Increased Risk of Recurrent Stroke in Symptomatic Large Vessel Disease With Impaired BOLD Cerebrovascular Reactivity.

BACKGROUND: Impaired cerebrovascular reactivity (CVR) has been correlated with recurrent ischemic stroke. However, for clinical purposes, most CVR techniques are rather complex, time-consuming, and lack validation for quantitative measurements. The recent adaptation of a standardized hypercapnic stimulus in combination with a blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging signal as a surrogate for cerebral blood flow offers a potential universally comparable CVR assessment. We investigated the association between impaired BOLD-CVR and risk for recurrent ischemic events. METHODS: We conducted a retrospective analysis of patients with symptomatic cerebrovascular large vessel disease who had undergone a prospective hypercapnic-challenged BOLD-CVR protocol at a single tertiary stroke referral center between June 2014 and April 2020. These patients were followed up for recurrent acute ischemic events for up to 3 years. BOLD-CVR (%BOLD signal change per mm Hg CO2) was calculated on a voxel-by-voxel basis. Impaired BOLD-CVR of the affected (ipsilateral to the vascular pathology) hemisphere was defined as an average BOLD-CVR, falling 2 SD below the mean BOLD-CVR of the right hemisphere in a healthy age-matched reference cohort (n=20). Using a multivariate Cox proportional hazards model, the association between impaired BOLD-CVR and ischemic stroke recurrence was assessed and Kaplan-Meier survival curves to visualize the acute ischemic stroke event rate. RESULTS: Of 130 eligible patients, 28 experienced recurrent strokes (median, 85 days, interquartile range, 5-166 days). Risk factors associated with an increased recurrent stroke rate included impaired BOLD-CVR, a history of atrial fibrillation, and heart insufficiency. After adjusting for sex, age group, and atrial fibrillation, impaired BOLD-CVR exhibited a hazard ratio of 10.73 (95% CI, 4.14-27.81; P<0.001) for recurrent ischemic stroke. CONCLUSIONS: Among patients with symptomatic cerebrovascular large vessel disease, those exhibiting impaired BOLD-CVR in the affected hemisphere had a 10.7-fold higher risk of recurrent ischemic stroke events compared with individuals with nonimpaired BOLD-CVR.

Heterogeneous motor BOLD-fMRI responses in brain areas exhibiting negative BOLD cerebrovascular reactivity indicate that steal phenomenon does not always result from exhausted cerebrovascular reserve capacity.

INTRODUCTION: Brain areas exhibiting negative blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR) responses to carbon dioxide (CO2) are thought to suffer from a completely exhausted autoregulatory cerebrovascular reserve capacity and exhibit vascular steal phenomenon. If this assumption is correct, the presence of vascular steal phenomenon should subsequently result in an equal negative fMRI signal response during a motor-task based BOLD-fMRI study (increase in metabolism without an increase in cerebral blood flow due to exhausted reserve capacity) in otherwise functional brain tissue. To investigate this premise, the aim of this study was to further investigate motor-task based BOLD-fMRI signal responses in brain areas exhibiting negative BOLD-CVR. MATERIAL AND METHODS: Seventy-one datasets of patients with cerebrovascular steno-occlusive disease without motor defects, who underwent a CO2-calibrated motor task-based BOLD-fMRI study with a fingertapping paradigm and a subsequent BOLD-CVR study with a precisely controlled CO2-challenge during the same MRI examination, were included. We compared BOLD-fMRI signal responses in the bilateral pre- and postcentral gyri - i.e. Region of Interest (ROI) with the corresponding BOLD-CVR in this ROI. The ROI was determined using a second level group analysis of the BOLD-fMRI task study of 42 healthy individuals undergoing the same study protocol. RESULTS: An overall decrease in BOLD-CVR was associated with a decrease in BOLD-fMRI signal response within the ROI. For patients exhibiting negative BOLD-CVR, we found both positive and negative motor-task based BOLD-fMRI signal responses. CONCLUSION: We show that the presence of negative BOLD-CVR responses to CO2 is associated with heterogeneous motor task-based BOLD-fMRI signal responses, where some patients show -more presumed- negative BOLD-fMRI signal responses, while other patient showed positive BOLD-fMRI signal responses. This finding may indicate that the autoregulatory vasodilatory reserve capacity does not always need to be completely exhausted for vascular steal phenomenon to occur.

Interrater and intrarater agreement superior for three-dimensional digital subtraction angiography (3D-DSA) over 2D-DSA classification for detecting remnants after intracranial aneurysm clipping, a GRRAS Reliability and Agreement Study.

BACKGROUND: Growing evidence suggests that three-dimensional digital subtraction angiography (3D-DSA) is superior to 2D-DSA in detection of intracranial aneurysm (IA) remnants after clipping. With a simple, practical quantitative scale proposed to measure maximal remnant dimension on 3D-DSA, this study provides a rigorous interrater and intrarater reliability and agreement study comparing this newly established scale with a commonly used (Sindou) 2D-DSA scale. METHOD: Records of 43 patients with clipped IAs harboring various sized remnants who underwent 2D- and 3D-DSA between 2012 and 2018 were evaluated. Using the 2D and 3D scales, six raters scored these remnants and repeated the scoring task 8 weeks later. Interrater and intrarater agreement for both grading schemes were calculated using kappa (κ) statistics. RESULTS: Interrater agreement was highly significant, yielding κ-values at 95% CI (p = 0.000) of 0.225 for the first [0.185; 0.265] and 0.368 s [0.328; 0.408] time points for 2D-DSA and values of 0.700 for the first [0.654; 0.745] and 0.776 s [0.729; 0.822] time points for 3D-DSA. Intrarater agreement demonstrated κ-values between 0.139 and 0.512 for 2D-DSA and between 0.487 and 0.813 for 3D-DSA scores. CONCLUSION: Interrater and intrarater agreement was minimal or weak for 2D-DSA scores, but strong for 3D-DSA scores. We propose that baseline 3D-DSA characterization may prove more reliable when categorizing clipped IA remnants for purposes of risk stratification and lifelong follow-up.

Adherence to Contouring and Treatment Planning Requirements Within a Multicentric Trial: Results of the Quality Assurance of the SAKK 09/10 trial.

PURPOSE: To evaluate the results of the radiation therapy (RT) quality assurance (QA) program of the phase 3 randomized SAKK 09/10 trial in patients with biochemically recurrent prostate cancer after prostatectomy. METHODS AND MATERIALS: Within the Schweizerische Arbeitsgemeinschaft für Klinische Krebsforschung (SAKK) 09/10 trial testing 64-Gy versus 70-Gy salvage RT, a central collection of treatment plans was performed and thoroughly reviewed by a dedicated medical physicist and radiation oncologist. Adherence to the treatment protocol and specifically to the European Organization for the Research and Treatment of Cancer (EORTC) guidelines for target volume definition (classified as deviation observed yes vs no) and its potential correlation with acute and late toxicity (Common Terminology Criteria for Adverse Events version 4.0) and freedom from biochemical progression (FFBP) were investigated. RESULTS: The treatment plans for 344 patients treated between February 2011 and April 2014 depicted important deviations from the EORTC guidelines and the recommendations per trial protocol. For example, in up to half of the cases, the delineated structures deviated from the protocol (eg, prostate bed in 48.8%, rectal wall [RW] in 41%). In addition, variations in clinical target volume (CTV) and planning target volume (PTV) occurred frequently (eg, CTV and PTV deviations in up to 42.4% and 25.9%, respectively). The detected deviations showed a significant association with a lower risk of grade ≥2 gastrointestinal acute toxicity when the CTV did not overlap the RW versus when the CTV overlapped the RW (odds ratio [OR], 0.43; 95% confidence interval [CI], 0.22-0.85; P = .014), and a higher rate of grade ≥2 late genitourinary (GU) toxicity when the CTV overlapped the RW (OR, 2.58; 95% CI, 1.17-5.72; P = .019). A marginally significant lower risk of grade ≥2 late GU toxicity was observed when the prostate bed did not overlap versus did overlap the RW (OR, 0.51; 95% CI, 0.25-1.03; P = .06). In addition, a marginally significant decrease in FFBP was observed in patients with PTV not including surgical clips as potential markers of the limits of the prostate bed (hazard ratio, 1.44; 95% CI, 0.96-2.17; P = .07). CONCLUSIONS: Despite a thorough QA program, the central review of a phase 3 trial showed limited adherence to treatment protocol recommendations, which was associated with a higher risk of toxicity by means of acute or late gastrointestinal or GU toxicity and showed a trend toward worse FFBP. Data from this QA review might help to refine future QA programs and prostate bed delineation guidelines.

Value of 3-Dimensional Digital Subtraction Angiography for Detection and Classification of Intracranial Aneurysm Remnants After Clipping.

BACKGROUND: The current gold standard for evaluation of the surgical result after intracranial aneurysm (IA) clipping is two-dimensional (2D) digital subtraction angiography (DSA). While there is growing evidence that postoperative 3D-DSA is superior to 2D-DSA, there is a lack of data on intraoperative comparison. OBJECTIVE: To compare the diagnostic yield of detection of IA remnants in intra- and postoperative 3D-DSA, categorize the remnants based on 3D-DSA findings, and examine associations between missed 2D-DSA remnants and IA characteristics. METHODS: We evaluated 232 clipped IAs that were examined with intraoperative or postoperative 3D-DSA. Variables analyzed included patient demographics, IA and remnant distinguishing characteristics, and 2D- and 3D-DSA findings. Maximal IA remnant size detected by 3D-DSA was measured using a 3-point scale of 2-mm increments. RESULTS: Although 3D-DSA detected all clipped IA remnants, 2D-DSA missed 30.4% (7 of 23) and 38.9% (14 of 36) clipped IA remnants in intraoperative and postoperative imaging, respectively (95% CI: 30 [ 12, 49] %; P-value .023 and 39 [23, 55] %; P-value = <.001), and more often missed grade 1 (< 2 mm) clipped remnants (odds ratio [95% CI]: 4.3 [1.6, 12.7], P-value .005). CONCLUSION: Compared with 2D-DSA, 3D-DSA achieves a better diagnostic yield in the evaluation of clipped IA. Our proposed method to grade 3D-DSA remnants proved to be simple and practical. Especially small IA remnants have a high risk to be missed in 2D-DSA. We advocate routine use of either intraoperative or postoperative 3D-DSA as a baseline for lifelong follow-up of clipped IA.

Increased Ipsilateral Posterior Cerebral Artery P2-Segment Flow Velocity Predicts Hemodynamic Impairment.

BACKGROUND AND PURPOSE: Increased Transcranial Doppler flow velocity in the ipsilateral P2-segment of the posterior cerebral artery (PCA-P2: cm/second) is associated with recurrent cerebrovascular events in patients with unilateral internal carotid artery occlusion. However, its predictive value and correlation with hemodynamic impairment in an overall stroke patient cohort remains to be determined. METHODS: Transcranial doppler PCA-P2 flow velocity was measured in 88 patients with symptomatic unilateral steno-occlusive disease who also underwent blood oxygenation-level dependent cerebrovascular reactivity imaging (blood oxygenation-level dependent [BOLD]-cerebrovascular reactivity [CVR]). A multivariate linear regression was used to evaluate the independent correlation between the ipsilateral PCA-P2 flow velocity measurements and hemispheric BOLD-CVR. Follow-up BOLD-CVR imaging data, available in 25 patients, were used to evaluate the temporal evolution of the BOLD-CVR and PCA-P2 flow velocity association using a mixed-effect model. Furthermore, a transcranial doppler cutoff for hemodynamic failure stage 2 was determined. RESULTS: The ipsilateral systolic PCA-P2 flow velocity strongly correlated with hemispheric BOLD-CVR (R=0.79; R2=0.61), which remained unchanged when evaluating the follow-up data. Using a PCA-P2 systolic flow velocity cutoff value of 85 cm/second, patients with BOLD-CVR based hemodynamic failure stage 2 were diagnosed with an area under the curve of 95. CONCLUSIONS: In patients with symptomatic unilateral steno-occlusive disease, increased ipsilateral transcranial doppler PCA-P2 systolic flow velocity independently correlates with BOLD-CVR based hemodynamic failure. A cutoff value of 85 cm/second appears to indicate hemodynamic failure stage 2, but this finding needs to be validated in an independent patient cohort.

Crossed Cerebellar Diaschisis in Patients with Diffuse Glioma Is Associated with Impaired Supratentorial Cerebrovascular Reactivity and Worse Clinical Outcome.

Crossed cerebellar diaschisis (CCD) can be associated with impaired cerebrovascular reactivity (CVR) and poor clinical outcome, but whether this holds true for patients with diffuse glioma is unknown. With blood oxygenation level-dependent (BOLD)-CVR imaging, we determined the presence of CCD in patients with diffuse glioma and investigated its relationship with cerebrovascular reactivity and clinical outcome. For eighteen enrolled subjects (nineteen datasets) with diffuse glioma, CCD was deferred from BOLD-CVR using a predetermined cerebellar asymmetry index (CAI) cutoff value of 6.0%. A FET-PET study was done as a verification of the CCD diagnosis. BOLD-CVR values as well as clinical performance scores (i.e., Karnofsky performance score (KPS), disability rating scale (DRS), and modified Rankin scale (mRS)) by BOLD-CVR scan at 3-month clinical follow-up were assessed and compared for the CCD-positive and CCD-negative group. CCD was present in 26.3% of subjects and strongly associated with impaired BOLD-CVR of the affected (i.e., the hemisphere harboring the glioma) and unaffected supratentorial hemisphere (CCD(+) vs. CCD(-): 0.08 ± 0.11 vs. 0.18 ± 0.04; p = 0.007 and 0.08 ± 0.12 vs. 0.19 ± 0.04; p = 0.007, respectively). This finding was independent of tumor volume (p = 0.48). Furthermore, poorer initial (by scan) clinical performance scores at follow-up were found for the CCD(+) group. The presence of crossed cerebellar diaschisis in patients with diffuse glioma is associated with impaired supratentorial cerebrovascular reactivity and worse clinical outcome.