Cerebral perfusion in corresponding blood supply areas of transient ischemic attack patients with intracranial stenosis
Seven cases of diamox-perfusion verified by magnetic resonance-perfusion-weighted imaging***☆

Li’an Huang1, Xuewen Song1, Anding Xu1, Xueying Ling2, Zhichao Lin2

1Department of Neurology, First Affiliated Hospital of Jinan University, Guangzhou  510632, Guangdong Province, China
2Department of Radiology, First Affiliated Hospital of Jinan University, Guangzhou  510632, Guangdong Province, China

Li’an Huang☆, Doctor, Associate chief physician, Department of Neurology, First Affiliated Hospital of Jinan University, Guangzhou 510632, Guangdong Province, China

Corresponding author: Li’an Huang, Doctor, Associate chief physician, Department of Neurology, First Affiliated Hospital of Jinan University, Guangzhou  510632, Guangdong Province, China   
huanglianfujian@hotmail. com

Supported by: Medical Scientific and Technological Research Foundation of Guangdong Province, No. 2007332*; 2009360*; the Natural Science Foundation of Guangdong Province, No. 9451063201002951*

Abstract
BACKGROUND: Due to collateral circulation and cerebrovascular reserve, arterial stenosis and reduced cerebral blood flow may not necessarily indicate impaired cerebral perfusion. Therefore, according to degree of stenosis and clinical symptoms, interventional surgery to relieve arterial stenosis in transient ischemic attack (TIA) patients with major intracranial stenosis is imprudent. Rather, cerebral perfusion and reserve capacity are direct indicators for the assessment of degree and presence of cerebral ischemia.
OBJECTIVE: To evaluate cerebral perfusion and reserve in TIA patients with major intracranial stenosis or occlusion using magnetic resonance-perfusion-weighted imaging (MR-PWI) data prior to and following diamox administration.
DESIGN, TIME AND SETTING: A self-comparative, neuroimaging observation was performed at the Neurological Department and Radiological Center of the First Affiliated Hospital of Jinan Uni-versity between December 2007 and April 2009.
PARTICIPANTS: Seven acute TIA patients, who were admitted to the Neurological Department of the First Affiliated Hospital of Jinan University between December 2007 and April 2009, were en-rolled in the present study. Magnetic resonance imaging confirmed that no acute cerebral infarction happened, nor did bleeding exist. Magnetic resonance angiography, transcranial Doppler ultrasound, and/or digital subtraction angiography confirmed the presence of major intracranial arterial stenosis. Clinical symptoms corresponded to blood supplying regions of the arterial stenosis.
METHODS: Baseline MR-PWI was performed on seven patients with intracranial stenosis or occlu-sion. Two grams of acetazolamide (diamox) were orally administered after 2 days. A second PWI was performed after 2 hours to compare cerebral perfusion parameters prior to and following diamox administration.
MAIN OUTCOME MEASURES: PWI results of cerebral perfusion prior to and following diamox administration.
RESULTS: The baseline PWI from five patients indicated decreased cerebral perfusion areas. Fol-lowing oral administration of diamox, cerebral perfusion significantly decreased in those areas. Moreover, new areas of decreased cerebral perfusion were observed in two out of the five patients. In one patient, no significant decrease in cerebral perfusion was found. In another patient, baseline PWI indicated decreased cerebral perfusion in the left hemisphere. However, normal perfusion was observed in both cerebral lobes following diamox administration.
CONCLUSION: TIA patients with intracranial stenosis, who are diagnosed by PWI and exhibited decreased cerebral perfusion and reserve, might require further treatment such as intervention by angioplasty.
Key Words: transient ischemic attack; stenosis; magnetic resonance-perfusion-weighted imaging; diamox; cerebral perfusion; cerebral reserve capacity

INTRODUCTION
  
The question remains as to whether cerebral ischemia patients with intracranial stenosis need further treatment against arterial stenosis. The Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial showed that nearly 20% of patients (569 patients) with symptomatic intracranial stenosis might suffer from recurrent stroke during 1.8-year treatment period of which they get with conventional anti-platelet or anti-coagulant drugs[1-2]. Therefore, in recent years, stenting-angioplasty has been introduced to treat transient ischemic attack (TIA) patients with intracranial stenosis. The purpose of stenting-angioplasty is to relieve arterial stenosis and to improve brain hemodynamics. The criteria for treatment are based mainly on degree of stenosis and clinical symptoms[3-5]. Treatment efficacy and safety have not yet been confirmed.
Progression of cerebral hemodynamic ischemia consists of three stages. Stage 1 is characterized by potential ischemia with intact cerebrovascular reserve (CVR) capacity. Vessel dilation occurs in response to vessel autonomic regulating mechanism, thereby increasing cerebral blood volume and compensation; ischemia occurs only in a stressed state. Stage 2 is characterized by decreased perfusion, partially impaired CVR capacity, and ischemia in normal time; ischemia is aggravated in a stressed state. Stage 3 is characterized by significantly reduced cerebral perfusion and exhaustion of CVR capacity[6-7]. Divani et al[8] found no correlation between level of intracranial arterial stenosis and regional ischemia, indicating that the extent of arterial stenosis and clinical symptoms do not accurately reflect the degree of cerebral ischemia. Instead, cerebral perfusion is the direct evidence whereby cerebral ischemia should be evaluated. Therefore, evaluation of cerebral perfusion and CVR capacity in intracranial stenosis TIA patients may help to determine whether pathogenesis is a result of abnormal hemodynamics, and to determine whether further treatment, such as stenting-angioplasty, is warranted.
Recent studies using magnetic resonance-perfusion- weighted imaging (MR-PWI) have investigated cerebral perfusion and vascular reserve in patients with internal carotid stenosis or occlusion, and these results provide the basis for clinical treatment[9-10]. However, there are very few studies on cerebral perfusion and vascular reserve in TIA patients with intracranial stenosis. It remains unclear whether cerebral perfusion and vascular reserve exist in all patients.
The present study observed cerebral perfusion and reserve capacity in seven TIA patients with intracranial stenosis prior to and following diamox administration. We hope that results from this study will provide evidence to determine whether these patients need further surgical treatment.

SUBJECTS AND METHODS

Design
A self-comparative, neuroimaging observation.
Time and setting
This study was performed at the Neurological Department and Radiological Center of the First Affiliated Hospital of Jinan University between December 2007 and April 2009. 
Subjects
TIA patients were selected from the Neurological Department of the First Affiliated Hospital of Jinan University between December 2007 and April 2009.
Inclusion criteria: (1) patients with acute TIA. TIA diagnostic criteria were based on the Guide on Diagnosis and Treatment for TIA patients (2005 edition), China[11]; (2) patients lacking cerebral lesions, such as acute infarction or bleeding, according to magnetic resonance imaging (MRI); (3) Magnetic resonance angiography (MRA), transcranial Doppler ultrasound (TCD), and/or digital subtraction angiography (DSA) were used to determine major intracranial arterial (carotid, middle cerebral, anterior cerebral, posterior cerebral, vertebral, basilar) stenosis. The degree of arterial stenosis was measured based on WASID and Grupo de Estudio de la Sobrevida en la Insuficiencia Cardiaca en Argentina (GESICA) studies[1-2,12-13]; (4) the clinical symptoms corresponded to the supporting region of the stenosis artery; (5) no stroke history.
Exclusion criteria: (1) patients with obvious side effects following oral diamox; (2) patients with history of cerebrovascular disease and exhibiting obvious sequelae; (3) patients with serious disease in a major organ.
Seven patients diagnosed with internal carotid arterial system TIA were enrolled. All patients suffered transitory weakness in one side of the body, and symptoms quickly disappeared without sequelae. All patients exhibited these symptoms for the first time. All patients signed informed consent forms regarding examinations. The study was in accordance with ethical standards and administrative regulations for medical institutions[14].
Methods
All patients were admitted to the Neurological Department of the First Hospital Affiliated to Jinan University due to symptoms of TIA. Baseline PWI, MRA, TCD, and DSA were performed within 48 hours after admission.
MRI (PWI, MRA included), TCD, and DSA tests
The MR protocol included a sagittal gradient echo T1-weighted sequence and an axial fast spin echo T2-weighted sequence (oriented along the bicommissural line) in a GE Signa Fx/I Echospeed 1.5 MR machine (GE, USA). The PWI measurements were obtained in the same axial plane utilizing a single-shot sagittal gradient echo-planar imaging sequence[15]. Four seconds after the beginning of the sequence, a dose of 0.1 mmol gadopentetate dimeglumine (Magnevist; Schering, Berlin, Germany) per killogram of body weight was intravenously injected at a rate of 10 mL/s with an MR-compatible power injector (Medrad, Pittsburgh, USA), followed by a 30-mL saline flush. In addition, arterial 3D time-of-flight MRA of the Willis circle was acquired and reconstructed with maximum intensity projections. TCD (GK D30002CWFFT, France) was performed by the same technician to examine blood flow velocity of major intracranial (carotid, middle cerebral, anterior cerebral, posterior cerebral, vertebral, basilar) arteries. Intra-arterial DSA was performed on a GE AdvantxLcv+DSA machine (GE, USA). A 5-F catheter was introduced using the Seldinger technique (femoral arteriotomy). Contrast material (Ultravist 300, Schering, Berlin, Germany) was injected at a flow rate of 3 mL/s. An image intensifier size of 16 cm was used with a matrix size of 1 024 ×1 024. DSA real-time imaging of cranial lateral, oblique, and Towne’s views was obtained after the guiding catheter was inserted into the arteries of interests. Stepping subtraction arteriography was performed when needed.
Diamox test
The diamox test consisted of intravenous injection of diamox (1 g) to test cerebrovascular reserve (CVR)[16-18]. After measuring baseline PWI and a wait of 24–48 hours, patients received 2 g acetazolamide (diamox, 0.25 g/tablet; Shanghai Pharmaceutical, China) orally. A second PWI was performed 2 hours after diamox challenge.
PWI image analysis and post-processing
Using GE ADW4. 2 workstation Functool PWI software (GE, USA), axial regional cerebral volume map and regional mean transit time map were obtained. Two experienced neuroimaging physicians analyzed images using the blind method. Consensus was obtained on abnormal perfusion areas, and semi-quantitative analysis was performed on regions of interests in symmetrical sites on both sides.
Main outcome measures
Cerebral perfusion prior to and following diamox injection.
Design, enforcement, and evaluation
This study was designed by the first author, conducted by all authors, and evaluated by the fourth and fifth authors using the blind method. All authors underwent professional training.

RESULTS

Quantitative analysis of the participants
A total of seven patients were included in the final analysis.
Baseline information
Baseline information from the seven included patients is shown in Table 1.
Imaging results
TCD, MRI, MRA, and DSA results indicated that all seven patients suffered from intracranial arterial stenosis, as well as occlusion (Figures 1 and 2, Table 2).

PWI results indicated that five out of the seven patients had regions with decreased cerebral perfusion. Following diamox administration, cerebral perfusion in these areas was significantly reduced (Figure 3). Furthermore, ischemia was detected in new regions in two out of five patients.
 

In one patient, no significant ischemic changes in cerebral perfusion were observed prior to and following diamox administration (Figure 4).
PWI results indicated ischemia in the left hemisphere in one patient, and no significant ischemic changes were observed following diamox administration  (Figure 5).

The PWI scanning results prior to and following diamox administration are shown in Table 3.

Adverse effect
No obvious adverse effects were observed in all patients.

DISCUSSION

Two major theories of the pathogenesis of TIA have been characterized by embolus and abnormal hemodynamics[19]. Abnormal hemodynamics, such as intracranial vessel stenosis or occlusion, high blood viscosity, and reduced blood flow velocity, may eventually reduce regional cerebral perfusion and cause ischemia. Patients with intracranial stenosis TIA show clear evidence of cerebral vessel stenosis, but it is unclear if this vessel-supported region impaired the cerebral perfusion. Reduced cerebral perfusion is direct evidence of the presence of cerebral ischemia, whereas vessel stenosis and reduced blood flow velocity are not valid indicators for cerebral perfusion, due to the presence of collateral circulation and cerebral vessel self-reserve capacity.
In the present study, MRA, TCD, and DSA were combined to evaluate the narrowness of cerebral blood vessels MRA is non-invasively used to reveal cerebral blood vessel anatomy, whereas measurements of blood flow velocity by TCD indirectly reveals the narrowness of cerebral blood vessels. DSA correctly and directly presents cerebral artery anatomy. Results indicated that all seven patients exhibited cranial arterial stenosis, as well as occlusion. Therefore, they were diagnosed as TIA patients with cranial arterial stenosis.
Cerebral perfusion can be measured by single photon emission-computed tomography, positive emission tomography, and MR-PWI. MR-PWI and single photon emission-computed tomography can be used to quantify cerebral perfusion, as well as to semi-quantitatively measure the amount of cerebral perfusion in a region of interest. Moreover, positive emission tomography can be used to quantify cerebral perfusion, and has become the gold standard. Nevertheless, positive emission tomography remains expensive in a clinical setting. Single photon emission-computed tomography is radioactive and has poor space resolution. MR-PWI has better space resolution and provides an index to evaluate hemodynamic regional cerebral blood volume, regional cerebral blood flow, and mean transition time[20]. The acetazolamide challenge test (also called “diamox test”) in MR-PWI is an accurate test to evaluate CVR  capacity[9, 21-22]. Compared with positive emission tomography, cerebral blood volume measured by MR-PWI can also accurately identify patients with hemodynamic impairment without exposure to ionizing radiation[23]. Diamox is a carbonic anhydrase inhibitor that acts as a cerebral vasodilator. Diamox injections are expensive and are not produced in China. In the present study, the patients received 2 g diamox orally. Almost 2 hours after oral diamox administration, blood pH values significantly decreased and oral reaction was tolerant to injection. The strongest effect on vasodilatation was measured 2 hours after oral diamox administration. Therefore, this was also the best time to measure vascular reserve. Ischemic or potential ischemic tissue exhibited decreased cerebral perfusion following diamox administration, because of decreased vascular reserve capacity. Patients with intracranial stenosis might still respond to the diamox test, if the vascular reserve capacity is sufficient. Therefore, the diamox test allowed for valuable data to be evaluated regarding cerebral perfusion and reserve capacity in PWI. In the present study, six of seven TIA patients with intracranial stenosis exhibited decrease perfusion. Five of these patients exhibited significantly decreased perfusion and/or new decreased brain perfusion areas. However, one patient exhibited normal perfusion after the diamox test. These results suggest that five of these patients had impaired CVR, and one had intact CVR. In addition, one patient exhibited no decreased brain perfusion before and after Diamox, which suggested intact perfusion and CVR.
Recent clinical trials have focused on the benefit of interventional therapy for arterostenosis in intracranial stenosis TIA patients[24-27]. To date, only a few intracranial stenosis TIA patients have received stenting-angioplasty. Therefore, the treatment effects and safety aspects remain unclear[28-33]. It should be noted that clinical symptoms and the presence of arterial stenosis are not good indicators for evaluating intracranial ischemia. Prior to surgical or interventional therapy, in addition to the extent of arterial stenosis, DSA surgery and other factors, such as cerebral perfusion and vascular reserve, should be analyzed in the blood supply region. If PWI results indicate that cerebral perfusion and CVR are markedly decreased, then surgical or interventional therapy should be required to relieve vascular stenosis and improve intracranial hemodynamics. If cerebral perfusion and CVR are intact, surgical or interventional therapy may not be necessary. Therefore, it is important to measure intracranial perfusion and reserve capacity in these patients to evaluate the presence of ischemia, and further provide reference for treatment. However, due to the small sample size in the present study, it was difficult to draw a statistically significant conclusion. Moreover, a large number of clinical applications are lacking to support these findings. Therefore, a large number of clinical cases are warranted to further verify conclusions of the present study.

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