Chronic Middle Cerebral Artery Occlusion: A Hemodynamic and Metabolic Study with Positron-Emission Tomography

Materials and Methods

We selected 13 consecutive patients with unilateral MCA occlusion, 10 men and 3 women, 8 symptomatic and 5 asymptomatic, 39–72 years of age (mean age, 57.6 ± 10.3 years), who had undergone a PET study between October 2000 and August 2006 at our institution. None of the patients had large infarcts of more than 30 mm in diameter in the internal carotid artery territory. Patients who had undergone a PET study after extracranial-intracranial bypass surgery were excluded. Symptomatic patients had a history of transient ischemic attacks (n = 3) or a minor disabling ischemic stroke (n = 5, modified Rankin Scale grade ≤3¹⁷). In the asymptomatic patients, including those who had nonfocal symptoms such as dizziness or headache, MCA occlusion was detected incidentally by MR angiography. We performed the PET study at least 1 month after symptom onset in the symptomatic patients. Clinical information on these patients, including their histories, neurologic deficits, medication, and atherosclerotic risk factors, was obtained from the medical records at the time of the PET study (Table 1). PET studies were also performed in 6 healthy volunteers (2 men and 4 women; 26 to 43 years of age; mean age, 33.0 ± 6.6 years) to determine the cutoff point for the normal oxygen extraction fraction (OEF) value. None of the volunteers had a history of neurologic or medical disease, including hypertension or diabetes mellitus. Informed written consent was obtained from each volunteer before the PET study. All protocols were approved by the Ethics Committee for Clinical Research of our institution.

Data Analysis

All PET measurements were analyzed with the Dr. View Linux 1.1 image analysis software system (AJS, Tokyo, Japan). We analyzed the images in 3 tomographic planes: the levels of the basal ganglia and thalamus, body of the lateral ventricle, and the centrum semiovale. Each image was examined by placing circular regions of interest, 10 mm in diameter, over the gray matter of the cortex (Fig 1). According to the atlas of Kretschmann and Weinrich,²⁰ the region of interest included the cortical territories of the ACA, MCA, PCA, and the corona radiata. The anatomic watershed areas between the ACA and MCA and between the MCA and PCA were excluded in the analysis to examine each territory independently. Areas of prior infarction identified on the CMRO₂ images and MR images were also excluded from the analysis. The mean values of the CBF, CBV, CMRO₂, OEF, and the CBF/CBV ratio were then calculated. These values were compared between the symptomatic and asymptomatic patients. Next the patients were divided into 2 groups, the increased OEF group and the normal OEF group in terms of the absolute OEF values in the occluded MCA territory. Because the mean OEF value in the MCA territory in the 12 hemispheres from the 6 healthy volunteers was 42.0 ± 2.3%, we defined pathologically increased OEF as an OEF of >49.3% (absolute hemispheric values of the upper 99% confidence limits in healthy volunteers).^10,12

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Fig 1.

Locations of regions of interest: cortical territories of the ACA, MCA, PCA, and the corona radiata. The watershed areas between the ACA and MCA (AWS) and the watershed areas between the MCA and PCA (PWS) were excluded from the analysis.

Differences in the mean hemispheric values of the CBF, CBV, CMRO₂, and the CBF/CBV ratio between the symptomatic and asymptomatic groups or between the normal and increased OEF groups were tested with a 2-tailed t test. Differences in the proportions of the clinical variables between the normal and increased OEF groups were tested by the Fisher exact test (2-sided). Differences in the means of the background clinical parameters between the normal and increased OEF groups were tested by the 2-tailed t test. A value of P < .05 was considered to be statistically significant.

Results

All except 1 of the patients had unilateral occlusion at the proximal site of the M1 portion. The remaining 1 patient had occlusion at the distal site of the M1 portion (Table 1). The average regional values in the occluded MCA territory were as follows: CBF, 42.1 ± 7.4 mL · 100 g⁻¹ · min⁻¹; OEF, 46.3 ± 4.9%; CMRO₂, 3.3 ± 0.52 mL · 100 g⁻¹ · min⁻¹; CBV, 4.9 ± 1.4 mL · 100 g⁻¹; CBF/CBV, 9.3 ± 2.9 minutes⁻¹. The average regional values in the contralateral MCA territory were as follows: CBF, 45.5 ± 7.3 mL · 100 g⁻¹ · min⁻¹; OEF, 44.2 ± 5.2%; CMRO₂, 3.4 ± 0.54 mL · 100 g⁻¹ · min⁻¹; CBV, 4.6 ± 1.3 mL · 100 g⁻¹; CBF/CBV, 10.6 ± 3.5 minutes⁻¹. There were no differences in the values between the symptomatic and asymptomatic patients. (Table 2)

There were 9 patients with normal OEF values in the occluded MCA territory (normal OEF group, patients 1–9) and 4 patients with increased OEF values (increased OEF group, patients 10–13) in the occluded MCA territory. The clinical backgrounds were not significantly different between the 2 groups, except for a higher proportion of women in the increased OEF group (Table 3). There were no significant differences in the hemodynamic parameters, such as the hemoglobin concentration, blood pressure, or O₂ content, which could influence the OEF values between the 2 groups. The PaCO₂ levels remained stable throughout the PET examination (Table 3).

Compared with the normal OEF group, the increased OEF group showed higher CBV values and lower CBF/CBV ratios in the occluded MCA territory (Table 4). The increased OEF group also showed significantly higher OEF values in the other cortical territories (Table 4).

None of the patients showed vascular lesions in the basilar artery or either vertebral artery. Two patients had unilateral intracranial vertebral arterial stenosis (patients 9 and 10). The remaining vascular findings are shown in Fig 2. Significantly, all patients in the increased OEF group had >1 intracranial steno-occlusive lesion (P = .008), especially in the ACA. All except 1 patient had collaterals either from the ACA or PCA, which reconstituted the M1 or M2 segment. One patient in the increased OEF group showed no retrograde contrast filling of the occluded MCA territory from either the ACA or the PCA.

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Fig 2.

Angiographic assessment of the patients. This diagram shows schematic representations of the circle of Willis and the major intracranial vessels in each patient. Black lesions indicate the location of the stenosis or occlusion. Acom indicates the anterior communicating artery; Pcom, the posterior communicating artery; Rt; right, Lt; left; M1-M3, collaterals reconstituting the M1, M2, or M3 segments; None, little or no significant reconstitution of the territory of the occluded vessel.

Discussion

We confirmed the findings in previous studies of cerebral hemodynamic and metabolic disturbances in patients with chronic unilateral MCA occlusion. The hemodynamic status in the occluded MCA territory varied among the patients. The mean regional cortical CBF was only 5.7% lower than that in the contralateral MCA territory. Nine of the 13 patients with MCA occlusion showed no hemodynamic compromise in the chronic state. Of the 5 patients reported by Derdeyn et al,¹⁵ 2 had an increased OEF and the rest had a normal OEF and reduced CBF. In a previous SPECT study, 9 of 29 patients showed reduced cerebrovascular reactivity in the occluded MCA territory.¹³

One of the new findings of our study was that an increase of the OEF was associated with multiple intracranial steno-occlusive arterial lesions. In particular, 3 of the 4 patients in the increased OEF group had steno-occlusive lesions in the collateral pathways. Blood supply to the occluded MCA territory is maintained mainly via pial anastomoses and their upstream vessels of both the ipsilateral ACA and PCA. One patient had stenosis of the ipsilateral ACA, and another had stenosis of both the ipsilateral ACA and PCA. In Patient 12, the ipsilateral ACA was supplied from the contralateral side through the anterior communicating artery because the ipsilateral A1 was congenitally absent. However, stenosis was observed in the contralateral A1. In contrast, none of the subjects in the normal OEF group showed vascular lesions in the collateral pathways. Steno-occlusive lesions in the collateral pathways upstream of the pial anastomosis reduce the pial arterial pressure (ie, the perfusion pressure in the territory of the occluded MCA) and may thus cause misery perfusion. In the increased OEF group, the OEF values were also increased in the territories of the ipsilateral ACA, ipsilateral PCA, and contralateral MCA. The steno-occlusive lesions may directly induce misery perfusion in their original territory. A similar pathologic process was reported in patients with Moyamoya disease. Mugikura et al²¹ indicated that progressive steno-occlusive changes in the anterior and posterior circulations were associated with the frequency and extent of cerebral infarctions in patients with Moyamoya disease.

Poor collateral development is considered a risk factor for stroke in patients with occlusive cerebral artery disease. Some studies have indicated an association between collateral vasculature and the hemodynamic status.^22–24 However, this association was limited to patients with carotid disease, and the results obtained remain controversial to date.^25,26 One of the reasons for these conflicting results is that collateral pathways can be varied and complicated in patients with carotid occlusion and it is difficult to assess all potential collateral routes. Compared with that in patients with carotid artery occlusion, the collateral vasculature is simpler in patients with MCA occlusion. In the report by Derdeyn et al,¹⁵ the MCA territory was supplied solely by pial collaterals in all 5 patients with MCA occlusion, regardless of the OEF.¹⁵ They concluded that pial collateralization is not a specific sign of increased OEF. Our subjects did not demonstrate significant association between the OEF values and pial collateral development either. Pial collaterals from the ACA and PCA play a complementary role, and most patients showed retrograde contrast filling of the occluded MCA segment or at least 1 segment distal to the occluded site. Our results indicate that a major arterial lesion upstream of the pial arteries may be a more important factor causing hemodynamic compromise.

The treatment for patients with MCA occlusion associated with hemodynamic impairment has not been established. It is not clear whether surgical treatment for providing additional blood supply to the brain in these patients can reduce the incidence of stroke. For the case of symptomatic carotid artery occlusion, there is an ongoing trial designed to determine whether extracranial-to-intracranial (ECIC) arterial bypass surgery can reduce the incidence of stroke in patients with increased OEF.²⁷ The patients with increased OEF in the present study had steno-occlusive lesions in the collateral pathways and other areas showing hemodynamic impairment. Progression of collateral stenosis could induce extensive infarction, and ECIC bypass surgery may be expected to be effective in these patients. One patient with increased OEF had undergone ECIC bypass surgery aimed at reducing the risk of stroke before coronary bypass surgery, and the cerebral blood flow had improved. However, few patients with MCA occlusion show hemodynamic compromise; therefore, the usefulness of bypass surgery should be evaluated in a multicenter trial.

PET has been the standard perfusion imaging technique used to select patients who would benefit from ECIC bypass surgery; however, it is not easily available for daily clinical practice. Surrogate perfusion imaging techniques that are more easily accessible are needed for the management of each patient. Perfusion-weighted MR imaging (PWI) and quantitative CBF imaging, such as CT perfusion or SPECT with an acetazolamide challenge test, are reasonable choices for this purpose. Unfortunately, their quantification is less reliable than that possible with PET, and they are not recommended for the evaluation of patients with chronic ischemia by the guidelines of the American Heart Association.²⁸ These techniques should be compared with PET in the same settings to determine their roles. More recent studies comparing PWI with PET in chronic occlusive carotid disease and Moyamoya disease reported that patients with abnormally increased OEF as measured by PET could be discovered on the basis of the time-to-peak delay of more than the threshold as measured by PWI.^29,30

There are 2 limitations of this study. First, the controls were much younger than the study patients. We used the OEF values in the control group to determine the cutoff point of the normal OEF values for the patients. However, several studies have reported that OEF values are not significantly influenced by age.^31–33 Leenders et al³⁴ reported the correlations between the PET data and age in each part of the brain. A slight increase of the OEF with age was seen in some regions but not in the MCA cortical ribbon. According to these reports, the assumption of mean OEF value in the control group would not be much different from the original one if their ages were matched with those of the patients. We determined the upper 99% confidence limits of the OEF values instead of the upper 95% confidence limits as the cutoff, to make the cutoff applicable to older patients. Second, this study was performed in a retrospective manner, and the association between the status of the collaterals and cerebral hemodynamics was not assessed with time. The conditions of the collaterals may be affected with time from the onset. Also, PET was performed after varying times from onset in the symptomatic patients. There were no differences in the OEF, CBV, or the mean transit time between the symptomatic and asymptomatic patients with MCA occlusion in the chronic state; however, the results may differ in the acute state. Prospective studies are needed to confirm the findings in these patients.

Conclusions

Most of the patients with chronic MCA occlusion with no symptoms or only a minor stroke did not show any severe hemodynamic impairment. Those with increased OEF tended to have other areas of severe hemodynamic impairment and other vascular lesions in the collateral pathways.