The usefulness of a definition of a condition in clinical medicine depends on whether it informs clinicians and patients by reliably identifying groups with a specific prognosis or requirement for treatment. In this study, tissue-positive TIA corresponded to stroke with rapid and complete recovery according to the ASA definition. Our findings support the concept of this tissue-based definition of TIA and stroke and show that DWI is superior to CT on prognostic grounds.
The substantial difference in outcome between these groups is clinically relevant and should influence management decisions involving the urgency of treatment such as triage and admission to the hospital. For DWI cohorts, a 7-day stroke risk of 7.1% in tissue-positive events probably necessitates hospital admission or at least some other form of emergency investigation and treatment, whereas a stroke rate of 0.4% at 7 days could represent a low enough risk for patients to be managed safely on an outpatient basis. This difference in outcome could also be exploited in the efficient design of clinical trials of secondary prevention by identifying subjects with a potential for higher rates of outcome events, thereby reducing the total numbers needed to recruit. Recent guidelines highlight the importance of management in specialist neurovascular units offering urgent treatment and investigations.4–6
Interestingly, when cohorts from these units only are considered,24–28
the observed rate of stroke at 7 days was 1.9%, consistent with the benefits of urgent treatment observed in the EXPRESS and SOS-TIA studies.25,29
Of the 3,206 patients who underwent DWI, 884 (27.6%) were tissue-positive and 2,322 (72.4%) were tissue-negative. Rates of recurrent stroke at 7 days in these groups were 7.1% vs 0.4%, respectively, an 18-fold difference. In acute coronary syndromes (ACSs), troponin levels are considered to generate prognostic information by distinguishing between tissue-positive and tissue-negative events. However, in patients with non-ST elevation ACS, rates of recurrent myocardial infarction or death are 2- to 5-fold different in those with elevated vs normal levels of troponin.30,31
Moreover, studies of ACS have tended to use longer periods of follow-up and varying definitions of reinfarction, which may exaggerate differences in observed rates. This comparison with ACS underlines the predictive power and clinical usefulness of infarction on DWI.
Although DWI was developed more than 20 years ago,32
its technology continues to advance. Improvements in magnetic field strength and spatial resolution with reductions in scan slice thickness are likely to improve sensitivity for infarction.33
Compared with follow-up brain imaging, the false-negative rate for DWI is appreciable, with poorer detection of lacunar infarcts in the brainstem and internal capsule areas.34
If the small group of patients without infarction on DWI who had early strokes represents those with false-negative imaging, then prognostication is likely to improve as DWI becomes more sensitive. Moreover, our study used a blunt definition of the presence of any acute infarct, whether correlating or inappropriate to the presenting symptoms, which may have diminished prognostic power. Similarly, we did not distinguish some other factors that may have yielded further prognostic information such as vascular territory, region (cortical vs subcortical), age, or multiplicity of infarcts.35
Studies of the prognostic yield of plain CT scanning after TIA have yielded conflicting results. However, studies have tended to recruit subjects in the subacute phase, reported longer-term vascular outcomes and survival, and analyzed other imaging abnormalities such as leukoaraiosis in addition to infarction.36
To our knowledge, there have only been 2 published studies in the acute phase of TIA specifically addressing the predictive power of infarction on CT imaging for early stroke recurrence.19,20
Both reported a significantly higher rate of recurrent stroke in tissue-positive cases. Although we used a pragmatic definition of acute or old infarction in the current study because of the uncertainty in reliably determining infarct age on CT, those with tissue-positive and tissue-negative events were still found to have different outcomes (recurrent stroke rate at 7 days of 12.8% vs 3.0%). CT is less sensitive for acute ischemia than DWI, but infarction on CT could be a marker of particular stroke etiologies such as large artery disease or cardioembolic stroke, possibly explaining predictive value in the acute phase. Alternatively, (silent) infarction on CT is a marker for vascular disease elsewhere or other vascular risk factors,36
but this association is more likely to explain outcomes in the longer term. We did not find a significant difference in predictive power of CT as measured by AUC in the 0–7 vs 8–90 day periods, although our sample was not powered to detect such a difference.
In addition to reduced sensitivity for ischemia, CT also has the drawback of radiation exposure and therefore is not recommended for TIA when MRI is available and not contraindicated. However, our results show that, when MRI is unavailable, contraindicated, or not tolerated, CT can yield useful prognostic information. Further prognostication may be possible using newer CT techniques such as CT angiography and perfusion, but their role is currently uncertain.
Although the presence of infarction is the major determinant of early stroke, we have found that the ABCD2 score has predictive value in the acute phase in both tissue-positive and tissue-negative patients, identifying individuals at higher and lower risk within both these groups. Some authors have claimed that the predictive power of the ABCD2 score is explained mainly by its diagnostic function, by discriminating between those with genuine TIA at high risk of further vascular events and other non-neurovascular diagnoses. The score has been found to distinguish between these groups. 37,38
However, the finding that the ABCD2 score is predictive in TIA patients with infarction shows that the score cannot work by diagnostic discrimination alone. We argue that the score remains clinically useful, particularly when applied to tissue-positive patients. In those with DWI tissue-positive events, the observed 7-day stroke rate was 7.1% overall but was 1.8%, 7.5%, and 12.5% in those with ABCD2 scores of 0–3, 4–5, and 6–7, respectively (ABCD2 cutpoints commonly used to identify low-, intermediate-, and high-risk groups) (). A similar degree of risk stratification was observed in those with CT tissue-positive events.
also shows that recurrent stroke rates are comparable in tissue-negative events with high ABCD2 scores and tissue-positive events with low ABCD2 scores. Indeed we found overlaps in stroke rates in tissue-negative events with high clinical risk scores and tissue-positive events with low clinical risk scores at both 7 and 90 days in CT cohorts and at 90 days in DWI cohorts. These findings show that transient neurologic events represent a continuous spectrum of risk and support the use of a combined approach to prognostication, using both clinical and imaging information.7,8
The association between infarction and risk in the longer term has not been addressed in large studies.
Although we believe our findings are valid, we acknowledge some shortcomings. There was a considerable difference in outcomes observed between cohorts using DWI compared with those using CT. Outcomes in observational studies of TIA depend on the health care setting because of treatment effect and referral bias.1
CT tended to be used in ED- and population-based cohorts, and DWI was used in cohorts from specialist units, so it is likely that the difference in observed stroke rates between CT and DWI cohorts is partly explained by study methodology. If our results are to be generalized, they should be calibrated according to the health care setting. Scans were interpreted by individual centers, and there was no central adjudication, potentially leading to less reliability in interpretation but reflecting clinical reality. Our findings are based on patients with time-defined TIA, who, by definition, had transient symptoms that resolved within 24 hours. Although we have subcategorized these as tissue-positive and tissue-negative, our findings cannot be generalized to all tissue-defined stroke. Among those with a neurologic deficit lasting longer than 24 hours, the risk of subsequent stroke varies, with particularly high risk, comparable to that of time-defined TIA, observed in those with nondisabling symptoms and lower risk in those with major or disabling deficits.39,40
It has been proposed that a new syndrome—transient symptoms with infarction—should be recognized because of the differing prognosis between those with transient symptoms with and without infarction and those with a permanent deficit.15
In conclusion, we have found that subcategorization of patients with TIA as defined by time-based criteria into tissue-positive and tissue-negative groups yields helpful prognostic information, especially when brain infarction is found on DWI. The ABCD2 score further refines risk in both tissue-positive and tissue-negative groups.