- Department of Neurosurgery, Graduate School of Medicine, Kumamoto University, Kumamoto, Japan
- Department of Neurology, Graduate school of Medicine, Kumamoto University, Kumamoto, Japan
- Department of Neurosurgery, Graduate School of Medical Sciences, Kanazawa University, Kanazawa, Japan
Department of Neurosurgery, Graduate School of Medicine, Kumamoto University, Kumamoto, Japan
DOI:10.4103/2152-7806.76145Copyright: © 2011 Kai Y This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Kai Y, Watanabe M, Morioka M, Hirano T, Yano S, Ohmori Y, Kawano T, Hamada J, Kuratsu J. Cilostazol improves symptomatic intracranial artery stenosis - Evaluation of cerebral blood flow with single photon emission computed tomography. Surg Neurol Int 24-Jan-2011;2:8
How to cite this URL: Kai Y, Watanabe M, Morioka M, Hirano T, Yano S, Ohmori Y, Kawano T, Hamada J, Kuratsu J. Cilostazol improves symptomatic intracranial artery stenosis - Evaluation of cerebral blood flow with single photon emission computed tomography. Surg Neurol Int 24-Jan-2011;2:8. Available from: http://sni.wpengine.com/surgicalint_articles/cilostazol-improves-symptomatic-intracranial-artery-stenosis-evaluation-of-cerebral-blood-flow-with-single-photon-emission-computed-tomography/
Background:To evaluate the effectiveness of cilostazol in patients with intracranial arterial stenosis, we used magnetic resonance angiography (MRA). The drug's effect on the cerebral blood flow (CBF) was examined by single photon emission computed tomography (SPECT).
Methods:In this retrospective study, we evaluated the clinical outcomes of 20 patients with stenosis in the M1 segment of the middle cerebral artery (MCA) who had suffered ischemic stroke within 12 weeks or manifested asymptomatic stenosis exceeding 50%. All patients received cilostazol (100 mg twice daily). MRA and SPECT (at rest and after acetazolamide challenge) studies were performed before and 6 and 12 months after the start of cilostazol treatment.
Results:In 5 patients the stenotic lesion showed improvement on MRA. Mean stenosis before cilostazol therapy was 71.7 ± 4.9%, which improved to 39.0 ± 3.2% at 6 months and to 27.2 ± 2.8% at 12 months. SPECT study showed that CBF was improved in 3 patients; in one there was improvement at rest and the other 2 manifested improvement upon acetazolamide challenge.
Conclusions:Cilostazol had a remodeling effect on stenotic lesions due to arteriosclerotic changes and improved CBF in some patients.
Keywords: antiplatelet therapy, cerebral blood flow, intracranial artery stenosis, single photon emission computed tomography
Antiplatelet drugs are effective for the secondary prevention of cerebral infarction. The long-term daily administration of aspirin is useful in efforts to prevent serious vascular events in survivors of ischemic stroke; it reduces the recurrence rate and improves survival.[
In their cilostazol stroke prevention study, a placebo-controlled double-blind trial, Shinohara et al. found that cilostazol effectively prevented the recurrence of vascular events in patients with lacunar infarction.[
We performed a retrospective study on patients with symptomatic intracranial arterial stenosis who were treated with cilostazol. We used MRA to evaluate improvement of their stenoses and single photon emission computed tomography (SPECT) to study their CBF.
Our retrospective study included 20 patients with stenosis in the M1 segment of the middle cerebral artery (MCA) who were treated between April 2007 and March 2010. All patients had suffered ischemic stroke within 12 weeks or presented with asymptomatic stenosis exceeding 50%. None of the patients had other stenotic lesions in the other internal carotid or vertebro basilar arteries. Inclusion criteria were as follows: (1) almost independent pursuit of the activities of daily living (ADL) (modified Rankin scale 0—2), (2) no or small ischemic lesions on magnetic resonance images (MRI), (3) absence of enhanced ischemic lesions on MRI, and (4) stable general condition without heart failure. Patients with malignant tumor, liver dysfunction, renal failure, heart failure, or respiratory dysfunction were excluded, as were patients who had suffered cardiac infarct within 6 months, were treated for diabetes and had a fasting blood glucose level exceeding 300 mg/dl, manifested artery to artery embolism or cardioembolic infarction, congestive heart failure, uncontrolled hypertension (diastolic blood pressure >110 mmHg), bleeding tendency, or hypersensitivity to cilostazol.
Consequently, 20 patients underwent cilostazol treatment (100 mg twice daily). They were 16 men and 4 women (mean age 64.5 ± 6.5 years); 12 (60%) had suffered atherothrombotic infarction and 8 (40%) were asymptomatic. Patients manifesting palpitation, tachycardia, or headache after cilostazol trial were changed to 100 mg cilostazol per day for a week, and then 100 mg twice a day. If their symptoms failed to improve, cilostazol treatment was stopped.
Patients included in this study were evaluated for ischemic stroke recurrence, hemorrhagic stroke including hemorrhagic infarction, additional stroke of unknown etiology, and death. All analyses were performed in our outpatient department. Follow-up studies were performed 6 and 12 months after the start of cilostazol treatment.
MRI scans were inspected for changes in ischemic lesion, for the development of new cerebrovascular incidents, and for unknown nonspecific changes. MRA studies to assess the degree of stenosis were performed with a 3D time-of-flight gradient echo technique for intracranial arteries. CBF was evaluated on SPECT scans using 99m Tc- hexomethyl propylene amine oxime (HMPAO, 740 MBq). After completion of the 1st scan, within less than 10 min, stress was induced with an intravenous (iv) injection of 1g acetazolamide; a 2nd scan was obtained 5 min after the 2nd iv delivery of 99m Tc-HMPAO.
Patients with pre-treatment MRA and SPECT evidence of lesions were re-examined 6 and 12 months after the start of cilostazol treatment using the same neuroimaging techniques. Changes in the M1 stenosis were analyzed by MRA. Continuous data are shown as the mean ± standard deviation (SD). The unpaired t test was used to compare continuous variables in 2 patient groups, those in whom cilostazol was effective (stenosis improved to less than 50%) and patients in whom it was not (stenosis did not improve to less than 50%). The χ2 test or Fisher's exact test was used to compare ratios. Statistical significance was defined as P < 0.05.
Three patients experienced drug-induced tachycardia or headache (tachycardia, n = 1; mild headache, n = 2). In these three patients we changed the administration method (100 mg per day for a week followed by 100 mg twice daily). Consequently, two patients experienced symptom abatement and they were continued on cilostazol for 12 months. The other patient was changed to aspirin. Therefore, 19 patients received cilostazol treatment and were evaluated by MRI, MRA, and SPECT 6 and 12 months after the start of cilostazol therapy.
The overall rate at 6 months for stroke, myocardial infarction, and death was 5.1% (1/19); the affected patient suffered an ipsilateral atherothrombotic infarction. At 12-month follow-up there were no additional cases of stroke. Consequently, the overall 1-year outcome for stroke, myocardial infarction, and death remained at 5.1%. No patient suffered hemorrhagic complications.
Cilostazol was effective in 5 patients. Their mean stenosis pre-treatment was 71.7 ± 4.9% on MRA; it improved to 39.0 ± 3.2% at 6 months and to 27.2 ± 2.8% at 12 months. Cilostazol was not effective in 14 patients; their mean stenosis pre-treatment was 75.8 ± 5.3%; it was 71.6 ± 4.7% at 6 months and 70.3 ± 4.8% at 12 months [
Three of five patients in whom cilostazol was effective showed improvements in CBF on SPECT study; one manifested improvement at rest and the other 2 improved upon acetazolamide challenge. The other two patients in the effective group and all 14 patients in the non-effective group showed no improvement in CBF on SPECT study at rest and upon acetazolamide challenge.
Case 1 - Figure 2
2A: Pretreatment magnetic resonance angiography (MRA) showing a stenotic lesion (60%) at the right M1 (white arrow).
2B: Magnetic resonance imaging (MRI) scan acquired 6 months after treatment shows improvement of the stenotic lesion (20%) at the right M1(white arrow).
2C: MRA obtained 12 months after the start of cilostazol treatment shows improvement of the stenotic lesion (16.7%) at the right M1 (white arrow).
2D: Pretreatment single photon emission computed tomography (SPECT) shows a decrease in CBF in the right cerebral hemisphere (white arrowhead).
2E: SPECT obtained 12 months after the start of cilostazol treatment shows improvement of the CBF in the right cerebral hemisphere (white arrowhead).
This 50-year-old man had a history of transient motor weakness on the left side. MRA confirmed right MCA stenosis (60%); it improved to 20% and 16.7% at 6 and 12 months after the start of cilostazol treatment (200 mg per day). Before cilostazol therapy, his CBF at rest was decreased in the right cerebral hemisphere; it improved at 12-month follow-up and he was free of symptoms.
Case 2 - Figure 3
3A: Pretreatment MRA shows a stenotic lesion (85%) at the left M1 (white arrow)
3B: Pretreatment SPECT shows no laterality in CBF at rest.
3C: Pretreatment SPECT shows hypovasoreactivity in the left temporo-occipital region after acetazolamide challenge (white arrow head).
3D: MRA obtained 6 months after the start of cilostazol treatment shows improvement of the stenotic lesion (30%) at the left M1 (white arrow).
3E: MRA acquired 12 months after the start of cilostazol treatment shows improvement of the stenotic lesion (20%) at the left M1 (white arrow).
3F: SPECT obtained 12 months after the start of cilostazol treatment shows increased CBF in the left cerebral hemisphere.
3G: SPECT obtained 12 months after the start of cilostazol treatment shows CBF improvement in the left cerebral hemisphere after acetazolamide challenge (white arrowhead).
This 60-year-old woman had a history of mild sensory disturbance on the right side. MRA revealed left MCA stenosis (85%). Before treatment, her CBF at rest manifested no marked laterality. However, acetazolamide challenge disclosed extensive CBF reduction in the left temporo-occipital region. Her stenosis improved to 30% and 20% at 6 and 12 months after the start of cilostazol administration (200 mg per day). Acetazolamide challenge at 12-month follow-up showed a CBF increase in the right cerebral hemisphere and she was free of ischemic events.
Stenosis of intracranial arteries is causative in ischemic stroke and antiplatelet therapy is important for its prevention.[
Kim et al.[
We found that the 12-month administration of cilostazol improved stenosis in the M1 segment in five of 19 patients (26.3%). In three of these, SPECT showed improved CBF. Although the prevention of intracranial arterial stenosis by cilostazol has been reported, that study did not address CBF.[
What mechanisms participate in improving M1 arterial stenosis? Other antiplatelet drugs exhibited no remodeling effect on intracranial arteriosclerotic lesions. The mechanisms of action of cilostazol were multimodal. One effect is the inhibition of type III phosphodiesterase activity in platelets and the increase of intracellular levels of cyclic adenosine monophosphate (cAMP).[
In the present study, cilostazol decreased triglycerides, low density lipoprotein, and total cholesterol and increased high density lipoprotein cholesterol.[
Factors involved in the remodeling of the stenotic M1 segment after cilostazol administration remain to be elucidated. Large trials are needed to identify the role of cilostazol in the improvement of symptomatic intracranial artery stenosis.
Our preliminary retrospective investigation of the effectiveness of cilostazol in a small series of patients with stenosis in the M1 segment of MCA. The drug had a remodeling effect on stenotic lesions due to arteriosclerotic changes and improved CBF in some of these patients.
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