Perfusion Computed Tomography in Transient Ischemic Attack

Background  Diffusion- and perfusion-weighted imaging after transient ischemic attack (TIA) has been well studied, while less data exist on perfusion computed tomographic (PCT) imaging.

Objectives  To examine the frequency of PCT abnormalities in patients with anterior circulation TIA and to identify factors associated with the presence of PCT abnormality.

Design  Retrospective study.

Setting  Academic hospital.

Patients  Sixty-five consecutive patients admitted to Rush University Medical Center, Chicago, Illinois, between June 1, 2007, and November 30, 2009, for anterior circulation motor or aphasic TIA in whom PCT was performed.

Main Outcome Measures  Using an automated software algorithm, perfusion abnormality was defined as brain tissue associated with a mean transit time greater than 145% of that of the contralateral hemisphere and cerebral blood volume greater than 2.0 mL/100 g. Demographic, risk factor, clinical, radiographic, and in-hospital outcome data were reviewed.

Results  Of 65 patients with anterior circulation TIA who underwent PCT (median age, 62.4 years; 49.2% male), 22 (33.8%) had focal perfusion abnormalities. The presence of motor symptoms (95.5% vs 67.4%, P = .01), multiple (>1) episodes (18.2% vs 2.3%, P = .04), ipsilateral arterial stenosis greater than 50% or occlusion (77.3% vs 11.6%, P < .001), large-artery atherosclerosis subtype (59.1% vs 9.3%, P < .001), and subsequent in-hospital events (22.7% vs 0%, P = .001) were more frequent in those with perfusion abnormality.

Conclusions  On acutely performed PCT, one-third of patients with hemispheric TIA have perfusion abnormalities. Perfusion abnormality may mark patients at greater risk for subsequent early deterioration. This requires further study.

Insights from diffusion-weighted imaging (DWI) studies have shaped our understanding of the pathogenesis and natural history and have led to a new definition of transient ischemic attack (TIA).¹ Although DWI identifies cytotoxic damage and defines infarction (ie, stroke) with rare exceptions,² penumbra without core infarct (perfusion abnormality with no areas or only reversible areas of restricted diffusion) should be the signature imaging correlate of transient brain ischemia in the acute setting. Thus, perfusion imaging abnormalities might serve as an objective marker of TIA.³

Several magnetic resonance perfusion (MRP) studies^4-6 have detected hypoperfused (ischemic) regions, in addition to smaller areas of restricted diffusion, after TIA. Perfusion computed tomography (PCT) has been less rigorously assessed in TIA⁷ despite being more widely available in the emergency department setting than MRP. We, therefore, assessed the prevalence of perfusion abnormalities as detected by PCT in consecutive patients with TIA admitted to Rush University Medical Center. The objectives of this study were to describe the frequency of PCT abnormality in anterior circulation TIA and to identify factors associated with the presence of PCT abnormality.

In June 2007, we instituted a clinical protocol using PCT in patients with suspected acute ischemic stroke or TIA presenting within 24 hours of symptom onset. All patient data were prospectively entered into a stroke registry database. A TIA was defined as any syndrome of focal neurologic dysfunction ascribable to a vascular territory and lasting less than 24 hours. Diagnosis of TIA was definite if an appropriate acute ischemic lesion was seen on brain imaging (DWI or PCT) and probable if alternative causes were excluded and there was agreement by 2 stroke neurologists (S.P. and V.H.L.).

We retrospectively identified all probable and definite TIA cases diagnosed between June 1, 2007, and November 30, 2009. Study inclusion criteria were (1) PCT within 24 hours of symptom onset; (2) transient language, speech, or motor symptoms lasting less than 24 hours; and (3) anterior circulation localization. The last criterion was determined by a stroke neurologist (S.P.) based on clinical symptoms and signs on hospital admission and confirmed, if possible, by neuroimaging results (ie, diffusion or perfusion abnormality). Cases were also excluded if symptoms were sensory only or if the perfusion study was of poor quality. Last, contraindications to iodinated contrast included previous documented contrast allergy, receipt of contrast within the previous 24 hours, a baseline creatinine level greater than 1.5 mg/dL (to convert to micromoles per liter, multiply by 88.4), and pregnancy.

Baseline data included demographics (age, sex, and race/ethnicity), clinical features (symptoms, number and duration of episodes, initial National Institutes of Health Stroke Scale score, hospital admission blood pressure, and calculated ABCD² [age (A), blood pressure (B), clinical features (C), and symptom duration and diabetes (D)] score⁸), medical history (vascular risk factors, including hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, current smoking, and coronary artery disease), radiographic features (computed tomography [CT] and magnetic resonance imaging [MRI] results, including PCT abnormalities, intracranial or extracranial large-artery stenosis greater than 50% or occlusion, and DWI abnormalities), and in-hospital events (recurrent TIA or ischemic stroke). Recurrent TIA required transient focal language or motor symptoms as defined for entry TIA. Ischemic stroke was defined as persistent symptoms lasting longer than 24 hours associated with new infarcts on repeated DWI. Based on the clinical and diagnostic tests, etiology was classified as large-artery atherosclerosis, small-vessel disease, cardioembolism, or undetermined/other mechanism. The study was approved by the Rush University Medical Center institutional review board.

The PCT studies were conducted using a 64-section scanner (Philips Medical Systems, Cleveland, Ohio). A bolus of 40 mL of intravenous contrast material was infused at a rate of 4 to 5 mL/s. Perfusion maps were generated using Philips Brilliance software (Philips Medical Systems), producing 4 sections separated by 10 mm. Manual postprocessing was performed only to define arterial and venous inputs for the automated PCT variable calculations. Using an automated algorithm, areas of perfusion abnormality were defined by a mean transit time greater than 145% of that of the contralateral hemisphere and cerebral blood volume greater than 2.0 mL/100 g (Figure). We chose this threshold because of previous validation as optimally representing tissue at risk for infarction in acute stroke.³ The automated algorithm using the previously mentioned variable thresholds yielded brain tissue maps in 4 sections, outlining ischemic tissue in green.

Using univariable analyses, we aimed to evaluate factors associated with perfusion abnormality. The proportions, means, or medians of relevant variables among those with and without PCT abnormality were compared using the Fisher exact, χ², t, and Mann-Whitney tests, as appropriate. A multivariable logistic regression model was developed to explore potential independent predictors of PCT abnormality. P < .05 was considered statistically significant. All statistical analyses were performed using a software program (SPSS, version 14.0; SPSS Inc, Chicago, Illinois).

We identified 122 patients during the study diagnosed as having probable or definite TIA and evaluated within 24 hours of symptom onset. Of these 122 patients, 65 (53.3%) met the inclusion criteria for the study (Table 1). The most frequent reason for exclusion was posterior circulation TIA (15.6%). Degraded or nondiagnostic PCT accounted for 9.8% of exclusions, with the most common cited reason being improper timing of contrast-enhanced bolus due to congestive heart failure (n = 7). Median time from symptom onset to PCT was 758 minutes (interquartile range, 403-1325 minutes). No patient experienced a study-related complication during hospitalization.

The mean age of the cohort was 62.4 years; 49.2% were male and 49.2% were white. Symptoms had resolved completely at the time of presentation in 58.5% of patients. Perfusion abnormality was detected in 22 patients (33.8%). On univariable analysis, patients with focal hypoperfusion were more likely than those without focal hypoperfusion to present with motor deficits (95.5% vs 67.4%, P = .01) and to report multiple (>1) episodes since onset (18.2% vs 2.3%, P = .04). Patients with perfusion abnormality were also more likely to have ipsilateral arterial stenosis greater than 50% or occlusion (77.3% vs 11.6%, P < .001), large-artery atherosclerosis subtype (59.1% vs 9.3%, P < .001), and a higher occurrence of subsequent in-hospital events (22.7% vs 0%, P = .001). Other factors, including demographics, medical history, time to perfusion imaging, and clinical features, such as blood pressure and ABCD² score, were not associated with the presence of PCT abnormality (Table 2). In an exploratory multivariable logistic regression model, the presence of an ipsilateral occlusive lesion was associated with PCT abnormality (adjusted odds ratio, 25.8; P < .001) independent of motor symptoms (P = .07), multiple episodes (P = .60), and large-artery atherosclerosis subtype (P = .88).

All 5 patients who experienced in-hospital events (4 recurrent TIAs and 1 ischemic stroke) had perfusion abnormality, and in 2 patients, in-hospital recurrence occurred in the absence of large-vessel occlusive disease and DWI abnormality. Recurrent events were referable to the areas of perfusion abnormality and were similar to the initial presentation. Bed rest and volume expansion with saline boluses were instituted in each patient with recurrent symptoms; induced pharmacologic hypertension was also instituted for 24 hours in the 1 patient with ischemic stroke. Repeated PCT (a median of 3 days after initial PCT) in these 5 patients showed delayed but complete resolution of the perfusion abnormality.

In patients with TIA who also underwent subsequent MRI ([50], 76.9%; median time to MRI, 33 hours 20 minutes), DWI abnormalities were noted in 72.2% of those with and 25.0% of those without PCT abnormality (P = .002). In this subset, 13 patients (26.0%) were PCT+/DWI+, 8 (16.0%) were PCT−/DWI+, 5 (10.0%) were PCT+/DWI−, and 24 (48.0%) were PCT−/DWI−. The combined yield of a PCT or DWI abnormality was 52.0%.

In the largest study to describe the frequency of perfusion abnormalities in patients with hemispheric TIA using CT, we observed that 1 in 3 had evidence of focal perfusion abnormality. Furthermore, perfusion abnormality was observed in 28.9% of patients in whom symptoms had resolved completely. These results are consistent with those of previous studies^4-6 of perfusion abnormality after TIA using MRP, suggesting that the 2 modalities may perform similarly in the detection of acute anterior circulation ischemia. In the present patients in whom both PCT and DWI were performed, the positive yield of PCT alone was 36.0% compared with 42% for DWI alone, with a combined yield of 52.0%. Given its widespread availability in the emergency setting, PCT may be the preferred imaging modality in patients with TIA.

Patients with demonstrable perfusion abnormality were more likely to have ipsilateral arterial stenosis or occlusion, motor symptoms, multiple presenting TIA episodes, and a large-artery atherosclerosis mechanism. Other studies^4-7,9 have observed similar associations. Although a hemodynamic process should be assessed in every patient with TIA, these cumulative findings suggest that perfusion abnormality can be seen even in the absence of large-artery hemodynamic compromise. Distal branch occlusive lesions at the arteriolar or capillary level (microcirculation) not visible on noninvasive vascular imaging may be operant in these cases.¹⁰

Studies^11-14 have shown that the presence of DWI abnormality after classic TIA is a predictor of short- and long-term stroke risk. From these data, the risk of stroke after DWI-positive TIA is as high as 30% in the first 90 days. However, had these been instead classified as minor ischemic strokes by virtue of irreversible tissue damage on neuroimaging, the risk of stroke after DWI-negative TIA (true TIA by the new definition) would have been exceedingly low. Identifying tissue at risk for infarction or the ischemic penumbra after true TIA should better stratify stroke risk radiographically and may better predict risk of clinical deterioration. All 5 patients with recurrent cerebrovascular events had PCT abnormalities, and in 2 of these 5 patients, no large-vessel or DWI lesion was found. Those with rapid radiographic resolution of the focal ischemia may harbor lower risk of subsequent stroke, whereas those with persistent tissue at risk (irrespective of symptom resolution at the time of imaging or the presence of large-artery occlusive disease) may mark those with limited cerebrovascular reserve and an elevated risk of clinical deterioration.

Perfusion CT has several advantages over MRP. First, the techniques are based on helical and spiral CT scanners that are widely available in hospitals, including emergency departments. The median time from symptom onset to PCT was considerably shorter (approximately 12 hours compared with nearly 24 hours) than in some MRP studies. Furthermore, PCT is a rapid test, requiring only approximately 40 seconds for data acquisition; can be performed in sequence with other techniques, such as CT angiography, without an overdose of contrast material; and has the potential for quantitative and qualitative interpretation. In addition, it can be performed in patients with MR contraindications, such as claustrophobia and metal implants. The major disadvantage of PCT is the limited amount of brain that can be studied.¹⁵ Calculation of brain ischemic volume remains limited in cases in which the ischemic lesion extends beyond the covered area. In recent years, multisection scanners of 128 sections and higher have made these limitations less problematic. Other disadvantages, relative to MRI, are the risks of x-ray radiation and the use of iodinated contrast agent.¹⁵ Notably, no contrast-related complications occurred in this study, a result attributable to the strict exclusion criteria (15 patients had prespecified contraindications).¹⁶ However, because serial kidney function testing and long-term follow-up for adverse events were unavailable and given the recent Food and Drug Administration warning regarding PCT and excess radiation risks to patients (http://www.fda.gov/medicaldevices/safety/alertsandnotices/ucm185898.htm), the safety of PCT in TIA requires further study.

This study has several limitations besides the small sample size and the absence of long-term follow-up. Because only anterior circulation TIAs were studied, the utility of PCT in posterior circulation TIAs is unknown. Given the challenges of posterior fossa imaging with CT, MRP may be better suited for this purpose. Although automated processing of PCT data has been shown to have less variability in parameter measurements and improved interobserver agreement,¹⁷ the selected parameter thresholds, around which there is considerable debate, can have a significant effect on the reported prevalence of perfusion abnormality. In addition, because serial perfusion imaging was not performed systematically in each patient, we cannot be certain that hypoperfusion seen with chronic occlusive disease did not lead to an overestimate of the prevalence.⁹ Alternatively, given the limited brain coverage (4 sections compared with newer-generation scanners capable of 16 and 32 sections), the present reported detection rates may actually underestimate the true prevalence of perfusion abnormality after acute TIA. Nondiagnostic results were noted in nearly 10% of all patients, most of which were attributable to inaccurate bolus timing due to congestive heart failure. Finally, the treating physicians were not blinded to the PCT results; this may have affected management decisions. These factors should be considered in future studies.

Overall, this study demonstrates that PCT detects perfusion abnormalities in carefully selected patients with anterior circulation motor or aphasic TIA, similar to that observed in MRP studies. Given the association with early deterioration and its widespread availability in the emergency department, PCT also has potential in guiding early management and therapeutic interventions. Further study that includes adjustment for other factors in larger cohorts is necessary to confirm these findings.

Correspondence: Shyam Prabhakaran, MD, MS, Department of Neurological Sciences, Rush University Medical Center, 1725 W Harrison St, Ste 1121, Chicago, IL 60612 (shyam_prabhakaran@rush.edu).

Accepted for Publication: May 3, 2010.

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Prabhakaran and McClenathan. Acquisition of data: Prabhakaran, Samuels, and McClenathan. Analysis and interpretation of data: Prabhakaran, Patel, Samuels, Mohammad, and Lee. Drafting of the manuscript: Prabhakaran and Patel. Critical revision of the manuscript for important intellectual content: Prabhakaran, Samuels, McClenathan, Mohammad, and Lee. Statistical analysis: Prabhakaran. Administrative, technical, and material support: McClenathan and Lee. Study supervision: Prabhakaran and Mohammad.

Financial Disclosure: None reported.