Clinical Stroke Penumbra: Use of National Institutes of Health Stroke Scale as a Surrogate for CT Perfusion in Patient Triage for Intra-Arterial Middle Cerebral Artery Stroke Therapy

Discussion

The goal of revascularization therapy in acute MCA occlusion is timely flow restoration to salvageable brain. Historically, time from symptom onset has been a surrogate marker of tissue viability. Pre-IAT imaging is aimed at identifying patients with substantial tissue at risk and smaller areas of irreversible core infarct. Major IV-tPA^2,13 and IAT^3,4 trials have used only NCCT before intervention. To justify routine use of CTP (with associated increased iodinated contrast and radiation dose as well as increased imaging time and cost) for IAT triage, differences in decision making or improvements in outcome must be demonstrated. Two central premises underlie our study. The first is that NIHSS, combined with the site of arterial occlusion on CTA, provides adequate estimation of infarct core plus penumbra, while providing an anatomic guide for lesion accessibility. The second is that patients in whom revascularization is unlikely to help and could potentially be detrimental (ie, from hemorrhage) can be identified by using NCCT.

Among the standard CTP parameters, MTT is elevated in both penumbra and infarct core, whereas CBV is typically diminished only in the infarct core.⁶ Thus, MTT-CBV mismatch is commonly thought to reflect the ischemic penumbra. Because penumbra represents nonfunctioning ischemic brain, an alternative estimate for infarct core plus penumbra would involve a combination of clinical examination (NIHSS) and a proximal arterial occlusion on CTA. There is significant correlation between admission NIHSS score and the site of arterial occlusion,^11,12,14 with patients with NIHSS scores ≥12 likely having a proximal MCA occlusion and corresponding ischemia. There is also a strong correlation between NIHSS score and MR PWI lesion volume.^15,16 We, therefore, believe that a large clinical deficit (NIHSS score ≥8) in conjunction with a proximal arterial occlusion on CTA allows estimation of total infarct core plus penumbra, obtainable without CTP. The use of clinical examination alone has been previously evaluated as the “clinical diffusion mismatch,” which initially showed promise but has more recently not been shown to correlate as well as PWI.^15⇓–17 Most interesting, when MRA-DWI mismatch has been evaluated, it does appear to be predictive of patients improving with recanalization.¹⁸ We, therefore, believe that the combination of NIHSS and vascular status provides a robust justifiable estimation for the presence of large territories of tissue at risk.

Other reasons to use CTP might be to potentially reduce the risk of intracerebral hemorrhage, especially parenchymal hematoma type 2,¹⁹ and to prognosticate clinical outcome; however, studies suggest that NCCT may be sufficient. Trials of IV-tPA²⁰ and IAT²¹ demonstrated increased risk of hemorrhage when more than one-third of the MCA territory had hypoattenuation on NCCT. Similar thresholds by using ASPECTS have been demonstrated for both IV-tPA and IAT, with ASPECTS ≤7 having worse outcomes²² and patients with ASPECTS >7 receiving IAT in the PROACT trial 3 times more likely to have independent functional outcome.²³ Good correlation between CBV and NCCT has been demonstrated, with NCCT ASPECTS ≤7 and CBV ASPECTS ≤8 predicting poor outcome.²⁴ Patients with ASPECTS >7 are also most likely to benefit from combined IV-tPA and IAT,²⁵ and ASPECTS <7 has been shown to provide a conclusive estimate of more than one-third of the MCA territory infarction.²⁶ Further estimation of infarct core was available in our study by using CTA source images, which have been shown to approximate CBV and final infarct volume under certain conditions.^9,10

Our results show very high correlation (κ = 0.83) for IAT recommendation by using our IAT inclusion criteria between a reader group using CTP and another relying on NCCT, CTA source images, and NIHSS for infarct core and penumbra determination. Unblinding the latter group to CTP did not significantly alter intergroup κ; this finding suggests that CTP may not contribute to the IAT triage algorithm in a substantive manner. One caveat is that while CTA source images have approximated CBV and final infarct volume in the past,^9,10 the advent of faster 64-, 256-, and 320-detector scanners has rendered these images more CBF-weighted and less CBV-weighted,^27,28 which could potentially limit their use as a surrogate for infarct core on CBV maps. We think, however, that use of NCCT ASPECTS (with a threshold value of 7) may alleviate this potential problem in identifying patients not likely to benefit from IAT.²⁶

Scanners providing varying degrees of MCA territory coverage on CTP were used in this study, raising the question of whether scanner differences affected intra- and intergroup agreement and IAT recommendations. Somatom 16 examinations were performed with two 12-mm slabs covering 2.4 cm, without coverage of the entire MCA territory, theoretically rendering it more difficult to estimate the one-third MCA rule, compared with the LightSpeed scans using eight 5-mm sections covering 4.0 cm (Qx/I 16) and sixteen 5-mm sections covering 8.0 cm (VCT 64). Of the 8 intragroup discrepancies in the CTP group (5 for infarct core, 3 for penumbra), 5 were obtained on a GE Healthcare scanner with the greater degree of volume coverage, implying that limited volume coverage does not impact the variability of core or penumbra estimation.^29,30 Potential secondary benefits of our hybrid CT resources were that by blending patient studies, we reduced bias resulting from manufacturer-specific CTP calculation algorithms and simulated the cross-section of CTP methodologies in the community.

It is worth considering whether the high intergroup κ is due to a predominance of inaccessible lesions or large infarct cores, which would render CTP-based penumbra estimation moot. In our patient series, there were 8 inaccessible lesions; for the 28 patients with accessible lesions, the intergroup κ for IAT triage is still 0.78 (SE, 0.12) and the McNemar test is unchanged. There were 10 cases with accessible lesions and intergroup consensus of infarct core of more than one-third of the MCA territory; infarct core was disputed in 1 case, leaving 17 cases in which both groups agreed that penumbra estimation would affect IAT triage. There were 2 discrepant penumbra estimations in these 17 cases. Assuming that CTP yields the “correct” estimation of penumbra, one would predict a 2/17 (12%) chance of selecting the “wrong” treatment plan on the basis of CTA and NIHSS in patients with accessible lesions and small infarct cores. In actuality, these 2 patients did not receive IAT. In 1 case rated “treat” by the stroke scale group and “no treat” by the CTP group (Fig 5), the follow-up infarct on CT 17 days after CTP matched the CBV core with no appreciable infarct extension. In the other case rated “treat” by the stroke scale group and “no treat” by the CTP group (Fig 4), the follow-up infarct on CT approximately 1 year after CTP demonstrated extension to the midanterior right temporal lobe, and it is unclear whether this represented infarct progression or a new interval infarct. In the case in which infarct core size was disputed (Fig 2), the patient did not receive IAT in actuality, and no follow-up imaging was available. How the risk of selecting the “wrong” treatment plan by omitting CTP compares with the benefit of cost-savings (radiation dose, administered contrast material) is a matter of debate. A compromise protocol might be to only perform CTP in those cases with an accessible lesion and small infarct core, which occurred in 17/36 (47%) of our cases.

There is no consensus within the stroke imaging community on the ideal IAT selection criteria, and this remains an area of active investigation; we chose common published criteria used for clinical trials summarized in Mishra et al.³¹ The optimal CTP postprocessing algorithms for defining infarct core and ischemic penumbra have yet to be determined.³² In fact, the paradigm of CBV-CBF mismatch as the optimal measure of penumbra has been challenged, and collateral vessels rather than core/penumbra mismatch may be a superior overall predictor of clinical outcome.³³ Our study could be extended to compare NIHSS with other CTP parameters and thresholds. CTP acquisition, reconstruction, and postprocessing are highly variable and vendor-dependent.^34,35 We used different scanners from different vendors in this study, which introduces variability; it is possible that a particular stroke may satisfy penumbra criteria on 1 scanner but not another. We used subjective rather than quantitative analysis of core size and penumbra extent. Although this potentially introduces error for any given IAT criteria threshold, it may better match the general “real-time” approach used in the community without time-consuming postprocessing.

Our study was not designed to address the controversial question of whether CTP-generated CBV accurately reflects infarct core analogous to DWI or whether CTP mismatch correctly depicts penumbra. For instance, there is evidence that DWI infarct core may have high, low, or normal CBV depending on infarct age.³⁶ We acknowledge that CTP is not necessarily a criterion standard facilitating “correct” IAT triage with which the stroke scale group's decision should be compared. Our objective was to determine whether triage decisions with and without the use of CTP are analogous, with our hypothesis being that CTP does not significantly alter the triage decision that would have been made by using NIHSS without CTP. We conclude that this is true in most cases, regardless of whether it is the “right” decision or not.

The main limitations of our study are its retrospective nature, small sample size, and possible lack of applicability to other acute stroke-management programs. Neuroradiologists reviewed all of our studies, whereas general radiologists or neurologists might review most acute stroke imaging nationwide. An additional limitation is the lack of a criterion standard for outcomes because it is not possible to compare infarct progression, hemorrhage, and clinical status for both “treat” and “no treat” states in each patient. Furthermore, DWI is generally thought to be the best imaging measure of infarct core and may therefore provide additional benefit in triaging IAT candidates; the applicability of our results to MR PWI is unknown, but DWI, MRA, and NIHSS, without PWI, may be analogously sufficient for IAT decision making using MR imaging.¹⁸ Although this presents less of a contrast agent and radiation issue, it would still offer a reduction in imaging time. We think that our focus on CT is important because CT is prevalent in community emergency departments, and there is increasing concern about radiation exposure. Nonetheless, an MR imaging analog of our study could be performed by comparing DWI/MRA with MR PWI and DWI/MRA with NIHSS.