Improvement of cerebral blood flow after balloon angioplasty and stenting for symptomatic middle cerebral artery stenosis

Abstract

Objective

Although reports of endovascular treatment for intracranial arterial stenosis have been increasing recently, their efficacy remains to be elucidated. This study aimed to investigate the changes in cerebral hemodynamics of severe middle cerebral artery (MCA) stenosis patients by performing CT perfusion (CTP) after endovascular treatment.

Methods

Subjects were those who underwent balloon angioplasty and stenting for symptomatic MCA M1 stenosis refractory to medical therapy at our hospital between 2008 and 2022. We included 36 patients (mean age 63.69 ± 15.24 years, 20 males) who underwent CTP before and within three weeks after treatment. The CTP parameters such as relative cerebral blood flow (rCBF), relative cerebral blood volume (rCBV), and relative mean transit time (rMTT) were calculated as ipsilateral values divided by contralateral value.

Results

Endovascular treatment consisted of 26 balloon angioplasty and 10 stenting procedures performed at an average of 1 month from onset. CTP was performed at an average of 5.5 days postoperatively. The mean overall stenosis rate decreased from 79.0% to 30.3%. In the balloon angioplasty group, it decreased from 77.6% to 35.3%, and in the stent group, it decreased from 82.7% to 17.5%. After treatment, rCBF and rMTT measured by CTP improved significantly (both p < 0.001), whereas there was no significant change in rCBV. The improvement rates of rCBF and rMTT were mild higher in the stent group, but not significantly so.

Conclusion

Balloon angioplasty and stenting for symptomatic MCA improved cerebral hemodynamics, resulting in significantly increased rCBF and decreased rMTT.

Introduction

Intracranial atherosclerotic stenosis is one of the most important etiological factors for acute ischemic stroke. It has been reported in 8–10% of patients in the USA, 18% in Japan, and 30–46% in China. ¹ The recurrence rate is high even with medical treatment; however, the benefits of neuroendovascular treatment remain to be elucidated. ² Randomized control trials have not proved the efficacy of endovascular treatment such as balloon angioplasty and stenting.^3,4

In Japan, where many patients have intracranial atherosclerotic stenosis as the cause of their stroke, endovascular treatment has long been performed at each hospital based on strict patient selection. Recent surveillance study of endovascular treatment for patients with intracranial stenosis indicated that the incidence rates of ischemic and hemorrhagic complications were as low as 5.3% and 3.1%. ⁵

The etiologies of cerebral infarction with intracranial atherosclerotic stenosis include hemodynamic ischemia, artery-to-artery embolism, branch occlusive disease, and in-situ thrombotic occlusion. Endovascular therapy is considered to be effective against hemodynamic ischemia. However, few studies have examined changes in cerebral blood flow after endovascular treatment for patients with intracranial atherosclerotic stenosis.^6,7 The present study investigated cerebral hemodynamics by CT perfusion (CTP) before and after treatment in patients who underwent endovascular treatment with balloon angioplasty and stenting for symptomatic severe middle cerebral artery (MCA) stenosis.

Methods

Study design

We retrospectively studied 36 patients who underwent endovascular treatment for symptomatic atherosclerotic MCA(M1) stenosis between December 2008 and June 2020 at our hospital and whose cerebral blood flow was evaluated by CTP before and after treatment. Informed consent for the procedure was obtained from all patients before balloon angioplasty and stenting. Patients who underwent endovascular treatment following mechanical thrombectomy for acute occlusion of the MCA were excluded. This study was approved by the Ethic Review Board of our institution (approval no. 5860).

Patient selection

The inclusion criteria were (a) patients with ≥70% stenosis of the main trunk of the middle cerebral artery (MCA-M1); (b) those with a history of a stenotic lesion, including transient ischemic attack or non-disabling ischemic stroke (modified Rankin Scale ≤ 2); (c) those with stenosis length ≤ 10 mm; and (d) those who were medical treatment-resistant. In this study, we defined that the M1 segment is just up to bifurcation. However, there were no cases of early M1 bifurcation or short M1 segment. We performed cerebral angiography for all possible candidates to include patients in this study. Measurement of lesion lengths and stenotic rates was performed by cerebral angiography.

Neuroendovascular techniques

For the endovascular treatment technique, balloon angioplasty was used for the initial treatment. After balloon angioplasty, stents were placed in cases with moderate to severe dissection, inadequate dilation, or restenosis. All patients received dual antiplatelet agents at least 1 or 2 weeks before endovascular treatment. All treatments were performed under continuous intravenous propofol with local anesthesia at the femoral artery puncture site. After an 8-Fr guiding catheter was inserted, 5000 units of heparin were intravenously administered. A 0.014-inch micro-guidewire was guided into a distal artery vessel across the stenotic lesion, then a Gateway Monorail PTA Dilatation Catheter (Stryker, Michigan, USA) or Unryu PTA Balloon Dilatation Catheter (Kaneka Medics, Tokyo, Japan) was guided. The balloon catheter measured 1.5 to 2.5 mm in diameter, slightly smaller than that of a normal artery distal to the site of stenosis. The balloon catheter was dilated to a maximum atmospheric pressure of 6 to 8 atm by increasing the pressure by 1 atm every 10 s and maintained for approximately 90 s, which was performed only once.

The procedure was successful when adequate dilation was obtained on post-treatment imaging. In cases with dissection or insufficient dilation, a Wingspan stent (Stryker, Michigan, USA) was placed, and the appropriate stent size was selected based on the standard vessel diameter and lesion length before and after the procedure. No anticoagulant therapy was administered postoperatively. Antiplatelet agents administered preoperatively were continued postoperatively.

Analysis of CTP

Cerebral blood flow was evaluated preoperatively and within 3 weeks postoperatively using CTP with a 64-row multi-slice CT (Aquilion; Toshiba Medical Systems, Tokyo, Japan). After nonenhanced CT of the whole brain, a cross-section, including the basal ganglia and the body of the lateral ventricles, was set as the imaging range. For CTP analysis, CTP imaging data were post-processed using Ziostation 2 (Ziosoft, Tokyo, Japan). As described in Yoshie et al., ⁸ we used the middle artery contralateral to the stenosis as the arterial input function and the superior sagittal sinuses as the venous output function. Regions of interest (ROI) were manually set in the cortical gray matter, which was defined as the MCA region excluding cortical vessels, on the CT images of the reference. ROI was created using a CTP software workstation. The relative cerebral blood flow (rCBF; ml/100 mg/min) was calculated as ipsilateral CBF/contralateral CBF × 100, and relative cerebral blood volume (rCBV; ml/100 mg) and relative mean transit time (rMTT; sec) were similarly calculated from the results. The percent changes in rCBF, rCBV, and rMTT values obtained from CTP after treatment were calculated as follows: {(post-treatment CTP value/pre-treatment CTP value) − 1} × 100 (%).

Statistical analysis

For the analysis of CTP, pre- and post-treatment comparisons were made for all patients.

Corresponding t-tests were used for changes in CTP values and pre-and postoperative stenosis improvement rates. Pearson's χ-square test was used for vascular risk and cerebral infarction. p < 0.05* was considered significant. We used JMP®14 statistical software (SAS Institute, North Carolina, USA).

Results

The baseline characteristics, CTP parameters, and stenosis rate of the patients (n = 36) are shown in Table 1. The mean age was 63.69 ± 15.24 years, and 20 patients (55.6%) were male. Dyslipidemia (67%) and hypertension (64%) were common comorbid diseases. Most of the patients had cerebral infarction (88.9%).

Table 1.

Baseline characteristics of patients receiving endovascular treatment.

	Total	Balloon angioplasty (n = 26)	Stenting (n = 10)	p-value
Age, mean ± SD, y	63.69 ± 15.24	62.96 ± 15.09	65.60 ± 16.30	0.649
Sex, male, n (%)	20 (55.6)	12 (46.2)	8 (80.0)	0.067
Vascular risk factors
hypertension, n (%)	23 (63.9)	18 (69.2)	5 (50.0)	0.282
diabetes mellitus, n (%)	10 (27.8)	7 (26.9)	3 (30.0)	0.854
hyperlipidemia, n (%)	24 (66.7)	16 (61.5)	8 (80.0)	0.293
Symptom				0.895
ischemic stroke, n (%)	32 (88.9)	23 (88.5)	9 (90.0)
TIA, n (%)	4 (11.1)	3 (11.5)	1 (10.0)
Site of stenosis in the M1 region				0.801
proximal, n (%)	6 (16.7)	5 (19.2)	1 (10.0)	—
mid, n (%)	20 (55.6)	14 (53.9)	6 (60.0)	—
distal, n (%)	10 (27.8)	7 (26.9)	3 (30.0)	—
Stenosis rate
pre-treatment, mean ± SD, %	79.0 ± 9.56	77.6 ± 8.0	82.7 ± 12.5	0.153
post-treatment, mean ± SD, %	30.3 ± 15.3	35.3 ± 13.5	17.5 ± 12.3	0.001
Time of CTP after treatment, median (IQR), days	5.5	6	3	0.801

TIA, transit ischemic attack; M1, middle cerebral artery M1 segment; mid, middle; CTP, CT perfusion imaging; SD, standard deviation; and IQR, interquartile range.

p-values refer to the comparison between the balloon angioplasty and stenting groups.

Balloon angioplasty and stenting were performed in 26 and 10 patients, respectively. Perioperative complications included one subarachnoid hemorrhage in the stenting group due to peripheral vessel perforation, which was associated with only mild headache. There were no differences in age, sex ratio, presence of vascular risk, onset form, or site of stenosis between the two groups (Table 1). The overall stenosis rate significantly decreased from 79.0 ± 9.6% to 30.3 ± 15.3% (p < 0.001). In the balloon angioplasty group, it decreased from 77.6 ± 8.0% to 35.3 ± 13.5%, and in the stent group from 82.7 ± 12.5% to 17.5 ± 12.3%. Post-treatment stenosis rate was significantly lower in the stenting group than in the balloon angioplasty group (p = 0.001).

CTP evaluations and stenosis rate are shown in Table 2. Pre-treatment rCBF and rMTT significantly improved after treatment (p < 0.0001) (Figure 1). Pre-treatment stenosis rate also significantly improved after treatment (p < 0.0001). Table 3 shows the changes in CTP parameters after treatment in balloon angioplasty and stenting groups. Relative CBF and rMTT improved significantly after treatment in both groups (p < 0.001). However, rCBV did not change much after treatment in both groups.

Table 2.

CTP parameters of patients receiving endovascular treatment.

	Pre-treatment	Post-treatment	p-value
CTP parameters, mean ± SD
rCBF ratio	0.75 ± 0.16	0.91 ± 0.14	<0.0001
rCBV ratio	1.09 ± 0.23	1.01 ± 0.09	0.05
rMTT ratio	1.41 ± 0.40	1.10 ± 0.19	<0.0001
Stenosis rate, mean ± SD, %	79.0 ± 9.56	30.3 ± 15.3	<0.0001

rCBF, relative cerebral blood flow; rCBV, relative cerebral blood volume; rMTT, relative mean transit time; SD, standard deviation; and CTP, CT perfusion imaging.

Figure 1.

Changes in CT parameters after treatment in balloon angioplasty and stenting groups. (a) relative cerebral blood flow; (b) relative cerebral blood volume; and (c) relative mean transit time. Pre-treatment rCBF significantly improved after treatment both balloon angioplasty and Stenting(Balloon angioplasty; p < 0.001, Stenting; p = 0.002). Pre-treatment rMTT significantly improved after treatment both balloon angioplasty and Stenting (Balloon angioplasty; p = 0.001, Stenting; p = 0.013). rCBF, relative cerebral blood flow; rCBV, relative cerebral blood volume; rMTT, relative mean transit time; and CTP, CT perfusion imaging

Table 3.

Changes of CTP parameters in balloon angioplasty and stenting groups.

	Balloon angioplasty group		Stenting group		p-value
	Pre-treatment	Post-treatment	Pre-treatment	Post-treatment
CTP parameters, mean ± SD
rCBF ratio	0.76 ± 0.17	0.89 ± 0.14	0.73 ± 0.13	0.98 ± 0.14
rCBV ratio	1.09 ± 0.25	1.01 ± 0.08	1.10 ± 0.17	1.01 ± 0.13
rMTT ratio	1.42 ± 0.41	1.14 ± 0.17	0.73 ± 0.13	1.00 ± 0.21
Rate of change in CTP parameters, %
rCBF	20.1		39.3		0.069
rCBV	−3.0		−6.2		0.698
rMTT	−15.3		−24.4		0.216

rCBF, relative cerebral blood flow; rCBV, relative cerebral blood volume; rMTT, relative mean transit time; SD, standard deviation; and CTP, CT perfusion imaging.

Discussion

Patients with atherosclerotic intracranial artery stenosis have an exceptionally high risk of recurrent cerebral infarction, even with medical therapy.^9,10 There is no evidence that endovascular treatment of symptomatic severe stenosis of intracranial arteries is more effective than medical therapy in preventing recurrent stroke. A recent randomized controlled trial comparing an intracranial stent implantation group with a medical treatment group found no difference between the two groups in the combined outcome of stroke and death within 30 days or recurrent stroke related to the stenotic vessel within 1 year. ¹¹ On the other hand, in Japan, after the approval of the Wingspan stent specifically for intracranial arteries in 2014, endovascular treatment of intracranial artery stenosis refractory to medical therapy has been performed under careful patient selection in many facilities.^12,13

It has been reported that endovascular treatment for intracranial artery stenosis is associated with a high incidence of intracranial ischemic and hemorrhagic complications in the acute phase of cerebral ischemic event onset. ² The Weave trial reported periprocedural safety of the Wingspan stent with a 2.6% periprocedural stroke and death rate with strict selection criteria, such as excluding acute phase patients and surgeon requirements. ¹⁴ In the present study, appropriate drug therapy was first given for the vascular risks of hyperlipidemia, diabetes, and hypertension in addition to antithrombotic therapy using two antiplatelet agents for atherothrombotic infarction caused by atherosclerotic lesions in intracranial arteries. Endovascular treatment was performed in the chronic phase after approximately 2 weeks from the onset of ischemic stroke, when the clinical symptoms were stable. There were no treatment-related perioperative complications except for one case of peripheral vascular perforation at the time of stent implantation, which was associated with only mild headache. In a previous report from our institution, the incidence of perioperative stroke in percutaneous transluminal angioplasty for 72 patients with MCA stenosis was 4.2%. ¹⁵

Studies in which balloon angioplasty and stenting were performed after the acute phase of stroke reported fewer perioperative complications.^16,17 A problem with balloon angioplasty alone without stent implantation is the high incidence of restenosis. Balloon angioplasty, diabetes mellitus, and lesion length have been reported as independent factors associated with restenosis in the endovascular treatment of intracranial artery stenosis. ¹⁷

Several studies have reported that endovascular treatment of intracranial artery stenosis improves cerebral hemodynamics. Abe et al. ⁶ performed acetazolamide-loaded SPECT before and after treatment in 17 patients who underwent balloon angioplasty for symptomatic MCA stenosis. They found that cerebrovascular reserves were significantly improved after treatment compared to resting rCBF. In a study of 10 patients who underwent balloon angioplasty for MCA stenosis using CTP, cerebral hemodynamics (especially time to peak) improved after treatment. ⁷ On the other hand, in a study of 107 patients with intracranial artery stenosis who underwent CTP before and after treatment, cerebral perfusion improved in 72% of patients. ¹⁸ Furthermore, they reported that recurrent strokes were more common in patients who did not show improvement in perfusion.

In the present study, after endovascular treatment of symptomatic MCA stenosis, there was a significant increase in rCBF, and a decrease in rMTT, indicating improvement in cerebral hemodynamics. Postoperative rCBF and rMTT showed significant improvement in both the balloon angioplasty and stenting groups and the improvement rate was mild higher in the stenting group, but not significantly so. In contrast to previous reports, our study showed the improvement in cerebrovascular dynamics in patients who had symptomatic MCA stenosis separately by balloon angioplasty and stenting.

The most common mechanism by which atherosclerotic intracranial artery stenosis causes ischemic stroke is reported to be a mixed type of artery-to-artery embolism and hypoperfusion (37.3%), followed by isolated hypoperfusion (35.3%). ¹⁹ Stenting of intracranial artery stenosis is performed to improve cerebral hemodynamics and may be an effective treatment option for the hypoperfusion-related mechanisms of stroke.

There are several limitations to this study. First, it was a single-center retrospective study with only 36 patients, which may have led to selection bias. Second, automated analysis software could not be used to evaluate CTP. Third, some follow-up data on clinical course and imaging were insufficient.

Conclusions

Balloon angioplasty and stenting for symptomatic MCA stenosis improved cerebral hemodynamics, resulting in significantly increased rCBF and decreased rMTT. rCBF and rMTT improvement rates were higher in the stent implantation than in the balloon angioplasty group.