This retrospective study was conducted as a preliminary study after approval by the Research Ethics Committee of Hiroshima City Asa Citizens Hospital and Hiroshima University (E-466–3, E-1554–2). Written, informed consent was obtained from all participants. In this study, 18 consecutive patients who underwent EC-IC bypass for severe unilateral steno-occlusive disease of the intracranial internal carotid artery (ICA) or middle cerebral artery (MCA) at Asa Citizens Hospital from September 2017 to April 2020 were reviewed. All patients experienced transient ischemic attacks (TIAs) or non-disabling strokes within 6 months derived from the hemisphere ipsilateral to the lesion.
CBF and CVR were estimated by SPECT. The regional CBF (rCBF) of the ipsilateral cerebral cortex region was compared by the value divided by the rCBF of the ipsilateral cerebellar cortex region . Then, according to the JET study, EC-IC bypass was indicated for rCBF reduction of less than 80% and regional CVR (rCVR) reduction of less than 10% [5, 6]. In all cases, no stenotic lesions causing decreased cerebellar blood flow were observed in the vertebrobasilar arteries.
The inclusion criteria for this study were patients with available pre-operative and post-operative (3–6 months or later after surgery) CVR studies. Exclusion criteria were as follows: (1) allergy to contrast media; (2) renal dysfunction (estimated glomerular filtration rate < 30 ml/min/1.73 m2); or (3) medical illness, physical disability, or aphasia (modified Rankin scale score ≥ 3) precluding the VC task. Eighteen patients were selected on the basis of the inclusion criteria (5 women; mean age at the time of bypass 68.1 years). The etiology included atherosclerosis (n = 18) (Table 1).
Assessment of cognitive functions (time and accuracy score)
We routinely perform cognitive function tests (mini-mental state examination, trail making test, and the Clinical Assessment for Attention (CAT)) within 3 days of SPECT before and 3–6 months after surgery. Of these cognitive tests, the duration and accuracy of visual cancellation (VC), position Stroop test, and Continuous Performance Test could be evaluated at the same time, but only the VC was performed in all 18 cases. Thus, the results of VC were used for the following analysis. VC consisted of four kinds of subtests (Kana, Triangle, Symbol, Number) included in CAT, which is a standardized test for attention deficit, that were used as previously described . Participants used a pencil to cross out a target stimulus dispersed within rows of randomly placed interfering stimuli displayed on a sheet. These tasks were scored as speed (completion time) and accuracy. Accuracy was based on the ratio of the number of correct answers to the total number of items (% correct answers) or the number of accurate answers compared to the number of total responses (both correct and incorrect responses) (% accurate answer).
It is known that the scores of the VC depend on age. To correct by age, age-matched values were calculated as (VC score) / (age-specific mean VC value); the lower the age matched % correct answer and % accurate answer, the greater the attentional disturbance, and the higher the age-matched completion time (the slower the speed), the greater the attentional disturbance.
The accuracy of each VC subtest was evaluated by (age matched % correct answer + age-matched % accurate answer) / 2, and the following analysis was performed with the average value of the four accuracies (accuracy score). In addition, the following analysis was performed using the average value of the age-matched completion times of four VCs (time score). A score of 1 of both the accuracy score and the time score indicates the age-corrected average value.
Measurement and analysis of CBF and CVR using SPECT
All subjects in this study received a 222-MBq dose of N-isopropyl-123I-p-iodoamphetamine (IMP) intravenously. Siemens e.cam (Siemens Medical Solutions, Erlangen, Germany) was used in 18 patients to acquire the projection data in a continuous mode at 150 s/cycle (180° rotation of dual heads) for 2 cycles, repeated 6 times. In both machines, low-energy high-resolution collimators were used, with a matrix size of 128 × 128 and an energy window of 159 keV ± 15%. After the data were obtained, a three-dimensional stereotactic surface profile program (3D-SSP, Nihon Medi-Physics, Tokyo, Japan) was used to spatially normalize the local distribution. In brief, the coordinate data were converted to the normal brain based on the Talairach brain atlas, classified into segments, and the Z score was calculated by comparing with a normal database using SEE (stereotactic extraction estimation) analysis, and the CBF and CVR in each brain region were evaluated .
In this study, the rCBF values were obtained by SPECT with the graph plot method that uses IMP, which does not require arterial blood sampling . Thus, arterial sampling was not performed during SPECT.
Scans for rCBF were performed just before and 10 min after injection of 1.0 g of acetazolamide. Regional cerebrovascular reactivity (rCVR) was calculated as follows: rCVR(%) = [(acetazolamide challenge rCBF − resting rCBF) / resting rCBF] × 100. The change in CVR (post-operative CVR − pre-operative CVR) was calculated.
The CVR was divided into three areas (ACA, MCA, and PCA) or the 31 supratentorial areas of 50 regions of level 3 of the anatomical classification based on the Talairach Daemon database on each side (supplemental Table 1) .
Under general anesthesia, with continued antiplatelet medication perioperatively, a skin incision was made just over the superficial temporal artery (STA) frontal branch or parietal branch. Under microscopy, meticulous STA dissection was conducted. The skin incision was then extended toward the forehead, and a skin flap was reflected. The frontal branch of the STA was dissected. After craniotomy, an STA-MCA single or double anastomosis was performed between each STA branch and the recipient M4 (cortical MCA branch). Successful bypass was confirmed by microvascular Doppler evaluation. EC-IC bypass in this study included only the direct procedure and was not combined with indirect bypass procedures.
To compare differences between two groups, Fisher’s exact test was used for categorical variables, and the Mann–Whitney U-test was used for quantitative variables. The level of significance was set at p < 0.05.
To test the correlations between the time or the accuracy score and the CVR in the 31 brain areas on each side (62 in total), bivariate analysis (Spearman’s rank correlation coefficient, ρ) was performed.
Stepwise multiple linear regression analysis was used to estimate the independent effects of predictor variables on the time or accuracy score (forward–backward selection method). These predictor variables were as follows: age, sex, laterality of the operation, and the CVR changes in the brain region with a p-value of 0.05 or less in the above bivariate analysis. Logworth was calculated as -log10 (p value), and higher values were more significant. To assess multicollinearity, the variance inflation factor (VIF) was calculated. A value of 10 was considered to be sufficiently large to indicate multicollinearity . The prediction performance of this model was evaluated through a leave-one-subject-out cross-validation (i.e., k-fold cross-validation with k = 18).
The values were considered significant at p < 0.05. All data were analyzed using JMP pro 16.0 (SAS Institute Inc., Cary, NC).