, recent ischemic stroke, and excessive use of heparin.[25],[26] In our current series, all three patients had other arterial stenoses or occlusions besides the treated artery. The first and third patients also showed poor intracranial collateral flow, and the third patient had an additional recent infarction. Repeated dilation of the stenosis is also regarded as a risk factor for CAS-associated ICH. The first patient in our report underwent two pre-dilation procedures, and the third patient underwent two pre-dilation procedures and one post-dilation procedure.

One risk factor for ICH is repeated dilation. In our three patients, the affected ICA seemed to be overdilated. Dilation of the ICA to the normal size from severe stenosis should be avoided. In this study, we avoided repeated dilation in each case and ensured that overdilation did not affect the ICA under any condition.

Post-CAS ICH

ICH after CAS usually occurs within a few hours and often has catastrophic consequences. Once patients have ICH, rapid and effective neurocritical care may be lifesaving. Discontinuation of antiplatelets and anticoagulants for at least 3 days can prevent stent-site thrombosis.

Therapy and prevention of ICH

An immediate brain CT scan is needed if patients develop a headache, nausea, vomiting, focal seizures, or neurological deterioration. When ICH is confirmed, protamine is initially injected for its anti-heparin effects. Anti-hypertensive medication should also be injected if the systolic blood pressure is >180 mmHg. If severe subarachnoid hemorrhage has occurred and the ventricles are enlarged, ventricular drainage should be performed. The mortality rate remains high even when suitable therapies are performed in a timely manner; therefore, prevention in the early stage in patients with high risk factors is vital. The most important component of perioperative management is vigilant monitoring and control of the systemic blood pressure. Additional efforts to reduce the risk of ICH may include limiting the duration of balloon inflation and employing emboli-prevention devices.[7],[27] Continuous monitoring of the blood flow velocity of the MCA with transcranial Doppler ultrasonography is recommended during CAS and 24 hours postoperatively. Reperfusion injury should be considered if the blood flow velocity is twice the preoperative level.[5]

Conclusion

ICH following CAS is associated with high mortality and morbidity rates. High-risk patients include those with severe ICA stenosis, high-level stenosis or occlusion of the contralateral ICA, poor intracerebral collateral flow, MCA velocity of twice the preoperative value following the procedure, and perioperative hypertension. Careful screening to identify high-risk patients, vigilant postoperative monitoring for signs of hyperperfusion syndrome, and aggressive management of perioperative blood pressure are important steps in both preventing and minimizing the impact of this potentially devastating complication.