TIA, when using the tissue-based definition, should be thought of as an extremely low-risk condition. According to a recent pooled analysis of 4574 patients with conventionally-defined TIA from 12 centers9
, the 7-day risk of stroke after a “TIA with no infarction” is 0.4%. In contrast, TSI (that is, TIA with infarction) is a high-risk condition; the 7-day risk of stroke ranges from 4% and 16%5-8
. In settings where brain imaging is available and feasible, the fundamental question is, therefore, no longer about whether a patient with a traditionally-defined TIA will develop a subsequent stroke, but rather, the question is which patient with TSI is at imminent risk of developing a stroke. Our results indicate that the RRE criteria segregate the TSI population into different risk groups with a high degree of predictive power (AUC=0.85). Using RRE, approximately two thirds of patients with TSI can be classified as low risk (risk ≤ 1%, score ≤ 2) and one third as high risk (risk > 18%, score >2). The implication of these findings for the practitioner is that the RRE tool can allow determination of who is at high short-term risk and therefore may need very urgent intervention.
Recent studies have shown that the risk of early recurrence after minor stroke is relatively comparable to the risk after TSI14, 15
. One could, thus, retain the prognostic information in TSI by adjusting the current tissue-based definition to accommodate for prognostically different categories (such as defining a separate minor stroke category). Nevertheless, we suspect that such an approach would not be practical and may even cause confusion because prognostic categories in stroke are many (minor vs. moderate vs. major stroke, small vs. large infarct, single vs. multiple infarcts, etc.) and most are definition dependent; at least 4 different definitions have been used in the literature to describe minor stroke (NIHSS score ≤1, ≤3, ≤5, and ≤9)16, 17
. Here, we offer an alternative approach: a simple score that can be universally applied to anyone with “ischemic stroke” as defined by the tissue-based definition to identify prognostically similar subsets. After one internal and one independent validation10
, this is another validation of RRE for a new application in a different population. The score has been previously shown to reliably predict short-term risk (14-day risk) of recurrence in patients with ischemic stroke per the conventional definition. The present study shows that RRE can also predict short-term risk (7-day risk) of stroke after a TSI (which is now called stroke per the tissue-based definition). Hence, if further validated for 7 and 14 day risk prediction, RRE could be applied to any patient with clinically relevant brain infarction, regardless of whether neurological symptoms are transient or persistent, to identify individuals at risk of early recurrence. By this way, RRE may complement the tissue-based definition by providing a prognostic component to it.
In contrast to RRE, the ABCD2
score reveals little predictive value in patients with TSI; the point estimate of AUC (0.57) was not different from predictions based on chance alone although a modest predictive value could not be excluded (95% CI, 0.45–0.69). The ABCD2
score appears to predict stroke risk partly because of its ability to discriminate between a true TIA and a suspected TIA with eventual diagnosis of a non-vascular TIA-mimic18-20
. The predictive value of the ABCD2
score shows marked variation among studies with different methods of patient selection and case-mix (true and suspected TIA)9,21
. In contrast to the general TIA population, TSI represents a fairly homogenous subset consisting of definite cerebral infarctions. The prognostic value of a score in this homogenous group in large part relies on its ability to account for the underlying stroke mechanism3
. All individual components of RRE directly relate to the underlying stroke mechanism. Etiologic stroke subtype itself is a predictor in RRE. Imaging predictors such as location, age, and number of infarcts and their spatial relationship with respect to each other provide information on whether the underlying stroke mechanism is unstable with potential to cause another stroke10
. Other predictors such as “recent history of TIA/stroke” and “multiple infarcts of different ages” further add to the system’s ability to mark an unstable etiology by providing the continuity information.
The complexity of stroke and current nomenclature require one additional clarification. Pragmatic definition of recurrent stroke includes any clinical incident that is associated with a new ischemic lesion spatially distinct from the initial infarct. While in general this is straightforward, the special case of “stuttering lacunar infarction” causes some pause. In stuttering lacunar infarction, patients present with a cluster of repetitive, stereotypic, and short lasting events -- which sometimes might be thought of as TIAs -- and then subsequently develop a permanent deficit with no imaging evidence of a spatially distinct new lesion beyond the initial index lacunar infarct. This special case, then, consists of a TSI patient developing a subsequent clinical stroke without a new, spatially distinct infarct. The dissociation between the changing clinical symptoms and the stable imaging findings is important, and we propose the terminology, “lacunar infarct paradox,” to clarify this dissociation. Also, we point out that the RRE criteria should not be applied in this special case.
This study has several limitations. First, 7-day follow-up information was not available in approximately 15% of patients. Missing follow-up data, however, would not be expected to significantly alter the predictive performance of RRE unless patients with incomplete follow-up more often developed a recurrent stroke (hence they had lower RRE scores). It is unlikely that the stroke rate was higher in the cohort with missing follow-up information because, in our practice, the primary neurologist taking care of TIA is often notified in an event of stroke occurring within days of TIA and the data collection methods would have captured this. Second, the number of outcome events was small for reliable validation of a prognostic score and therefore limited the power of the predictive model22
. The 95% confidence intervals around the point estimate for AUC were large. Nevertheless, the lower confidence limit was still well above the threshold set for random prediction. Moreover, the predictive performance of RRE in this dataset was comparable to those in prior validation and derivation datasets, suggesting that the current estimate for AUC reflects the true predictive capacity of the RRE score. Third, although it is recommended that MRI as the method of imaging in TIA1
, approximately 5-10% of patients cannot be scanned because of contraindications and this may limits widespread applicability of RRE. While the RRE requires an imaging study but the ABCD2
score does not, the improved performance and widespread use of MRI in the evaluation of stroke reduce this concern for most practice settings. We note that current guidelines for the management for TIA already recognize the helpful role of imaging, and specifically state, “MRI…can help to determine which TIA patients to admit to hospital and it may help in identifying patients to treat with more aggressive therapies”1
. Our current data support this recommendation and demonstrate the added value of imaging beyond the ABCD2
score in identifying patients for the most aggressive treatment. Finally, the predictive performance of RRE may be different in clinical settings where patient profile, and type and timing of preventive stroke treatments substantially differ from that is reported in this study. Therefore, further validation is critical for the generalizability of our results.
Our findings offer utility in clinical management of TSI. The major concept behind using prognostic tools in medicine is to identify individuals who are at risk of developing a potentially avoidable adverse event. Prognostic information becomes more critical if future events are prevalent and occur soon after the index disease so that acute care at specialized centers can be organized on an individual basis. TSI is an ideal condition for prognostic risk evaluation because the risk of subsequent stroke is high and imminent. The RRE score may allow physicians to identify high risk patients who benefit most from timely identification of the underlying etiology, early institution of specific preventive treatment such as carotid endarterectomy, and care at specialized centers where timely administration of acute treatments in the event of a subsequent stroke is possible23