Perfusion Deficits Detected by Arterial Spin Labeling (ASL) in TIA Patients with negative diffusion and vascular imaging

Abstract

Background and Purpose

A substantial portion of clinically diagnosed TIA cases is imaging-negative. The purpose of the current study is to determine if arterial spin-labeling (ASL) is helpful in detecting perfusion abnormalities in patients presenting clinically with TIA.

Materials and Methods

Pseudo-continuous ASL with 3D background suppressed gradient and spin echo (GRASE) was acquired on 49 patients suspected of TIA within 24 hours of symptom onset. All patients were free of prior stroke history and had no lesion-specific findings on general MR, DWI and MRA sequences. The calculated ASL CBF maps were scored from 1 to 3 based on the presence and severity of perfusion disturbance by three independent observers blinded to patient history. An age-matched cohort of 36 patients diagnosed with no cerebrovascular events was evaluated as a control. Inter-observer agreement was assessed using Kendall concordance test.

Results

Scoring of perfusion abnormalities on ASL scans of TIA cohort was highly concordant among the 3 observers (w=0.812). The sensitivity and specificity of ASL in diagnosing perfusion abnormalities in TIA was 55.8% and 90.7%, respectively. In 93.3% (70 out of 75) of the ASL CBF map readings with positive scores (≥2), the brain regions where perfusion abnormalities were identified by 3 observers matched with the neurological deficits at TIA onset.

Conclusion

In this preliminary study, ASL showed promise in detecting perfusion abnormalities that correlated with clinically diagnosed TIA in patients with otherwise normal neuro-imaging.

INTRODUCTION

TIA is traditionally defined as the sudden onset of a neurological deficit(s) due to transient ischemia of eloquent brain, which resolves completely within 24 hours. TIA is presumed to have a vascular etiology and is considered to be an important risk factor for stroke [1,2]. In practice, the unequivocal diagnosis of TIA has been limited by the high percentage of patients who had suspected neurological deficits, but lacked confirmatory imaging. This contributes to lack of agreement in the diagnosis of TIA among practicing physicians [3], and has led to proposals advocating the incorporation of imaging data, in addition to clinical findings, in the diagnosis of TIA. For instance, this new paradigm has been adopted by American Stroke Association [4]. In addition to diagnosis, detection of mal-perfused tissue is considered to be important in understanding the extent of the initial perfusion deficit and may be helpful in guiding therapeutic decisions.

SPECT and PCT has been previously used to investigate perfusion disturbances in clinical TIA cases [5,6,7], however, these CT-based imaging techniques have several disadvantages including invasiveness, reliance on radioactive materials, adverse contrast reactions, as well as technical difficulties in covering large brain volumes [5,8,9]. More recently, the introduction of advanced MRI technology has enabled better visualization of ischemic cerebral regions corresponding both anatomically and temporally to symptoms of TIA. For example, DWI was positive of acute ischemic lesions in 24–40% of the patients referred for evaluation of TIA [10–14]. In addition, contrast-based PWI has shown promise in identifying abnormalities in approximately one third of the TIA patients, some of whom had negative DWI [16–17]. Nonetheless, a substantial portion of patients diagnosed with TIA clinically lack confirmatory imaging findings.

Arterial spin-labeled (ASL) technique provides CBF measurements without the use of a contrast agent. ASL has shown promise in clinical studies of ischemic pathological conditions, such as acute stroke [18–20] and large artery occlusion [21, 22]. In a limited number of published studies, ASL has demonstrated a high sensitivity for detection of minor perfusion alterations in TIA patients [12, 23]. With the goal of establishing a vascular etiology of TIA symptomatology, the current study investigated the value of ASL in detecting hypoperfusion abnormalities in a TIA cohort free of prior stroke history and without confirmatory findings on standard MR, DWI and MRA exams.

METHODS

Patients

From an ongoing prospective registry of consecutive patients evaluated for suspected TIA from July, 2010 to July, 2011 at our Medical Center, imaging data were selected from all patients who had: 1) Transient neurologic symptoms judged by clinical neurologists at the end of the evaluation to have a possible vascular etiology; 2) No prior stroke history; 3) MR scans performed within 24 hours of symptom onset; and 4) Non-specific findings on general MR, DWI and MRA exams. ASL imaging was used only in this retrospective analysis, but not in the clinical evaluation of the patients. The selected patients were then followed-up in clinic for complaints of any new neurological symptoms until December 31, 2011, when the study was terminated. A control cohort of age-matched patients (> 40 years old) who had received a brain MRI scan due to neurologic symptoms thought to be irrelevant to vascular events, was selected from another ongoing prospective registry of consecutive patients during the same period. For all selected patients in the TIA cohort, ABCD² scores were generated based on the presence of pre-existing conditions [10, 11]. This study was approved by Institutional Review Board and was HIPAA compliant.

MRI protocols

MRI scans were performed on a Siemens 1.5-T Avanto or 3.0T TIM Trio system (Erlangen, Germany) using a 12-channel head coil. The stroke imaging protocol included DWI, FLAIR, and gradient recalled echo (GRE). ASL scans were performed using a pseudo-continuous pulse sequence with background suppressed 3-D gradient and spin echo (GRASE) readout (labeling pulse duration 1.5 seconds, post-labeling delay 2 seconds, no flow crushing gradient, field of view (FOV) = 22 cm, matrix size = 64 × 64, 26 5-mm slices, GRAPPA=2, echo time (TE)/repetition time (TR) = 22ms/4000ms, with 30 pairs of tag and control volumes acquired within a total of 4 minutes) [24, 25].

ASL post-processing and evaluation

ASL images were corrected for motion, pair-wise subtracted between labeled and unlabeled images, and averaged to generate mean difference images, or ASL CBF maps. ASL CBF maps of TIA (n=49) and control (n=36) patients were scored by three independent observers (two board-certified neuro-radiologists and one non-radiologist physician experienced in MR imaging processing) blinded to patient history on a scale of 1 to 3, reflecting the presence and severity of the perfusion disturbance (usually hypo-perfusion in this study), with 1 for normal (no readable altered perfusion), and ≥2 being defined as “positive” readings indicating recognizable ischemic lesions (2 for subtle abnormalities only identified by careful study of ASL CBF maps, and 3 for prominent perfusion deficits easily identified in ASL CBF maps). The laterality of the perfusion disturbance was recorded in patients with hemispheric TIA for comparison with neurologic symptoms at onset. ASL reading scores were compared between patients grouped by field strength (1.5T versus 3.0T) of the scanner on which ASL images were obtained.

Statistical analysis

The agreement in reading scores from three observers (n=49×3 for the TIA cohort; n=36×3 for the control cohort) was assessed using a Kendall concordance test. Kendall’s W, also known as Kendall’s coefficient of concordance, was calculated to evaluate the degree of consensus. Pooled observations from all 3 observers (n = 49×3 for the TIA cohort; n=36×3 for the control cohort) were recorded in a 2×2 contingency table reflecting the frequency of true positive, true negative, false positive and false negative observations as rated using ASL CBF maps compared to the clinical diagnosis of TIA (gold standard). A true positive result was one obtained from a clinically diagnosed TIA patient with an ASL CBF map reading score ≥2. Conversely, a true negative result was one obtained from a control patient with an ASL CBF map reading score of 1. Sensitivity and specificity were calculated. A t-test was used to compare ASL reading scores between imaging obtained on scanners with different magnetic field strengths (1.5T vs 3.0T). The significance level was defined as P < 0.05 (2-sided).

RESULTS

Patient characteristics

From July, 2010 to July, 2011 at our Medical Center, we recorded 165 patients who were suspected of having a TIA, among which 67 patients (40.6%) had prior history of ischemic stroke. In patients who were negative for prior stroke history (98 out of 165), 23 (23.4%) patients had positive DWI findings, 30 patients (30.6%) had vascular lesions identified by MRA. In this particular subgroup, 4 patients (4.1%) showed positive findings on both DWI and MRA. Finally, there were 49 patients (50.0%) who were “imaging negative” and selected for our current analysis. Until December 31, 2011, the selected imaging-negative TIA patients were followed-up in clinic for 164 to 538 days (median 370 days) for complaints of new neurologic symptoms. Patients did not receive follow-up MRI.

Another cohort of 36 age-matched patients (> 40 years old) who had received a brain MRI scan due to neurologic symptoms thought to be irrelevant to vascular events, was selected from another ongoing prospective registry of consecutive patients during the same period as a control (Supplemental data).

Table 1 shows baseline characteristics of “imaging negative” TIA patients (n=49) at symptom onset and control patients (n=36) on MR scan dates. Patients with a clinical diagnosis of TIA (n=49) but no prior stroke and positive MR imaging findings, had a sudden onset of neurological deficits that lasted anywhere from seconds to hours. In all cases, symptoms resolved by the time of MR scanning, which was performed from within 1 hour to 11 hours after initial onset of symptoms. The TIA and control cohorts showed no significant difference in mean age, but were significantly different for pre-existing conditions associated with stroke risk including the incidence of TIA, coronary heart disease, hyperlipidemia, hypertension and diabetes mellitus. The TIA cohort has a median ABCD² score of 4. All patients in the TIA cohort were followed up for an average period of 1 year (164 to 538 days) and none of the patients was found to suffer a post-TIA stroke based on absence of complaints of any new neurological symptoms.

Table 1.

Basic characteristics of patient cohorts

	TIAa (n=49)	Control (n=36)
Age (mean ± SD yr)b	65.6 ± 14.6	60.2 ± 12.2
Gender (F/M)	27 / 22	24 / 12
MRI delay median (hr)c	6.5	N/A
ABCD2 score median	4	N/A
Prior TIA, n (%)d	9 (18.4%)	0 (0)
Coronary artery disease, n (%)d	10 (20.4%)	3 (8.3%)
Atrial fibrillation, n (%)b	1 (2.0%)	1 (2.8%)
Hyperlipidemia, n (%)d	24 (49.0%)	5 (13.9%)
Hypertension, n (%)d	31 (63.3%)	7 (19.4%)
Diabetes, n (%)d	9 (18.4%)	2 (5.6%)

^aDiagnosis of TIA was made clinically without ASL imaging

^bThere is no significant difference between two groups

^cBased on 40 patients, data not available for 9 patients

^dThere is significant difference between two groups, p < 0.001

Evaluation of ASL CBF maps

Results suggested relatively high concordance scores (Kendall concordance test) indicating good agreement in evaluating ASL CBF maps of both TIA (W=0.812) and control cohorts (W=0.642) among three observers. With scores of ≥2 being defined as “positive” readings indicating recognizable ischemic lesions (82 out of 147=49×3 for TIA cohort, and 10 out of 108=36×3 for control cohort), the sensitivity and specificity of the ASL CBF map in diagnosing TIA were 55.8% (95% confidence interval [0.49, 0.63]), 90.7% (95% confidence interval [0.87, 0.95]), respectively (Table 2). The magnetic field strength (23 patients on 1.5T, 26 patients on 3.0T in the TIA cohort; 17 patients on 1.5T, 19 patients on 3.0T in the control cohort) was not associated with a significant difference in mean reading scores of ASL CBF maps (t-test). In the TIA cohort, 44 of 49 (89.8%) patients presented with hemispheric symptoms, such as focal weakness and aphasia. In this subgroup of patients with hemispheric TIA and positive ASL CBF map readings (score≥2), 93.3% (70 out of 75positive readings) of the cases showed brain regions where the hypoperfusion identified matched the laterality of the neurologic symptoms at TIA onset. In the rest of the observations (5 of 75), hyperperfusion was characterized in brain regions corresponding to transient neural deficits during TIA attacks.

Table 2.

Sensitivity and specificity of ASL CBF map reading^a

	TIAb	Control
ASL Positivec	82	10	92
ASL Negatived	65	98	163
	147	108
	Sensitivity 55.78%	Specificity 90.73%

^aBased on pooled data from 3 independent observers, n=49 for TIA cohort, n=36 for control cohort

^bDiagnosis of TIA was made clinically without ASL imaging

^cDefined as reading score = 2 or 3

^dDefined as reading score = 1

DISCUSSION

The widespread adoption of newer advanced MR sequences, such as DWI, has significantly improved the characterization of ischemic lesions in TIA patients. However, the diagnosis of TIA in a substantial proportion of cases remains purely clinical-based, as there is no corroborating imaging finding by standard MRI. Therefore, it would be of potential value to identify imaging technologies with a high sensitivity for detection of minor cerebral perfusion abnormalities, in order to more confidently establish the diagnosis of TIA in clinical practice. ASL has emerged as one such imaging technique with a purported high sensitivity for the detection of perfusion abnormalities in both TIA and acute stroke patients [18–20, 23]. In the current study, we explored the value of ASL in detecting perfusion deficits in a cohort of clinically diagnosed TIA patients with unremarkable standard MR imaging. To avoid confounding factors that are known to produce positive findings on ASL images, we excluded patients with a prior history of stroke and any brain lesions that can be identified by DWI and MRA sequences. As a preliminary investigation of the value of ASL in TIA, the current analysis was limited by small study size and discrepancy in the sex ratio between TIA and control cohorts (Table 1). The power of the study was further affected by the gap in the median age of the TIA and control cohort (70.7 and 61.4, respectively) although there was no significant difference in the mean age of the patient cohorts (65.6 and 60.2, respectively; P>0.05, t-test).

We found that ASL provided imaging evidence of disturbed perfusion (this study focused on hypoperfusion) in 55.8% of imaging-negative TIA cases, as judged by the standard imaging protocols including DWI and MRA. ASL CBF map reading also showed a high specificity (90.7%) for abnormal perfusion in our patient cohort. Positive ASL CBF map readings showed that the location of hypoperfusion was consistent with the neurological symptoms at TIA onset in 93.3% (70 out of 75) of the total observations. These findings support the hypothesis that ASL is a feasible and practical method for detecting perfusion abnormalities with good sensitivity in patients with clinical diagnosis of TIA. The evaluation of ASL CBF maps demonstrated good agreement in reading scores from three observers (W=0.812 for TIA and W=0.642 for control), suggesting that ischemic lesions in ASL CBF maps could be consistently recognized by different readers, and thus supporting the conclusion that ASL has good reliability as well. In practice, ASL has the advantages of being contrast-free and requires a relatively short scan time (less than 4 minutes in our protocol), which may allow this technique to be widely used in the clinical management of TIA and other clinical emergencies that mimic it.

Prospective studies have shown a high risk of stroke within the immediate hours and days after TIA [2]. In the current study, we followed the TIA cohort for an average period of 1 year (164 to 538 days) and none of the patients suffered post-TIA stroke. The reported factors correlating with risk of post-TIA stroke include ABCD / ABCD² scores [10, 11, 26] and positive MR imaging findings on DWI [26–30] and MRA [29–31]. As a clinical score based on the presence of pre-existing conditions to determine the risk for stroke following a TIA, the value of ABCD /ABCD² scores in predicting post-TIA stroke risk had been controversial, and varies greatly by patient cohort and clinical protocol [10, 11, 26, 31]. Our TIA cohort had a high median ABCD² score of 4; however, none of the patients appeared to suffer a stroke during the averaged 1-year follow-up period, although silent infarcts could have gone undetected (as patients had routine clinical follow-up, but no additional MRI).

The lack of clinically evident strokes in our TIA cohort may be surprising, but it may suggest that the negative standard imaging being used as a criterion for study inclusion could be associated with reduced stroke risk. Although the power of the current analysis was limited by relatively small cohort size, we found that TIA patients with positive findings on DWI and MRA are more likely to display readable abnormalities on ASL than imaging-negative cases used in the current study (data not shown), raising the question of whether ASL data should be included in criteria for evaluating stroke risk following TIA. Better characterization of such a patient cohort may help to clarify the value of ABCD / ABCD² scores in predicting post-TIA stroke. Specifically, future studies of much larger size will be necessary to determine stroke risks in these patient groups: i.e., TIA with MR imaging abnormalities (including DWI and MRA), TIA with ASL abnormalities only, and TIA with no imaging abnormalities or ASL abnormalities.

Low SNR and low spatial resolution are major limitations of ASL. The SNR is directly proportional to voxel size and the post-label delay (PLD) time, which is defined as the duration between labeling of the spins and acquisition of the images, and is typically between 1.5 and 2.0 seconds. Longer PLDs (> 2 seconds) could help to improve CBF quantification, however, at the cost of a further decrease in SNR [32]. In the current analysis, a single PLD of 2.0 seconds was used, resulting in the detection of focal hypoperfusion in 55.8% of imaging-negative TIA patients. Considering the universal existence of multiple conditions in TIA patients that related to vascular pathogenesis, arterial transit time (ATT) could vary greatly among individual patients. Therefore, one calculated CBF map based on a single PLD might not be the best approach to accurately reflect the perfusion status in these patients. In this case, one option would be to obtain images at multiple PLDs, which offers the potential to quantify ATT [33] and effectively map the inflow of label into the tissue [21, 34]. In future studies, we plan to perform ASL scans using multiple PLDs and calculate ATT-adjusted CBF maps, aiming to improve the sensitivity in detecting minor perfusion changes in TIA patients.

CONCLUSION

Our results suggest the potential value of ASL perfusion data in detecting abnormalities in TIA patients, which may help improve the diagnostic certainty in otherwise imaging-negative TIA patients.

Figure 1.

Representative cases from the control cohort.

A. A 50-year old female was evaluated for dizziness after the car accident. No specific finding is reported on the standard MR, DWI, and MRA. ASL reading scores are 1, 1, 1 by 3 raters.

B. A 49-year old female was evaluated for chronic headache of unknown causes. No specific finding is reported on the standard MR, DWI, and MRA. ASL reading scores are 2, 2, 2 by 3 raters.

Figure 2.

Representative cases from the TIA cohort.

A. A 75-year old female with a history of hypertension and diabetes had acute onset of transient blurry vision, slurred speech, dysarthria, and word-finding difficulties that lasted for 20–30 minutes. ABCD² score is 5. The standard MR reports a few non-specific T2/FLAIR hyperintensities in the cerebral white matter bilaterally. DWI, and MRA studies are reported normal. ASL CBF map shows perfusion deficits in the right MCA region (arrow). ASL reading scores are 2, 2, 2 by 3 raters.

B. A 57-year old female with a history of hypertension had right facial droop and right arm numbness for 6 hours. ABCD² score is 3. Non-specific T2/FLAIR hyper-intensities are seen in the cerebral white matter. DWI and MRA studies are normal. ASL CBF map shows perfusion deficits in the regions of left MCA and left PCA (arrow). ASL scores are 2, 2, 2 by 3 raters.

C. A 80-year old female with a history of hyperlipidemia had transient global amnesia, left-sided sensory deficit and positive Babinski’s sign on the left side for 6 hours. ABCD² score is 3. Scattered T2/FLAIR hyper-intensities are seen in the periventricular and subcortical white matter on standard MR. DWI, and MRA studies are reported normal. ASL CBF map shows perfusion deficits in the right MCA region (arrow). ASL scores are 3, 3, 3 by 3 raters.

D. A 57-year old female with a history of hypertension had right facial droop and slurred speech for more than 1 hour. ABCD² score was 4. The standard MR, DWI, and MRA studies are reported normal. ASL reading scores are 1, 1, 1 by 3 raters.

ABBREVIATION KEY

ASL

arterial spin labeling

SPECT

single photon emission CT

PCT

contrast-enhanced perfusion CT

ATT

arterial transit time

GRASE

gradient and spin echo

PLD

post-label delay