For anterior circulation subtypes, the primary challenge in clinical IVT lies in accurately identifying the ischemic penumbra when the time of onset is unclear (e.g., wake-up strokes) or exceeds standard windows. While the OCSP classification rapidly indicates the anatomical territory of vascular involvement, it lacks the capacity to precisely quantify clinical severity or definitive infarct volume. Consequently, integrating OCSP classification with the NIHSS score and neuroimaging becomes pivotal for optimizing IVT strategies.

To overcome the limitations of isolated clinical assessment, Dávalos et al. (13) pioneered the concept of “clinical-diffusion mismatch” (CDM), thereby establishing a critical link between clinical symptomatology and histopathological status. Prosser et al. (14) further validated the correlation between CDM and perfusion-diffusion (PWI-DWI) mismatch. This retrospective study demonstrated that, following the exclusion of posterior circulation strokes, the presence of a severe anterior circulation deficit (NIHSS ≥8) alongside a restricted ischemic core on diffusion-weighted imaging (DWI volume <25 ml) predicts the existence of the ischemic penumbra with high specificity. Effectively, this approach utilizes the NIHSS to complement the OCSP classification, leveraging the discrepancy between clinical severity and tissue necrosis volume to precisely target salvageable brain tissue.

Considering the accessibility and time constraints associated with advanced imaging, Wu et al. (15) retrospectively validated the feasibility of a CT-based screening strategy. Their study revealed that for anterior circulation stroke patients with an NIHSS ≥8, a high Alberta Stroke Program Early CT Score (ASPECTS ≥9)—indicating minimal early ischemic changes on CT—suggests that the core infarct has not yet extensively formed despite severe clinical symptoms. Patients exhibiting this “clinical-CT mismatch” demonstrated superior functional recovery following IVT. Recent meta-analyses have further corroborated the safety of this assessment strategy: in populations with wake-up strokes or unknown onset times, IVT administration following screening via CT (to exclude large infarcts) combined with clinical assessment did not increase the risk of symptomatic intracranial hemorrhage (sICH) and significantly improved functional outcomes (16).

In summary, for TACI and PACI subtypes, the OCSP classification should not be regarded as a solitary decision-making endpoint but rather as an anatomical anchor for clinical assessment. By integrating it with NIHSS scoring and neuroimaging, clinicians can more precisely delineate the “tissue window,” thereby expanding the population benefiting from reperfusion therapy without compromising safety. However, it is crucial to acknowledge that while current evidence is promising, it predominantly stems from retrospective analyses; consequently, further validation through prospective trials remains necessary.

Decision-making regarding IVT for posterior circulation infarction presents significantly greater challenges than for anterior circulation strokes. This complexity stems primarily from the higher ischemic tolerance of the posterior circulation territory and its intricate clinical presentation. Notably, studies indicate that even diffusion-weighted imaging (DWI)—the most sensitive MRI sequence for detecting acute cerebral infarction—retains a substantial false-negative rate in the context of POCI (17, 18). This limited radiological sensitivity, compounded by non-specific clinical manifestations such as vertigo and ataxia, frequently prolongs clinical assessment and delays diagnosis.

Data from a meta-analysis highlight the clinical repercussions of this dilemma: only 5%−19% of patients with POCI receive IVT, a shortfall largely attributable to diagnostic delays that push patients beyond the standard therapeutic time window (19). However, evolving therapeutic paradigms have challenged strict time constraints. A recent RCT demonstrated that IVT confers significant clinical benefit in patients with mild POCI presenting 4.5–24 h after onset, provided they have no contraindications and a pc-ASPECTS of ≥7 (20). This finding establishes an evidentiary basis for extending thrombolysis in the posterior circulation using a tissue-window approach.

Nevertheless, limitations remain regarding patient selection, which relied on the NIHSS. Originally designed with a bias toward anterior circulation symptoms, the NIHSS assigns insufficient weight to posterior circulation signs, such as disequilibrium and diplopia. To address this deficiency and enhance early recognition, researchers have proposed novel assessment scales incorporating specific posterior circulation indicators, aiming to more precisely quantify the clinical characteristics of POCI (21, 22). Moving forward, the validation and implementation of these specialized scales will be pivotal for identifying candidates suitable for thrombolysis and enhancing reperfusion rates in the posterior circulation.

Clinical decision-making regarding the lacunar infarction (LACI) subtype has long been confounded by the significant heterogeneity of its pathogenesis. This subtype may stem from intrinsic small vessel pathologies, such as lipohyalinosis, or be driven by non-small vessel mechanisms, including microembolism (7). Historically, this pathophysiological uncertainty prompted skepticism regarding the rationale for IVT; concerns centered on the premise that isolated structural lesions of the small vessel wall might not benefit from thrombolysis and could, conversely, increase the risk of hemorrhage.

However, accumulating evidence has since redressed this theoretical misconception. Multiple large-scale clinical trials and registry analyses have substantiated that, despite mechanistic complexity, IVT remains a highly effective therapeutic intervention for LACI patients, offering significant improvements in functional outcomes. Current academic consensus attributes this efficacy primarily to two mechanisms: (1) a substantial proportion of patients presenting with LACI syndrome may actually harbor etiologies involving micro-emboli of cardioembolic or arterio-arterial origin, for which thrombolytic therapy effectively promotes vascular recanalization. (2) Beyond direct thrombolysis, t-PA may exert pleiotropic neuroprotective effects, including improving microcirculatory perfusion within the ischemic penumbra, suppressing local inflammatory responses, and mitigating neuronal injury (23, 24).

Consequently, future research should no longer be confined to validating the efficacy of IVT in LACI. Instead, the focus must shift toward a deeper dissection of LACI pathogenesis, thereby providing more precise guidance for clinical IVT administration.

For anterior circulation stroke, the paramount clinical priority is the rapid identification of patients with LVO who are candidates for EVT. Evidence suggests that patients presenting with TACI and PACI phenotypes are highly correlated with MCA occlusion—a condition where mechanical thrombectomy yields superior prognostic outcomes. A retrospective study by Xu et al. demonstrated that within 4.5 h of symptom onset, a predictive accuracy of 94.1% for anterior circulation LVO can be achieved by combining the TACI classification with an ASPECTS ≥6 and an NIHSS ≥8 (28).

This implies that in primary stroke centers lacking multimodal CT capabilities, OCSP classification can serve as a reliable trigger for initiating patient transfer protocols. In the screening of anterior circulation stroke patients within the late time window (6–24 h), trials such as DEFUSE-3 have established the pivotal role of perfusion imaging in assessing the ischemic penumbra. However, the “clinically approximated hypoperfused tissue” (CAT) model proposed by Desai et al. offers a streamlined assessment pathway that obviates the need for advanced perfusion imaging. This study demonstrated that integrating the NIHSS with the ASPECTS allows for a straightforward estimation of hypoperfused tissue volume defined by Tmax >6 s. When compared to the DEFUSE-3 cohort, this approach achieved a sensitivity of 100% and a specificity of 92%, indicating that eligible candidates for EVT are virtually never overlooked (29).

Post-hoc analyses of two RCTs, DEVT, and RESCUE-BT, provide further corroboration: for patients with anterior circulation LVO, irrespective of the time window, clinical outcomes guided by basic imaging were not statistically distinguishable from those guided by advanced perfusion imaging (30). Collectively, these findings underscore the clinical efficacy of combining OCSP-based clinical assessment with basic neuroimaging for the efficient stratification of patients likely to benefit from EVT, although validation through further prospective RCTs remains necessary.

Decision-making regarding EVT for posterior circulation large vessel occlusion has long been plagued by uncertainty regarding its efficacy. Early landmark randomized controlled trials—specifically the BEST and BASICS studies—failed to demonstrate a significant benefit of EVT over medical management. This was largely because their inclusion criteria did not strictly limit infarct core volume, leading to the recruitment of patients with established, irreversible neuronal injury (31, 32). These setbacks underscored a critical clinical reality: reliance on rigid time windows, without a precise assessment of tissue pathophysiological status, is a primary driver of treatment futility.

A turning point in clinical screening strategies emerged with the introduction of semi-quantitative imaging metrics, such as the pc-ASPECTS and the Pons-midbrain index (33, 34). Leveraging these tools to optimize patient selection, the BAOCHE and ATTENTION trials successfully established a clear benefit for EVT in patients with vertebrobasilar artery occlusion within 24 h of onset (35, 36). This paradigm shift provides compelling evidence that, for the POCI subtype, a precision screening strategy based on the “tissue window” is significantly superior to one based solely on the “time window.”

Currently, the boundaries of therapeutic exploration are extending into the ultra-late window beyond 24 h. Multicenter observational data indicate that patients presenting with severe symptoms but small infarct cores may still derive prognostic benefit from EVT beyond the 24-h mark (37). Conversely, for patients with mild symptoms, indiscriminate intervention has not yielded significant clinical gain (38). In conclusion, therapeutic decision-making for POCI must transcend mechanical temporal limits, shifting instead toward an assessment centered on the interplay between clinical severity and infarct core volume to precisely identify beneficiaries within this complex pathology.

In the era of EVT, the LACI subtype presents a unique clinical dilemma: how should clinicians manage patients presenting with mild symptoms despite the presence of a LVO? While LACI is traditionally attributed to small vessel pathology, emerging evidence reveals that a substantial proportion of these patients harbor an underlying LVO (39). This finding mandates a re-evaluation of therapeutic strategies for these so-called “minor strokes.”

Currently, large-scale RCTs defining the optimal reperfusion strategy for this specific cohort are lacking; support for aggressive intervention is primarily driven by concerns regarding the natural history of the condition. Kim et al. (40) identified LVO as an independent risk factor for early neurological deterioration, suggesting that the potential risk of hemodynamic decompensation in LACI patients with concomitant LVO should not be underestimated.

While some studies indicate that carefully selected patients with low NIHSS scores and LVO derive significant functional benefit from EVT (41, 42), others comparing EVT with intravenous thrombolysis report no significant difference in efficacy, noting instead a heightened risk of symptomatic intracranial hemorrhage in the EVT group (43). This discrepancy may be attributed to futile reperfusion in some recanalized patients, potentially stemming from poor pre-procedural collateral circulation and lower ASPECTS scores (44). Consequently, we propose that treatment decisions for patients clinically presenting as LACI with underlying LVO should not rely solely on the presence of an occlusion. Instead, decisions must be guided by refined risk stratification incorporating collateral circulation status and baseline characteristics to ensure a cautious and evidence-based approach to EVT selection.

Based on the evidence reviewed above, navigating the therapeutic choices for each subtype requires a structured approach. We propose an integrated decision-making framework, illustrated in Figure 1, which synthesizes standard pathways with emerging strategies for diagnostic challenges and extended time windows.