Leukoaraiosis Attenuates Diagnostic Accuracy of Large-Vessel Occlusion Scales

Study Cohort

We retrospectively analyzed 274 consecutive patients with acute ischemic stroke shown on brain MR imaging who were included in the University of Massachusetts Memorial Medical Center Stroke Registry between January 2013 and January 2014.^15,18 Patient demographics, laboratory data, comorbidities, preadmission medications, and stroke pathogenesis (using the Causative Classification System for Ischemic Stroke as previously described^15,18) after completion of diagnostic evaluation were collected on all patients. NIHSS scores were assessed at the time of presentation by members of the stroke team certified in the NIHSS. Only patients with complete details on all NIHSS subcategories were included (On-line Fig 1). All patients underwent head CT and either CTA (n = 249) or MRA (n = 25) at admission. Ten patients underwent both CTA and MRA. To reliably determine the white matter lesion burden (leukoaraiosis), we only included patients with available brain MR imaging. Our investigation was approved by our Institutional Review Board (No. H00006964), and a Health Insurance Portability and Accountability Act waiver of informed consent was granted. We adhere to the Strengthening the Reporting of Observational Studies in Epidemiology (www.strobe-statement.org) and Standards for Reporting of Diagnostic Accuracy Studies (www.stard-statement.org) guidelines.

Neuroimaging Protocol

All MR imaging and MRA sequences were acquired on a 1.5T whole-body MR imaging scanner (Signa HD; GE Healthcare, Milwaukee, Wisconsin) between 1 and 7 days after stroke. Brain MR imaging sequences included T1, T2, FLAIR, and DWI. DWI was performed with echo-planar imaging with a TR of 8000 ms, TE of 102 ms, FOV of 22 × 22 cm, image matrix of 128 × 128, slice thickness of 5 mm with a 1-mm interslice gap, and b-values of 0 and 1000 s/mm². FLAIR was performed with a TR of 9002 ms, TE of 143 ms, FOV of 22 × 22 cm, image matrix of 256 × 224, and slice thickness of 6 mm with a 1-mm interslice gap. All MRA was performed with TOF–echo-spoiled gradient-echo pulse sequences. Head MRA was performed with a TR of 25 ms, flip angle of 20°, FOV of 20 cm, matrix of 256 × 224, and slice thickness of 1.4 mm. Neck MRA performed with contrast used a TE of 1.8, flip angle of 45°, FOV of 33, slice thickness of 1 mm, and matrix of 28.4 × 22.4 cm. Patients received 20 mL of gadobenate dimeglumine (MultiHance; Bracco Diagnostics, Princeton, New Jersey). Neck MRA was performed without contrast with a TR of 24 ms, TE of 5.1 ms, flip angle of 60°, FOV of 20, slice thickness of 1.5 mm, and matrix of 512 × 160.

All CT sequences were obtained on a 64–detector row scanner (Brilliance; Philips Healthcare, Best, the Netherlands).^17,19 CT was performed in a nonhelical mode at 120 kV(peak) and 200 mA, with data reconstruction at 5-mm axial sections. CTA was performed using a 64 × 0.625 mm detector configuration with a pitch of 0.673 from the arch of the aorta to the vertex using 120 kV(p), 300 mA, and 0.5-second rotation time. Patients received 60–80 mL of iopamidol (Isovue 370; Bracco Diagnostics) in the antecubital vein at a rate of 4 mL/s through a power injector, followed by 40 mL of saline. 3D orthogonal MIP images were created in 3 planes.

Leukoaraiosis Grading

In all patients, leukoaraiosis was defined on MR imaging as supratentorial white matter FLAIR hyperintensity lesions according to the Standards for Reporting Vascular Changes on Neuroimaging²⁰ criteria and graded according to the Fazekas scale as previously described in detail.^14,15 The total Fazekas scale score was calculated by adding the periventricular and subcortical scores.¹⁴ We have previously shown substantial interrater reliability with an intraclass correlation coefficient of 0.969 (95% CI, 0.943–0.983).¹⁴ In addition, we dichotomized the degree of leukoaraiosis according to the median Fazekas scale score to 0–2 (n = 145, absent-to-mild leukoaraiosis) versus 3–6 (n = 129, moderate-to-severe leukoaraiosis) for statistical purposes.

Definition of Large-Vessel Occlusion

Large-vessel occlusion was defined on the admission CTA or MRA as the presence of an apparent occlusion of the intracranial internal carotid artery and proximal middle cerebral artery (M1). The included prehospital stroke scales were not designed to assess the presence of occlusion in the distal MCA (M2), basilar, and intracranial vertebral arteries. Therefore, occlusion in these vessels was considered non-LVO for this study, and only considered in the exploratory analyses. All images were reviewed by a neuroradiologist as part of the routine clinical work-up. The site of the LVO was abstracted from the radiologic report and by cross-validating with the original scans by one of the authors (Y.M.), who was masked to clinical data. Discrepant interpretations were resolved by consensus after review by a second neurologist (N.H.).

Prehospital Stroke Scales

To determine the impact of pre-existing leukoaraiosis on LVO prediction, we examined 5 previously published scales that could be reliably reconstructed by abstraction from the admission NIHSS score sheet and the detailed neurologic examination documented in our medical records. We used the following additional prespecified rules for derivation of the scores because we previously found that severe leukoaraiosis substantially attenuates the classic hemispheric lateralization of the NIHSS deficit¹⁵: If both sides were weak, the weaker side determined the sign scored; and if both sides were equally weak, the presence of the sign was scored.

The Field Assessment Stroke Triage for Emergency Destination (FAST-ED) was calculated on the basis of the presence of facial palsy (scored 0–1), arm weakness (0–2), speech changes (0–2), eye deviation (0–2), and denial/neglect (0–2). A score of ≥4 was considered suggestive of LVO.⁹ The Rapid Arterial Occlusion Evaluation (RACE) was calculated on the basis of the presence of facial palsy (0–2), arm motor function (0–2), leg motor function (0–2), gaze (0–1), and aphasia or agnosia (0–2). A score ≥5 was considered indicative of LVO.⁸ The Vision, Aphasia, Neglect (VAN) score was calculated on the basis of the presence of arm motor weakness (0–1) plus the presence of visual disturbance (blindness, field cut, diplopia [0–1]), aphasia (0–1), and neglect (including forced gaze deviation [0–1]). In the absence of arm weakness, the patient received a score of zero. A score ≥2 was considered indicative of LVO.⁶ The Cincinnati Prehospital Stroke Severity Scale (CPSSS) was calculated on the basis of the presence of conjugate gaze deviation, (0–2), arm weakness (0–1), and impaired consciousness (0–1). A score of ≥2 was considered indicative of LVO.¹⁰ The 3-Item Stroke Scale (3I/SS) was calculated on the basis of the level of consciousness (0–2), gaze deviation (0–2), and hemiparesis (0–2). A score ≥4 was considered indicative of LVO.⁷

Statistics

Unless otherwise stated, continuous variables are reported as mean ± SD or median (25th–75th percentile). Categoric variables are reported as proportions. Between-group comparisons for continuous and ordinal variables were performed with the Mann-Whitney U test. Categoric variables were compared using the χ² test or Fisher exact test as appropriate. To determine the diagnostic accuracy of the LVO scales, we calculated the area under receiver operating curves (C statistics, ordinal scales) as well as sensitivity, specificity, positive predictive value, negative predictive value, and κ (dichotomized scales each) with corresponding 95% CIs.

We created multivariable logistic regression models to determine whether the tested LVO scale cutoffs predicted large-artery occlusion (dependent variable) independent of leukoaraiosis (as determined by the Fazekas scale score). All models were adjusted for factors known to be associated with leukoaraiosis, including age, sex, and preadmission mRS and a history of hypertension, stroke/TIA, and atrial fibrillation. In addition, models were adjusted for the Fazekas scale score × LVO Scale Interaction to determine whether the leukoaraiosis burden differentially modified the predictive ability of the tested scales. Variables were sequentially removed (likelihood ratio) from the models at a significance level of 0.1 to avoid model overfitting. Collinearity diagnostics were performed (and its presence rejected) for all multivariable regression models. The Hosmer-Lemeshow goodness-of-fit statistic was used to assess model fit.

Two-sided significance tests were used throughout; unless stated otherwise, a 2-sided P < .05 was considered statistically significant. All statistical analyses were performed with SPSS, Version 22 (IBM, Armonk, New York).