Time-to-Maximum of the Tissue Residue Function Improves Diagnostic Performance for Detecting Distal Vessel Occlusions on CT Angiography

DISCUSSION

The added value of Tmax maps on diagnostic performance for detecting DVOs on CTA was assessed in this study. Diagnostic accuracy, confidence, and speed were shown to improve significantly with addition of Tmax for readers with different levels of experience in interpreting stroke imaging. The beneficial effect of Tmax in aiding detection of DVOs on CTA was greater for more distal occlusions.

CTP is now widely included in the acute stroke CT protocol.¹⁴ Its primary purpose is to identify patients with proximal arterial occlusions with salvageable brain tissue who may, therefore, benefit from EVT. It also provides information about the macrovasculature that can be leveraged to improve detection of vessel occlusions.^11,19 Perfusion maps were shown to improve detection of intracranial arterial occlusions in 1 previous study that was not specifically designed to evaluate DVOs and included only a small number of these distal occlusions.¹¹ Another important point of distinction between this previous study and ours is that Tmax was not used in theirs.

Tmax was used in some EVT trials to identify salvageable ischemic penumbra and is now routinely available on most CTP-postprocessing software platforms.^16,17 It can also be used to assess early reperfusion with treatment.¹⁷ Tmax reflects the delay in contrast arrival in tissue relative to a proximal arterial reference point.^18,19 This arterial reference point is called the arterial input function and is an essential part of deconvolution-based perfusion analysis. An intracranial arterial occlusion prolongs arterial transit time and, therefore, Tmax within the territory that is supplied.¹⁹ TTP, another time-based parameter that has been used to assess penumbra, is also prolonged when there is delayed arterial transit.¹⁸ However, unlike Tmax, it is not obtained through deconvolution and is, therefore, not corrected for the shape of the contrast bolus. Thus, Tmax is less sensitive than TTP to bolus delay proximal to the arterial input function and is more specific for delays in arterial transit between the arterial input function and tissue caused by an occlusion.¹⁸ The distribution of Tmax delay can be used to narrow down the laterality, major territory, probable segment (eg, M2 versus M3), and likely location of an arterial occlusion. A more focused search can then be performed. The alternative of systematically interrogating all cerebral arteries to the most distal discernible level is very time-consuming and therefore not feasible under clinical time pressures. Clinical information regarding neurologic deficits narrows the search field but is not always available or reliable. Tmax maps are objective and consistently available when CTP is performed. To our knowledge, this is the first study evaluating the utility of Tmax for detecting intracranial arterial occlusions.

As hypothesized, diagnostic performance for detecting DVOs on CTA improved significantly with the use of Tmax. The effect size was sufficiently large to show significant improvement using a P value cutoff of .001, even with a sample size of 140, including 70 patients with a DVO. Because information on neurologic deficit was provided, the beneficial effect of Tmax was additive to any gain provided by clinical notes. Sensitivity for the detection of DVOs on CTA alone is likely lower, and improvement in performance with Tmax may, therefore, be even greater when reliable clinical information is unavailable.

Most important, fewer proximal M2 occlusions were missed. Patients with M2 occlusions are increasingly considered for EVT because it may improve their functional outcomes.^3,4 M2 occlusions are easily detected by experienced neuroradiologists but can be missed by trainees and general radiologists as shown in this study; 35% of M2 occlusions were missed on CTA evaluation in a previous study performed at a primary stroke center.¹³ Trainees interpret the bulk of CTAs performed at stroke referral centers, while these scans are typically interpreted by general radiologists at primary stroke centers. Improving detection of M2 occlusions by these less experienced readers is, therefore, of high clinical relevance, to ensure that patients do not miss out on potentially beneficial treatment.

The gain in sensitivity with the addition of Tmax and, therefore, the benefit were greater for more distal occlusions. Poor sensitivity for detecting M4 and distal ACA occlusions on CTA alone can be explained by the small caliber and large number of these vessels, making detection akin to finding a needle in a haystack, even with accurate clinical notes. Tmax maps narrowed the search field, increasing the chances of finding the culprit occlusion on CTA. Despite improvement in sensitivity, some distal anterior circulation occlusions were still missed by the readers. An occlusion is sometimes not clearly visible on CTA (due to the small caliber and poor opacification of the occluded artery), despite unequivocal territorial Tmax delay suggestive of a DVO. If an alternative cause cannot be found, it may be reasonable to diagnose a likely distal occlusion in these cases. The readers fared better in detecting distal PCA than MCA occlusions. This result may be due to the smaller spatial extent and less arborization of the PCA, compared with the MCA. Because sensitivity on CTA with Tmax was imperfect, it cannot be used to definitively exclude a DVO. Of note, sensitivity was not related to reader experience level. The scientist and the resident had the highest sensitivity, both with and without Tmax. A possible explanation is that these readers had a more methodical approach to reading the CTAs.

Specificity for detecting a DVO on CTA exceeded 95% with the addition of Tmax for all readers except the resident, which is important if the findings are used to guide treatment, to ensure that futile and potentially harmful reperfusion is avoided in patients without a DVO. Specificity was related to the level of experience in interpreting CTA and CTP; greater experience enabled the senior readers to differentiate between occlusions and poorly opacified distal vessels and to recognize and dismiss Tmax delay that did not conform to a vascular territory.

Interpretation of CTAs was significantly faster with the addition of Tmax. As expected, DVOs were detected faster due to the search field being narrowed, but occlusions were also dismissed more quickly. Faster diagnosis not only expedites treatment, it also improves workflow efficiency. The latter is important in clinical practice, particularly in the setting of busy comprehensive stroke centers. An important caveat in using Tmax to expedite interpretation is that readers must continue to methodically scrutinize CTAs for other, incidental findings and avoid succumbing to “streetlight effect.”

Diagnostic confidence in the presence or absence of a DVO on CTA increased for all readers with Tmax. One likely reason is that the Tmax maps provide additional evidence to corroborate or reject the findings on CTA alone; diagnostic confidence is greater when 2 separate tests indicate that an occlusion is either present or absent. Another factor that likely contributed to improvement in all metrics of diagnostic performance is that Tmax maps are easy to interpret. They have a high contrast-to-noise ratio. While CBF and CBV have substantial gray-white matter contrast, Tmax values do not vary with tissue type²⁰ and have rather flat contrast in the normal brain. Even small or subtle areas of Tmax delay, therefore, appear conspicuous and can be detected and characterized reliably and confidently. This feature, in turn, contributes to increased sensitivity when the findings on Tmax are used to guide the search for a DVO on CTA. Conversely, maps with no Tmax delay appear monochromatic, making it easy to interpret the absence of an abnormality and dismiss an occlusion with high certainty. While the findings of a DVO on CTA can be subtle due to the small caliber and poor opacification of distal vessels, the findings on Tmax are more apparent and therefore less prone to variable interpretation. Accordingly, the use of Tmax led to greater consistency of CTA interpretation, with higher interreader agreement.

An alternative method that has been reported to improve detection of DVOs is wavelet-transformed angiography (waveletCTA), which is also obtained by postprocessing of CTP data.²¹ Its clinical uptake has been limited by the requirement for thin-section CTP and specialist postprocessing software that is not widely available. In contrast, most CTP-postprocessing software packages are able to produce Tmax maps and can do so from thick-section CTP, making the use of Tmax feasible in routine clinical practice at even small peripheral centers.

An important limitation is that CTP is only recommended by the AHA guidelines in the late (6- to 24-hour) time window. Not all stroke centers routinely perform CTP in the early window because it incurs an additional radiation dose and its role in patients within 6 hours of stroke onset has not been established. However, because CTP has diagnostic utility beyond tissue classification, aiding the diagnosis of stroke and some stroke mimics such as migraine, and is therefore performed even in the early window at some centers, including ours.

A limitation of using Tmax maps to aid detection of DVOs on CTA is that nonterritorial Tmax delay can lead to false-positives and lower specificity. The experienced readers dismissed DVOs in these cases, suggesting that such errors can be avoided with training in the interpretation of Tmax maps, specifically to differentiate Tmax delay in a vascular territory from delays that either cross territories (eg, due to migraine) or are artifactual or “borderzone” in distribution. Borderzone Tmax delay occurs with contrast bolus dispersion, for example, due to a poor injection, proximal arterial steno-occlusive disease, and impaired cardiac output. It is manifested as Tmax delay in arterial watershed areas.^18,19 CTP acquisition with limited brain coverage is a potential cause of false-negatives if the territory supplied by the occluded vessel is not included. This situation is avoided with a whole-brain CTP acquisition on modern multidetector array CT scanners.¹¹ When only limited coverage is feasible, targeting the CTP acquisition to the clinical presentation (eg, posterior circulation) can avoid false-negatives.

A limitation of the study is that only 1 CT scanner and CTP postprocessing software package were used. This may limit the generalizability of the findings. The algorithms used by different postprocessing software packages are variable and most, but not all, use deconvolution-based postprocessing, a requirement for obtaining Tmax.²² There are also substantial differences in the derived perfusion parameters, even between packages that use deconvolution-based postprocessing, resulting in variability in quantification of the infarct core and penumbra.^22,23 The variability is less likely to affect qualitative assessment; however, differences in the display of parametric maps (eg, color scale) may impact visual assessment. In turn, these may affect diagnostic performance for the detection of territorial Tmax delay, which warrants further evaluation in a future study.

A potential limitation of the study is that the prevalence of DVOs in the study cohort (50%) was higher than in the population of patients with stroke who undergo multimodal CT. The true prevalence of DVOs is much lower and likely closer to the 14% observed in the cohort screened for the study. Use of a balanced sample may bias the absolute sensitivity and specificity for detecting a DVOs on CTA, both with and without Tmax. These values should, therefore, be interpreted with caution. However, the primary purpose of this study was to assess the relative change in diagnostic performance for detecting DVOs on CTA when Tmax was added, rather than absolute diagnostic performance.

Another potential limitation of the study is the choice of the reference standard: an expert read of the CTAs instead of DSA, which is the reference standard for detecting intracranial vascular pathology. Using CTA was justified because DVOs can recanalize or migrate between angiographic modalities, especially when thrombolysis is administered, which would render DSA inaccurate as a reference standard. The authors recognize that some very distal DVOs may have been missed by all readers, including the expert reader. This possibility would affect the determination of absolute accuracy. It is, however, less relevant for comparative assessment of the diagnostic performance on CTA with and without Tmax, which was the purpose of this study.