Yield of Computed Tomography Perfusion in Stroke Management

Abstract

OBJECTIVES

The use of computed tomography perfusion (CTP) is not supported by guidelines unless to diagnose penumbra in extended time window treatment. The purpose of this study was to define the yield of CTP for stroke diagnosis beyond penumbra imaging in hyperacute phase (0-6 hours) and extented time window (6-24 hours).

MATERIALS AND METHODS

All consecutive patients with acute onset of symptoms within 24-hour window underwent CTP. The diagnostic value of CTP was calculated against radiological and clinical diagnosis of stroke. CTP was positive in presence of core or penumbra on RAPID. Radiological diagnoses were established as acute infarction on follow up imaging or symptomatic occlusion on baseline CT angiography. Clinical diagnoses were discharge diagnoses of stroke.

RESULTS

BetweenNov/2018-Nov/2019, 585 consecutive patients with acute neurological deficit were scanned with multimodal CT imaging, 500 (85%) were included: 274 (55%) within hyperacute phase, 153 (31%) had radiological diagnoses of stroke, and 122 (24%) clinical diagnoses of stroke. CTP was positive only in patients with confirmed stroke (positive predictive value and specificity 100%). When CTP was negative, 43% had a stroke mimic. Patients with stroke mimics were younger (66±17 vs. 73±13) and had lower National Institutes of Health Stroke Scale (median 0; IQR 0-2 vs median 4; IQR 2-6) compared to patients with CTP negative stroke.

CONCLUSIONs: Our study newly documents that CTP is useful beyond penumbra imaging: if CTP is positive than stroke diagnosis is established, which should prompt acute recanalization treatments. If CTP is negative physicians should consider stroke mimics.

Introduction

CT perfusion (CTP) is used as a penumbra imaging for intravenous thrombolysis and mechanical thrombectomy in the extended time window, i.e., ≥4,5 or 6 hours from symptom onset. (1, 2, 3, 4) However, CTP provides information not only on the presence of penumbra, but on the presence of brain infarction, and such information could be useful for stroke management in general. Especially making the correct indication of treatment with intravenous thrombolysis (IVT) is important because it is not desirable either to treat patients without stroke or not to treat patients with stroke.

One of the specifics with the indication of intravenous thrombolysis is the need to make the decision urgently, although physicians frequently might not have all relevant information, e.g., from patient history, to their disposal. Stroke mimics, therefore, relatively frequently receive IVT, even in experienced stroke centers (5, 6). Knowledge of presence or absence of brain infarction should decrease false positive and false negative diagnoses of brain infarction. Consequently, fewer patients without stroke and more patients with stroke could be treated with IVT.

Therefore, the purpose of this study was to define the yield of CTP beyond established and guidelines supported recommendations, i.e. in radiological and clinical diagnosis of stroke in 0–6 hours and 6–24-hour time windows.

Methods

It is a cohort study of all patients with suspected acute ischemic stroke within both hyperacute phase (0–6 hours) and extented time window (6–24 hours) admitted to the Neurology Department with the presence of acute neurological deficit at admission between November 2018 and November 2019.

Statistics

Microsoft Excel version 2010 and SPSS statistics software were applied in the analyses and results were expressed as means, medians, and percentages. Sensitivity, specificity and positive and negative predictive values were calculated against clinical and radiological stroke diagnosis.

Results

In the period from November 2018 to November 2019, 585 patients with acute neurological deficit were scanned with multimodal CT imaging. 72 cases (12%) were excluded due to the CTP artefacts, another 6 patients because of secondary transport to comprehensive stroke center and another 7 patients were excluded for incomplete data. Remaining 500 (85%) patients were included in the analysis: 232 (46%) in 4,5-hour thrombolytic window and 274 (55%) patients had CTP in 6-hour window from symptoms onset. 267 (53%) were women, an average age of 71±16 years. Flow diagram representing excluded patients is presented in Fig. 1. One hundred and twenty-five (25%) of patients received intravenous thrombolysis with median door-to-needle time of 20 minutes. Table 1 presents all baseline characteristics of included patients.

Positive CT perfusion was found in 185 cases (37%). All of these patients (100%) were dismissed with the final clinical diagnosis of stroke. Of 315 cases (63%) with negative initial brain perfusion, 179 (57%) had a clinical diagnosis of stroke, and the remaining 135 (43%) patients were diagnosed with stroke mimics. The overall sensitivity, specificity, positive and negative predictive of baseline CT for the clinical diagnosis of stroke were 51% (CI 46–56), 100% (CI 97–100), 100% (CI 98–100), 43% (CI 41–46), respectively. In hyperacute phase (0–6 hours from symptom onset) the sensitivity, specificity, positive and negative predictive of baseline CT for the clinical diagnosis of stroke were 53% (CI 46–60), 100% (CI 95–100), 100 (CI 97–100), 41% (CI 38–45), respectively. Stroke mimics diagnoses and their frequencies are presented in Table 2. Also, patients’ characteristics in CTP negative patients with stroke mimics versus strokes are presented in Table 3. Patients with negative CTP with stroke mimics were younger (66±17 vs. 73±13) and with lower NIHSS (median 0, IQR 0–2 vs median 4, IQR 2–6) compared to patients with CTP negative stroke. Bar chart documenting decreasing likelihood of stroke with increasing NIHSS in patients with stroke mimics is demonstrated in Fig. 3.

Clinical diagnosis of stroke in CTP negative patients was made based on: follow-up neuroimaging findings (N = 51), symptomatic vessel occlusion (N = 6), significant symptomatic stenosis (N = 7), clinical presentation, and numerous stroke risk factors (N = 18). Eighteen patients underwent intravenous thrombolysis with symptoms resolution and no infarction on follow-up CT scan.

In patients with negative initial CT perfusion with no follow-up imaging (n = 65), diagnosis of stroke was made according to the presence of symptomatic vessel stenosis or occlusion (n = 20) or infarction on initial non-contrast CT scan (n = 5). In 46 of 65, the clinical presentation was unambiguous, the deficit was low (NIHSS ≤ 5), and there was no clinical uncertainty or indication for follow-up imaging.

Follow-up imaging (brain CT/MRI) was performed altogether in 314 cases (63%). In 180 of all 314 (57%), new hypodensity on CT was confirmed; in 10 (5%) cases, the infarction was localized outside the area of the brain covered by baseline CTP. In CTP positive patients, radiological diagnosis of stroke was confirmed in 129 cases (81%), while in CTP negative patients, 51 patients (33%) had infarction on follow-up imaging. CTP findings, follow-up imaging and definite diagnoses distribution in all patients see Fig. 2. The overall sensitivity, specificity, positive and negative predictive value of baseline CTP for radiological diagnosis of stroke were 74% (CI 68–79), 94% (CI 88–97), 97% (CI 93–98), 61% (CI 65–66), respectively. For patients with CTP within the 6 hours of symptom onset, the sensitivity, specificity, positive and negative predictive value of baseline CTP for radiological diagnosis of stroke were 80% (CI 72–86), 95% (CI 86–99), 97% (CI 92–99), 69% (CI 61–76), respectively.

Discussion

In our study we document the feasibility of conducting CTP as part of routine clinical practice. All patients with suspicion of acute stroke underwent CTP. Twenty-five percent of these patients received intravenous thrombolysis. We demonstrated that our median door-to-needle time for intravenous thrombolysis was only 20 minutes. Such finding has important clinical implications because some previous studies documented that CTP is prolonging initiation of IVT and thus should not be used before initiation of IVT (9). Our study documents, that despite adding few minutes for CTP imaging (usually 4–5 minutes), which is typically done in our center together with unenhanced CT and CTA, CTP in principle did not pose a barrier for achieving very short DNT. Main reason is that patients are directly transported to CT scan from ambulance and IVT is initiated in CT scanner as we publish before [7, 12]. Moreover, our study documented that CTP had important added value in decision making as demonstrated in the Results and discussed below.

Our first major finding is that once CTP is positive, regardless of time window, all patients had a stroke and none had stroke mimics. Such information is very useful, especially because it eliminates any diagnostic doubts that physicians might have in general and especially in the short amount of time needed to decide to initiate intravenous thrombolysis. Most likely, the value of stroke confirmation will be increased even more in those hospitals that lack the expertise in stroke. We could not confirm the results of some previous studies documenting that hypoperfusion (and even hyperperfusion) on CTP imaging can also be found in patients with other diagnosis then stroke such as status epilepticus or post-paroxysmal deficit (10, 11, 12, 13). Twenty-three patients in our cohort had epileptic seizures and all were correctly diagnosed by RAPID as stroke mimic. Different results can be explained by the fact that in previous studies no automatic software was used, no thresholds were defined, and numbers of patients were low. Our results are therefore applicable for clinical practice as long as certified postprocessing tools such as RAPID are used for evaluation of CTP.

CTP is used to define penumbra and accordingly our results documented that core or penumbra presence at baseline predicted infarction on follow up imaging. False negative results were obtained mainly in patients with lacunar supratentorial infarction (24 patients) or vertebrobasilar stroke (66 patients). Also, 10 infarcts were in the area of the brain which was outside of coverage by baseline CTP. These are known limitations of brain perfusion imaging (14, 15). Calculated specificity against radiological diagnosis of stroke is comparable with largest published meta-analysis (16). We found numerically just a bit lower sensitivity (74%) against radiological diagnosis as reported in previous largest and the most recent analyses (80%) (16). If CTP covers whole brain instead of 8cm width, as in our study, accuracy of CTP will slightly improve due to capture of infarctions in any part of the brain.

In patients with negative CTP, many patients (57%) suffered a stroke, which is not surprising because lacunar and vertebrobasilar strokes cannot be diagnosed by CTP as discussed above. However, 43% of those with negative CTP, which is quite a substation number, had stroke mimics and were discharged with another diagnosis such as vertigo of non-vascular cause (23%), epilepsy (18%), orthostatic collapse or others as described in Table 2. Patients with negative CTP with stroke mimics were younger (68 vs. 73, p < 0.001) and with lower NIHSS (0 vs. 4, p < 0.001) compared to patients with negative CTP and a stroke. Stroke mimic patients also had fewer cardiovascular risk factors, most likely due to younger age. The overall prevalence of stroke mimics in our study was 27% which is nearly the same as in metanalysis of 29 studies documenting 26% of stroke mimics (9, 17). Also, stroke mimics diagnoses were very similar to published data as shown in Table 2. Therefore, our study documented similar number and causes of stroke mimics and found that if CTP is negative, it should raise a red flag in younger patients with minor neurological deficit and fewer cardiovascular risk factors because they might have stroke mimics. In cases presenting with lacunar syndrome or suspicion for stroke in the vertebrobasilar territory, negative CTP should not preclude treatment with intravenous thrombolysis.

Limitations of our study are retrospective design and missing follow-up imaging in 37% of cases. Such missing cases could limit conclusion about CTP accuracy against radiological but not clinical diagnoses of stroke. In our clinical practice, follow up CT is omitted only when diagnoses of stroke or stroke mimic is established. In clinically uncertain cases, we always perform MRI. Therefore, missing follow up imaging should not limit validity of our study although confirmation of our results by future studies will be re-assuring.

For generalizability of our results, especially in terms of high proportion of stroke mimics, it might be important to consider referral pattern that is applied in our hospital as described in the Methods. Hospitals with different referral pattern might have less stroke mimics, especially if some triage criteria are applied before imaging and will refer to CT only the most obvious stroke candidates. Our results related to stroke mimics (negative predictive value) are thus generalizable to unselected patients’ population with acute neurological deficit. Our results related to 100% positive predictive value of stroke should be, however, applicable to any hospital regardless of referral pattern.

The major strengths of our study are the consistency of the use of multimodal imaging not limited to any patients' subgroups. This is the advantage over previous studies that included only patients with stroke in anterior circulation (18), patients in a short time window (19), or patients with MRI follow-up imaging only (20). Other advantage of our study is a relatively large number of patients, which was much less (usually up to 120 cases) in previous studies (18, 21, 22, 23).

Conclusion

Our study has several new and if confirmed, potentially guidelines modifying findings. First of all, we documented the feasibility of using CTP in routine clinical practice without negatively impacting stroke logistics measured as the door-to-needle time for intravenous thrombolysis. Secondly, we documented benefit of CTP beyond guidelines recommended application, which is currently penumbra imaging ≥4,5 and 6 hours from symptom onset. Our study revealed the usefulness of CTP as a diagnostic tool, even in hyperacute phase of stroke. CTP positivity improves physicians' confidence in the diagnosis of a stroke and rules out stroke mimics. Negative CTP should raise concerns about non - stroke diagnoses, especially in younger patients presenting with minor deficit and non - lacunar syndrome.

Declarations

Ethics approval and consent to participate

This research study was conducted retrospectively from data obtained for clinical purposes. Our Study meets STROBE criteria for observational studies. All methods were performed in accordance with the relevant guidelines and regulations. The study protocol was approved by the local Ethics Committee of the St. Anne’s University Hospital in Brno in view of the retrospective nature of the study and all the procedures being performed were part of the routine care. The informed consent was waived by the local Ethics Committee of the St. Anne’s University Hospital in Brno due to observational and retrospective nature of the study. 

Consent for publication
 Not applicable. 

Availability of data and materials

All data generated or analyzed during the study are available from the corresponding author by request.

Competing interests
 The authors have no relevant financial or non-financial interests to disclose. 

Funding

Study was funded by project No.   CA18118, IRENE COST Action funded by COST Association, by the IRIS-TEPUS and project No.  LTC20051 from the INTER-EXCELLENCE INTER-COST Program of the Ministry of Education, Youth and Sports of the Czech Republic, and by STROCZECH within CZECRIN Large Research Infrastructure No.  LM2018128 funded by the state budget of the Czech Republic.

Authors' contributions

All authors contributed to the study design and preparation. Data collection and analysis were performed by Martina Cviková, Iva Fojtová and Jan Vinklárek. The first draft of the manuscript was written by Martina Cviková and Robert Mikulík and all authors commented on all of the versions of the manuscript. All authors read and approved the final manuscript. 

Acknowledgements

We would like to kindly thank Irena Doležalová, MD for writing assistance and Petra Cimflová, MD for imaging review. 

Previous results presentations

The results of this study were presented by the first author in 2022 as an e-poster presentation at The European Stroke Organization Conference and 50. Český a slovenský cerebrovaskulární kongres (local Czech and Slovak cerebrovascular conference). E-poster presentation at 50. Český a slovenský cerebrovaskulární kongres included very brief 2-minute comment of purpose of the study and main results. Except these two e-poster presentations our results haven’t been published or presented elsewhere.

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