The spectrum of ischemic stroke

Stroke medicine has come a long way from the time the very first mechanical thrombectomy (MT) was done in 1994 (1). Yet, it took until 2015 for randomized controlled trials (RCTs) to definitively establish the safety and efficacy of MT over standard medical care (2). These earlier trials limited patient selection criteria to that of a small infarct core [defined by Alberta Stroke Program Early CT Score (ASPECTS) 6 to 10] with moderate-to-good collaterals and enrollment within 12 hours of symptom onset.

Further progress in clinical stroke research first studied extension of the traditional time windows with DAWN and DEFUSE-3 published in 2018 (3,4). These two still had strict criteria for size of the core (age-stratified up to 51 mL for DAWN and 70 mL for DEFUSE-3) and the requirement for clinical-core mismatch, which had significant influence on stroke management guidelines and by extension, on clinical practice.

The emergence of large core thrombectomy trials has further challenged the notion of rigid treatment boundaries and highlighted that patients with acute ischemic stroke exist along a multidimensional spectrum rather than within discrete categories. This continuum may be conceptualized across three principal domains: time from symptom onset, clinical severity [i.e., National Institutes of Health Stroke Scale (NIHSS)], and tissue status as defined by imaging biomarkers estimating perfusion mismatch, such as ASPECTS, CT perfusion or diffusion-weighted imaging-fluid-attenuated inversion recovery (DWI-FLAIR) characteristics. Rather than relying on binary eligibility criteria, clinical decision-making can be viewed as an assessment of the balance between expected treatment benefit and procedural risk across these interacting dimensions. At one end of the spectrum are patients with small infarct cores, severe deficits, and favorable imaging profiles, in whom benefit from reperfusion therapy is well established. At the other end are patients with extensive established infarction and limited salvageable tissue, where benefit is less certain. Between these extremes lies a substantial intermediate population, increasingly represented in contemporary trials, for whom treatment decisions are best informed by an integrated assessment of clinical, radiological, and temporal factors rather than single-threshold exclusions.

The study by Schlicht et al. (5), utilizing a large cohort of 5,448 patients from the German Stroke Registry-Endovascular Treatment (GSR-ET), allows us to see this full array of patients (with both high and low ASPECTS/mismatch) within a single study. It goes one step further by analyzing functional and mortality outcomes for different modified Treatment in Cerebral Infarction (mTICI) recanalization grades across the spectrum of clinical-core mismatch types. For instance, patients with NIHSS >16 and ASPECTS 10 derive the greatest benefit, with a 38-percentage point increase in the rate of good functional outcome [modified Rankin Scale (mRS) 0–2] compared to persistent occlusion. However, even with large infarct core, patients with NIHSS >16 have an 11-percentage point increase in functional independence with successful reperfusion and full recanalization reduces mortality by 21% compared to unsuccessful reperfusion. The authors also ensured that the study is more statistically robust with an inverse-probability-weighted regression adjustment to reduce confounding.

The results of this study are indeed reflective of prior trials, demonstrating while all patients may potentially benefit from intervention, those with greater clinical-core mismatch may benefit more. Furthermore, by stratifying outcomes based on recanalization grades, this study also delineated which subsets of patients benefited the most from improved recanalization. While mTICI 3 resulted in a 15-percentage point advantage in good functional outcome for high mismatch patients compared to mTICI 2b, there was no significant additional benefit for large core or low mismatch subgroups. This underscores the need to better identify and selectively pursue mTICI 3 only when risks of repeated attempts are outweighed, and mTICI 2b may be an adequate end result for large core or low mismatch subgroups.

Interestingly, successful reperfusion was associated with lower rates of symptomatic intracranial hemorrhage (sICH) (7.1% vs. 1.4%) and mortality across the board. One explanation for this counterintuitive finding is that stabilization of the blood-brain barrier once flow is restored, prevents the hemorrhagic transformation often seen in persistent occlusions.

A major point that draws attention is the large proportion of screened patients that were excluded due to missing variables or outcomes), only 30% of the entire registry of 18,069 patients were included which may skew the data, resulting in significant findings where these actually only exist in specific subgroups. As with many randomized clinical trials for stroke, preselecting candidates with a good premorbid mRS (usually 0–2) is normal practice, however this is a registry-based study, and stringent exclusion may not be necessary. In this study, the exclusion criteria of premorbid mRS >0 may bias selection towards those with a better chance for functional recovery and limit generalizability of the results to the heterogenous population encountered in clinical practice.

Another shortcoming is that the authors use the ASPECTS score of 0–7 to identify ‘large core’. This range is very wide, and MT outcomes for the lower half of the range (i.e., ASPECTS 0–4) would not be expected to be similar to that for the higher range of 5–7. If the proportion of patients in this group with a higher range of ASPECTS was greater, then this may have falsely ‘pulled up’ improvement in outcomes for the entire subgroup of ASPECTS 0–7. A more realistic reflection of outcomes for subsets of such ranges of ASPECTS scores is observed in the granular approach undertaken in the meta-analysis by Phan et al. (6). This meta-analysis compared thrombectomy outcomes of 3 ranges of ASPECTS scores (0–4, 5–7, and 8–10) with each subsequent range having better functional independence rates than the prior (90-day or discharge mRS ≤2 of 17%, 36% and 50% respectively). Caution is required when interpreting the benefits of MT for the lowest ASPECTS range as risks of intervention can potentially outweigh benefits and there is substantial heterogeneity even in the ASPECTS 3–7 group.

The other group of patients that is contentious in the context of MT is that of minor stroke, oft defined by a ‘low NIHSS’ clinically. The exact NIHSS cut-off for minor stroke that is used can have significant influence when assessing outcomes. Moreover, inconsistent NIHSS thresholds for minor stroke ranging ≤3 to ≤10 affect comparability of studies and interpretation of MT outcomes. Higher cut-offs (e.g., ≤10) may include moderate strokes, inflating perceived benefit, whereas stricter thresholds (≤5 or ≤6) may identify a smaller cohort with less clear advantage. In the study by Schlicht et al, the NIHSS cut off for ‘minor stroke’ was taken to be 10 and below, and while there was a small benefit of MT, even this could have been the result of the generous NIHSS threshold used to define ‘minor stroke’.

In contrast, a different study by Heitkamp et al. (7) which also used data from the GSR-ET registry, set NIHSS <6 as the cut-off for minor stroke. It found that at least a quarter of thrombectomy patients with minor stroke developed early neurological deterioration (as defined by an increase in NIHSS score of ≥4 within the first 24 hours after MT), and that these patients had twice the odds of experiencing unfavorable functional outcomes. Therefore, clinical decision-making should not only consider NIHSS but also deficit type, vessel occlusion, and risk of deterioration. A tiered approach—very minor [NIHSS 0–3], mild [4–6], and moderate [7–10]—may better reflect the clinical spectrum and guide individualized suitability for MT. This may better reflect the underlying nuanced stroke pathophysiology where a one-size-fits-all approach may not be appropriate.

While NIHSS and ASPECTS are practical surrogates for estimating a clinical-core mismatch, they remain imprecise. Early within the window, low ASPECTS may reflect penumbral tissue rather than true infarct core with reversible changes. Moreover, both ASPECTS and mTICI scores were reported locally by treating physicians rather than adjudicated by a blinded core lab. This introduces potential bias, as local scoring is prone to optimism and inter-rater variability. Consequently, the magnitude of benefit should be interpreted cautiously. Replication with core-lab adjudicated external datasets may reduce bias and thus improve reliability. Finally, it should be noted that most of the patients were treated in the <8 h window and these results may not be extrapolatable to the extended time window up to 24 hours.

Future directions

For stroke management to be truly a breakthrough, the treatment begins before the infarct becomes established. Hence strategies for the diagnosis and treatment of acute ischemic stroke must evolve to provide benefit to a greater population. Some such measures include pre-hospital imaging in the form of stroke ambulances to exclude hemorrhage so that bridging thrombolysis can be started in the ambulance, en-route to a tertiary center. Other stroke imaging techniques which can identify patients with the best outcomes coupled with other novel pre-hospital imaging may potentially drive us to offer a greater proportion of patient’s intervention whilst counselling of more individualized risks and outcomes.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Journal of Neurointervention. The article has undergone external peer review.

Peer Review File: Available at https://jni.amegroups.com/article/view/10.21037/jni-26-0016/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jni.amegroups.com/article/view/10.21037/jni-26-0016/coif). L.L.L.Y. serves as an unpaid editorial board member of Journal of Neurointervention from November 2024 to December 2026. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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