Mechanism-Oriented Treatment of Early Neurologic Deterioration in Acute Ischemic Stroke

Ji Hoe Heo; Kee Ook Lee; JoonNyung Heo; Hyun Sook Kim; Young Dae Kim; Hyo Suk Nam

doi:10.5853/jos.2025.05120

J Stroke > Volume 28(1); 2026 > Article

Heo, Lee, Heo, Kim, Kim, and Nam: Mechanism-Oriented Treatment of Early Neurologic Deterioration in Acute Ischemic Stroke

Review

Journal of Stroke 2026;28(1):29-45.

Published online: January 29, 2026

DOI: https://doi.org/10.5853/jos.2025.05120

Mechanism-Oriented Treatment of Early Neurologic Deterioration in Acute Ischemic Stroke

Ji Hoe Heo¹

, Kee Ook Lee¹, JoonNyung Heo², Hyun Sook Kim¹, Young Dae Kim², Hyo Suk Nam²

¹Department of Neurology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea

²Department of Neurology, Yonsei University College of Medicine, Seoul, Korea

Correspondence: Ji Hoe Heo Department of Neurology, CHA Bundang Medical Center, CHA University School of Medicine, 59 Yatap-ro, Bundang-gu, Seongnam 13496, Korea Tel: +82-41-780-6190 E-mail: jhheostroke@gmail.com

Received October 10, 2025 Revised December 22, 2025 Accepted January 5, 2026

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Early neurologic deterioration (END) is common and occurs within a few hours to days after an ischemic stroke. Traditionally, END has been treated as a collective entity, including the occurrence of new deficits (recurrence) and the aggravation of pre-existing neurologic deficits (progression). END arises from distinct mechanisms that require different therapeutic approaches. We reviewed clinical and experimental studies addressing the epidemiology, mechanisms, and treatment of END, focusing on differentiating END due to recurrence from END due to progression and on interventions including antiplatelet therapy, direct thrombin inhibition, and induced hypertension. Early recurrence is closely associated with thrombus growth and new ischemic events, particularly in atherothrombotic disease. Early recurrence is also common in patients with cancer-associated stroke. Thrombin and platelet activation play central roles under both conditions. In contrast, progression is mainly driven by infarct growth, that is, the evolution from incomplete infarction to complete infarction due to impaired perfusion, especially in lesions involving the subcortical fiber tracts. Therapeutic implications differ accordingly. Recurrence may respond to potent antithrombotic strategies, including combined antiplatelet and direct thrombin inhibition, whereas progression may benefit from induced hypertension. However, recurrence and progression often occur simultaneously, making clinical differentiation challenging. END should be conceptualized as a spectrum of clinical presentations arising from distinct mechanisms. Recognizing recurrence and progression as separate processes is essential for mechanism-oriented treatments. Future trials should adopt this framework to develop individualized strategies and improve outcomes in patients with acute stroke.

Keywords: Ischemic stroke; Neurologic deterioration; Thrombin inhibitors; Platelet aggregation inhibitors; Induced hypertension; Cancer

Early neurologic deterioration (END) is common following acute ischemic stroke, with a reported frequency ranging from approximately 11.6% to 50%, depending on the stroke subtype, study population, and diagnostic criteria [1-12]. END is generally defined as a ≥2-point increase in the National Institutes of Health Stroke Scale (NIHSS) score, while some definitions further encompass a ≥1-point increase in the motor score or the occurrence of any new neurological deficit. END typically occurs within hours to days after stroke onset, most often within the first 6 hours. Up to 50% of END cases occur within 48 hours and 90% within 72 hours [9,13]. In a large prospective observational study of 4,299 patients with neurologic deterioration, the most common cause was stroke progression (71.8%), followed by stroke recurrence (8.5%) and hemorrhagic transformation (6.1%) [9].

Multiple factors are suggested to be associated with END. These include advanced age, female sex, pure motor syndrome, capsular warning syndrome, hypertriglyceridemia, blood pressure (BP) reduction, diabetes, large artery atherosclerosis (LAA), intracranial atherosclerosis, relevant artery stenosis, hyperglycemia, elevated systolic BP, low diastolic blood viscosity, low ankle-brachial index, and elevated low-density lipoprotein cholesterol [2,5,7-9,14-16]. In a retrospective study, induced hypertension for the management of END was administered more frequently in patients with small-vessel disease or LAA than in those with cardioembolic stroke (CE) [17], suggesting that the underlying mechanisms and occurrence of END may differ across stroke subtypes.

Over the past few decades, stroke management has primarily focused on hyperacute treatments such as intravenous (IV) thrombolysis and endovascular thrombectomy and on long-term secondary prevention, including direct oral anticoagulants, antiplatelet agents, statins, and carotid endarterectomy or stenting. These therapies have significantly reduced mortality and disability in patients with stroke. However, therapeutic strategies aimed at mitigating END have not been sufficiently established.

Most previous studies have collectively defined END, encompassing both the occurrence of new deficits (recurrence) and the aggravation of pre-existing deficits (progression). END may result from diverse pathophysiological mechanisms, including recurrent infarction, infarct growth, intracerebral hemorrhage, and brain edema. Previous observational studies and randomized clinical trials have demonstrated the potential benefits of dual antiplatelet therapy (DAPT), argatroban combined with antiplatelet agents, and induced hypertension [11,18-20]. However, most studies did not differentiate between END due to recurrence and END due to progression. Therefore, therapeutic strategies should be tailored according to the underlying etiology of END. This review addresses the main underlying mechanisms of END—early recurrence and stroke progression—and will provide therapeutic perspectives on mechanism-based therapy.

END-recurrence

Ischemic stroke may recur in the early days after the initial event owing to various etiologies, including cardioembolism and atherothrombosis, and such recurrence can lead to END. Retrospective cohort studies have shown that large arterial stenoses or occlusions are associated with an increased risk of END [9,10.21]. Among different vascular territories, internal carotid artery occlusion conferred a threefold increase in the risk of END [10]. In patients with tandem intracranial artery occlusion, END attributed to recurrent ischemia occurred in 22% (5/23). Although cancerassociated stroke is relatively uncommon, it carries the highest risk of early recurrence [22]. This review specifically addresses therapeutic strategies for early recurrence related to atherothrombosis and cancer-associated stroke, with particular emphasis on their underlying mechanisms.

Atherothrombosis

Mechanism of thrombus growth in atherothrombosis

In situ thrombosis and embolism from a proximal atherosclerotic artery are major causes of cerebral infarction [23,24]. Once a cerebral artery becomes occluded by a thrombus, the local balance between thrombosis and thrombolysis within the intra-arterial milieu undergoes profound changes (Figure 1) [25]. Persistent high shear stress through the stenotic segment of the symptomatic atherosclerotic artery may promote recurrent thromboembolism [26]. Distal to the occluded artery, stagnant blood flow prevents adequate washout of coagulation factors. Consequently, the local concentrations of coagulation factors and their substrates increase, predisposing to further thrombosis. Endogenous tissue plasminogen activators may act on the thrombus, leading to partial or complete resolution. However, fresh or partially lysed thrombi expose thrombin, and clot-bound thrombin may contribute to thrombus propagation and rethrombosis [25]. These complex local changes ultimately promote thrombus growth and rethrombosis, leading to early recurrence and END.

Role of thrombin in thrombus growth and early recurrence

Thrombin is a serine protease that plays a central role in thrombosis and hemostasis (Figure 2). Once prothrombin is converted into thrombin, it cleaves fibrinogen to form fibrin and activates coagulation factor XIII, which stabilizes fibrin clots via crosslinking. Additionally, thrombin amplifies coagulation by activating factors V, VIII, and XI and inhibits fibrinolysis by activating thrombin-activatable fibrinolysis inhibitor. Thrombin is also one of the most potent platelet activators, acting through the proteolytic cleavage of protease-activated receptors (PAR1 and PAR4) on the platelet surface [27,28].

Thrombin contains an active (catalytic) site and two anionbinding exosites (I and II). The active site is responsible for proteolytic activity, which mediates the principal functions of thrombin. Exosite I serves as a recognition site for fibrinogen, proteaseactivated receptors on platelets, and thrombomodulin, while exosite II provides a binding site for heparin and other glycosaminoglycans (Figure 2).

Exposed clot-bound thrombin may contribute to thrombus growth or rethrombosis in patients with acute stroke whose arteries are occluded by fresh thrombi. As fresh thrombi mature into firm clots with fibrin retraction, thrombin is sequestered and is less likely to promote rethrombosis. Therefore, newly formed arterial thrombi are more prone to thrombus growth or rethrombosis than older thrombi originating from the cardiac chambers. Consequently, thrombin plays a central role in thrombus growth and rethrombosis following acute thrombotic occlusion, leading to recurrence and END.

Argatroban for the prevention of END

Heparin and low-molecular-weight heparin (LMWH) exert their anticoagulant effects indirectly by binding to antithrombin. The heparin-antithrombin complex subsequently interacts with thrombin, enabling antithrombin to inhibit thrombin’s active site. Heparin and LMWH effectively inhibit circulating (free) thrombin but not fibrin-bound thrombin because fibrin-bound thrombin is sequestered (structurally hidden) within the fibrin network, preventing heparin-bound antithrombin from accessing its active site (Figure 3).

In contrast, direct thrombin inhibitors, such as argatroban and dabigatran, can access the active site, thereby inhibiting both free and clot-bound thrombin (Figure 3). Their small molecular size enables them to reach the active site even when thrombin is embedded within the fibrin network [28]. Consequently, direct thrombin inhibitors, including argatroban, may effectively suppress thrombus growth or rethrombosis in occluded arteries with freshly formed thrombi and may be beneficial in patients at risk of or experiencing END.

Several retrospective observational studies have investigated the effects of argatroban on the occurrence of END in various atherothrombotic diseases. Overall, argatroban use was associated with a reduced risk of END. In patients with non-CE (LAA in 45.5%) within 48 hours of onset (median baseline NIHSS score, 6), argatroban users (n=519) had a lower incidence of END (3.1% vs. 5.6%, P=0.034, defined as a ≥2-point increase in NIHSS score at 7 days or discharge) and greater improvement in 7-day NIHSS compared with non-users (n=806) [29]. In a propensity score- matched study of patients with posterior circulation stroke (LAA in 52.9%), none of the patients in the argatroban plus DAPT group (n=34) developed END (≥2-point increase in NIHSS score at 7 days), whereas 5.9% of patients in the DAPT group (n=68) did [30].

In another study, argatroban combined with single antiplatelet therapy was compared with DAPT in 304 patients with a nonlacunar single subcortical infarction associated with mild intracranial atherosclerosis (median baseline NIHSS score, 4). END was defined as (1) an increase of ≥2 points in the total NIHSS score, (2) an increase in the motor score of ≥1 point, or (3) any new neurological deficit (including deficits that were not measurable by the NIHSS score). END occurred less frequently in the argatroban plus single antiplatelet group than in the DAPT group (7.3% vs. 22.0%, P<0.001) [31]. In a propensity score-matched cohort of 307 patient pairs with minor ischemic stroke (NIHSS ≤5), the argatroban plus aspirin group had a significantly lower risk of END compared with the DAPT group (aspirin plus clopidogrel, odds ratio [OR]=2.337) [32,33].

Among patients with LAA, 120 treated with argatroban plus DAPT were compared to 529 patients receiving only DAPT. Com-pared with the DAPT-only group, the argatroban plus DAPT group had a lower proportion of END (≥1-point increase in NIHSS at 7 days) (4.2% vs. 10.0%, adjusted P=0.046) [34]. However, in a retrospective study of 583 patients with LAA, argatroban plus antiplatelet therapy did not significantly reduce NIHSS score at day 7 or the incidence of END (≥2-point increase in NIHSS score) but was associated with better functional outcomes at 90 days (modified Rankin Scale [mRS] score 0-2), compared with antiplatelet therapy alone (single or dual) [35].

The effects of argatroban combined with antiplatelet agents were evaluated in patients with branch atheromatous disease (BAD). In a retrospective observational study including 80 patients, END (defined as a ≥2-point increase in NIHSS score within 48 hours after admission) occurred less frequently in the argatroban plus DAPT group (4%, 1 of 25) than in the DAPT group (38.2%, 21 of 55) (P=0.004) [36]. Patients with BAD were randomly assigned to receive argatroban plus DAPT (n=49) or DAPT alone (n=51) in a multicenter, open-label, blinded-end point, randomized controlled trial. The incidence of END, defined as a ≥2-point increase in NIHSS score within 7 days, was significantly lower in the argatroban plus DAPT group (20.4%) than in the DAPT group (47.1%) [33].

Argatroban after the occurrence of END

The effects of argatroban on patients who had already developed END were evaluated retrospectively and prospectively. In a retrospective observational study, the argatroban plus DAPT group (n=30) demonstrated greater reduction in NIHSS scores at 7 days compared with the DAPT group (n=50) (7.14±1.38 vs. 7.69±3.65, P=0.032) [37]. In an open-label, blinded end-point randomized clinical trial, patients were randomly assigned to standard therapy (mono- or DAPT, n=314) or argatroban in addition to standard therapy (n=314). The argatroban group achieved a higher rate of favorable functional outcomes (mRS 0-3) at 90 days (80.5% vs. 73.3%) compared with the standard therapy group. The rate of symptomatic intracranial hemorrhage was similar between groups [20]. These results suggest that argatroban in combination with antiplatelet therapy not only reduces the risk of END development but may also improve long-term functional outcomes in patients who have already developed END.

A meta-analysis of 14 studies (4 randomized controlled trials and 10 cohort studies) evaluated the efficacy and safety of argatroban in combination with either single antiplatelet therapy or DAPT compared with antiplatelet therapy alone. The addition of argatroban significantly reduced the risk of END (OR=0.42, 95% confidence interval [CI]: 0.21 to 0.85, P=0.02). It also improved functional outcomes at 90 days, increasing the proportion of patients achieving mRS 0-2 (OR=1.36, 95% CI: 1.05 to 1.76, P=0.02) and mRS 0-1 (OR=1.54, 95% CI: 1.08 to 2.20, P=0.02). No significant differences were found in stroke recurrence, intracranial hemorrhage, or mortality [38].

However, several issues remain to be addressed. The primary outcomes in previous studies were the occurrence of END, NIHSS score, and functional outcomes at 90 days. Therefore, whether the lower END rates observed in argatroban users are attributable to a reduced risk of early recurrence (thrombus growth), progression (infarct growth), or both remains unclear. The primary effect of argatroban on END may involve a reduction in the risk of early thrombosis-related recurrence by inhibiting clotbound thrombin and platelet aggregation. However, thrombin increases blood-brain barrier permeability and exacerbates injury to the neurovascular unit [25,39], which may contribute to an increased risk of hemorrhagic transformation and ischemic injury [40]. Given these deleterious effects of thrombin following cerebral ischemia, argatroban may exert microvascular protective effects, potentially mitigating infarct growth and clinical progression without substantially increasing the risk of intracerebral hemorrhage. Most previous studies have been conducted in Chinese cohorts with heterogeneous stroke populations characterized by mild-to-moderate neurological deficits. These included non-CE, single subcortical infarction with mild intracranial atherosclerosis, BAD, or LAA. Thus, the efficacy and safety of argatroban combined with antiplatelet therapy remain uncertain in other stroke populations. Randomized controlled trials are needed to define the target population with clear inclusion criteria to establish this regimen as an initial treatment for preventing END in stroke.

Antiplatelets for the prevention of END and early recurrence

Several observational studies have compared the effects of DAPT with those of single antiplatelet therapy on the risk of END. Among 458 patients with lacunar infarction, the occurrence of END was assessed, defined as a deterioration of ≥3 points in the NIHSS score, ≥2 points in the NIHSS score with limb paresis, or documented clinical deterioration within 5 days. END occurred in 130 patients (28%), 75% of whom were treated with DAPT, which was associated with improved functional outcomes compared with single antiplatelet therapy [19]. In 365 patients with lacunar infarction presenting within 12 hours of symptom onset, a dual antiplatelet loading dose was associated with a reduced risk of END—defined as any persisting increase in NIHSS score of ≥2 points within the first 24 hours (adjusted OR=0.10, 95% CI: 0.01 to 0.89)—but this effect was not observed with IV thrombolysis or high-dose single antiplatelet therapy [11]. Among 144 patients with BAD, progressive motor paresis by day 14 occurred less frequently in those treated with cilostazol combined with another antiplatelet agent than in a matched historical control group treated with single antiplatelet therapy (33.8%). However, the patients were co-treated with IV medications, including sodium ozagrel or argatroban, edaravone, and dextran [41], which confounded the interpretation of the results.

The recent Antiplatelet Therapy in Acute Mild to Moderate Ischemic Stroke (ATAMIS) randomized controlled trial enrolled patients with mild-to-moderate stroke (median NIHSS score, 5) within 48 hours of onset and randomized them to receive clopidogrel plus aspirin (n=1,541) or aspirin alone (n=1,459). The primary endpoint was END at 7 days, defined as an increase of ≥2 points in NIHSS score, not attributable to cerebral hemorrhage. The occurrence of END was significantly lower in the DAPT group (4.8%) compared with the aspirin-alone group (6.7%) (risk difference, -1.9%; 95% CI: -3.6 to -0.2; P=0.03), while bleeding events were similar between groups [42]. In a post hoc analysis of the ATAMIS trial, the reduction in odds of END with DAPT was significant in patients treated within 24 hours (5.7% vs. 9.2%, P<0.01), but not in those treated between 24 and 48 hours (3.5% vs. 2.9%, P=0.40) [43]. This suggests that the DAPT treatment should be initiated as soon as possible to reduce the risk of END.

The primary role of antiplatelet and anticoagulant agents, including DAPT and argatroban, is to inhibit thrombosis, which is presumed to reduce the risk of stroke. Previous randomized trials—the Clopidogrel With Aspirin in Acute Minor Stroke or Transient Ischemic Attack (CHANCE) trial and the Clopidogrel and Aspirin in Acute Ischemic Stroke and High-Risk TIA (POINT) trial—demonstrated that DAPT reduced the risk of stroke recurrence compared with aspirin alone but did not improve overall functional outcomes [44,45]. These findings suggest that the benefit of more potent platelet inhibition using DAPT in reducing END in acute stroke may be primarily related to the inhibition of further thrombus growth and reduction of early recurrence.

Cancer-associated stroke

The risk of early recurrence is high in patients with cancer-associated stroke. A total of 245 patients with stroke and active cancer were evaluated for stroke recurrence within 6 months. Among them, 20 had non-bacterial thrombotic endocarditis (NBTE), 96 had a cryptogenic etiology, and 129 had a determined etiology. The rate of stroke recurrence was 50% in those with NBTE, 25% in those with cryptogenic etiology, and 16.3% in those with a determined etiology [22]. Most patients with NBTE or cryptogenic etiology experienced recurrent stroke within a few days to one month [22]. These findings highlight the need for intensive treatment during the acute stage to prevent recurrence of cancer-associated stroke.

Characteristic features of cancer-associated stroke

Cancer and stroke commonly occur in the elderly and may coexist. The presence of active cancer does not necessarily indicate that cancer is the cause of stroke. Cancer-associated strokes have several characteristic features. They usually develop in the advanced stages of cancer with metastasis. On diffusion-weighted imaging, multiple ischemic lesions are typically located in different arterial territories, and D-dimer levels are markedly elevated. In addition to these clinical, imaging, and laboratory features, the presence of vegetations on transesophageal echocardiography can support the diagnosis of cancer-associated stroke. Cancer-associated stroke is almost certain when retrieved thrombi are white in patients undergoing endovascular thrombectomy and is confirmed by histological findings of platelet-rich and erythrocyte-poor thrombi [46].

Mechanism of thrombosis in cancer

Platelets are key mediators of tumor cell survival in the bloodstream, metastasis, and tumor growth. Enhanced thrombosis is a consequence of this process [46]. Tumor cells directly adhere to and activate platelets. Activated platelets, in turn, aggregate with tumor cells to form tumor cell-induced platelet aggregates (TCIPA) [47]. Within TCIPA, platelets shield tumor cells from natural killer cell-mediated cytotoxicity and shear stress in the circulation. Platelets also release transforming growth factor-β, which suppresses natural killer cell activity. These mechanisms facilitate tumor cell survival in the bloodstream and promote distant metastasis [48,49]. This explains why cancer-associated stroke often develops in the advanced stages of cancer. Indeed, in one study, all 20 stroke patients with active cancer and NBTE had metastases [22].

Thrombin plays a central role in tumor cell-induced platelet activation. Tumor cells generate thrombin through tissue factor- dependent and -independent mechanisms. They express tissue factor on their surface, which initiates the extrinsic coagulation pathway by binding to factor VIIa and activating factor X, ultimately leading to thrombin generation [50]. Additionally, tumor cells promote thrombin production through phosphatidylserine exposure and microvesicle secretion [51,52]. Thrombin is also the most potent activator of platelets. Thus, in addition to direct platelet binding, tumor cell-induced thrombin generation amplifies platelet activation. The interplay between platelet activation and thrombin generation is the central mechanism underlying cancer-associated thrombosis [46,53].

The mechanism of NBTE in cancer is closely related to the high shear stress at the cardiac valve leaflets and cancer-associated platelet activation. Shear stress is markedly elevated near valve leaflets and induces conformational changes in von Willebrand factor (vWF). These changes expose the A1 domain, enabling vWF to bind to the platelet glycoprotein Ibα (GPIbα) receptor and thereby activate platelets on the leaflet surface [54]. Circulating TCIPA contain highly activated platelets, which can tether to valve leaflets through vWF-GPIbα interactions, even under high-flow conditions. Additionally, the mechanical forces generated by shear stress may cause subtle endothelial injury or dysfunction, further promoting platelet adhesion to the valve surface. Consequently, platelet-rich thrombi develop on the cardiac valve leaflets as vegetations (Figure 4).

Arterial thrombi in patients with cancer-associated stroke are characterized by being platelet-rich and erythrocyte-poor [55-57]. These histological features resemble those of NBTE vegetation, which is also composed of platelet-rich thrombi [58]. Such similarities support the notion that NBTE represents a major mechanism of cancer-associated stroke. In one study, thrombi from patients with cancer demonstrated 5.8-fold higher thrombin expression and 1.6-fold higher tissue factor expression than those from controls. Moreover, thrombin content correlates with platelet content within thrombi in patients with cancer-associated stroke patients [53]. These findings underscore the central role of thrombin and platelets, as well as their close interplay, in the pathogenesis of cancer-associated stroke.

Treatment

With accumulating evidence on the role of platelets in tumor growth and metastasis, numerous studies, including several meta-analyses, have consistently demonstrated the significant benefits of long-term antiplatelet therapy in patients with cancer, even after diagnosis (extensively reviewed elsewhere) [46,59-63]. Consequently, TCIPA has emerged as an important therapeutic target in cancer [64]. Moreover, the use of antiplatelet and antithrombotic agents has been proposed as an adjunctive strategy in cancer therapy [59].

Given the high risk of early recurrence of cancer-associated stroke, aggressive antithrombotic strategies may be necessary. However, evidence regarding the optimal antithrombotic regimen remains limited [46]. Although LMWH has been used empirically, its clinical efficacy has not been established, and its use is not based on the underlying mechanisms of cancer-associated thrombosis. According to the 2021 American Heart Association/American Stroke Association guidelines, evidence regarding the optimal treatment regimen for stroke caused by cancerassociated hypercoagulability is scarce, and the potential benefit of empirically using LMWH to prevent recurrence remains unknown [65].

The mechanisms underlying thrombosis in cancer-associated stroke suggest that targeting both thrombin and platelets may be an optimal therapeutic strategy. Although thrombin generation can be suppressed by blocking the coagulation pathway using LMWH or heparin, tumor cells can produce thrombin through both tissue factor-dependent and -independent mechanisms. Moreover, LMWH only inhibits free thrombin and not clot-bound thrombin, whereas direct thrombin inhibitors block both free and clot-bound thrombin (Figure 3). Additionally, some patients are reluctant to use LMWH because of the discomfort associated with subcutaneous injections [66]. Therefore, direct thrombin inhibitors may offer advantages over LMWH. Antiplatelet agents may be used as alternative therapeutic options, either as standalone therapies or in combination with direct thrombin inhibitors. However, during the first few weeks after stroke onset, when recurrence is most common, combined therapy with direct thrombin inhibitors and antiplatelet agents may be required [22]. These treatment strategies may also have potential benefits for the underlying cancer.

END-progression

Stroke progression is the most common cause of END [9]. Whereas stroke recurrence typically results in the abrupt development of new neurological deficits, stroke progression commonly manifests as a gradual worsening of neurological deficits, most often motor weakness, over several hours to days.

Several studies have investigated the association between progression and lesion location on imaging. Deep perforating artery infarctions have been more frequently associated with progressive motor deficits [4]. Lesions involving the striatocapsular region and pons, and anterior choroidal artery territory in-farctions have also been predictive of progression [7,8,67-69]. The extent of pontine infarction along the conduction tracts, such as corticospinal and corticobulbar tracts, has been shown to contribute to progression, suggesting that the degree of tract involvement is related to progression [70]. Early progression most commonly occurs in cases of deep perforating infarctions involving the corona radiata, subcortical white matter, striatocapsular area, and pons, where the corticospinal and corticobulbar tracts run.

In a cohort of 252 patients with small subcortical infarction, 28 (11%) developed END, all of which represented progression of pre-existing symptoms [71]. The fluid-attenuated inversion recovery sequence signal intensity ratio (FLAIR-SIR) on brain magnetic resonance imaging was calculated as the ratio between the infarct region of interest and the contralateral mirrored anatomic location on FLAIR sequences. A low FLAIR-SIR has been used as an indicator of incomplete infarction [72,73]. A FLAIR-SIR cutoff of ≤1.15 was associated with a threefold increased likelihood of progression, suggesting that delayed infarct completion may underlie early progression [71].

The progression is associated with perfusion deficits. Infarct growth correlates with progressive reductions in cerebral blood flow [74,75]. In cases of large artery occlusion, poor collateral blood flow was associated with infarct growth [76-78]. BAD, particularly in the anterior pontine and lenticulostriate artery territories, was strongly associated with progressive motor deficits [69,79]. Of 155 patients who achieved successful reperfusion following endovascular thrombectomy, 94 patients (85.1%) showed infarct growth between 2 and 24 hours, and infarct growth was associated with the 24-hour NIHSS [80]. Perfusion deficits on perfusion imaging or radiomics on diffusion-weighted imaging and FLAIR were predictive of END [1.11,81,82]. Among patients with lacunar infarction, normal perfusion-weighted imaging was associated with lower risks of END [83], whereas infarct regions in progressive strokes showed lower cerebral blood flow and higher mean transit time [12].

In summary, early progression is characterized by the progression of preexisting symptoms, lesion locations involving motor or conduction tracts, imaging features of incomplete infarction or infarct growth, and perfusion deficits.

Pathophysiological perspectives of progression

The vulnerability of nerve fiber tracts to ischemia is uncertain, and only a few studies have specifically investigated this issue. In a rat ischemic model, pathological swelling of oligodendrocytes was observed as early as 30 minutes after arterial occlusion [84]. Actively myelinating oligodendrocytes in juvenile mice were resistant to ischemia, whereas adult astrocytes were sensitive [85]. The vulnerability and temporal course of ischemic injury in human nerve fiber tracts remain unknown.

Capillary density in the white matter, including nerve fiber tracts, is two to three times lower than that in the gray matter, reflecting lower oxygen and energy demands in these regions [86]. These findings suggest that responses to ischemia, or reduced blood flow, may differ between nerve fiber tracts (white matter) and neurons (gray matter). Progressive symptoms over hours to days, along with imaging patterns of delayed infarction, further indicate that the dynamics of ischemic injury and subsequent clinical presentations may differ between neurons and nerve fiber tracts. The degree of neurological deficits, such as weakness, may depend on the extent of nerve fiber damage within the tract. Gradual loss of functioning nerve fibers following ischemia may underlie the progression of symptoms, sometimes manifesting as gradual worsening.

Neurons located farthest from their nearest detectable capillaries in the ischemic core are more likely to be injured [8]7. This spatial relationship between capillaries and ischemic injury may also exist in the white matter and nerve fiber tracts. These findings suggest that islands of undamaged tissue may persist even within the ischemic core during the early stages of cerebral ischemia and may subsequently progress to complete infarction over time. Given the spatial relationship between capillaries and cellular responses to ischemia, low perfusion pressure in the ischemic region could facilitate the conversion from incomplete infarction to complete infarction. This also implies that the speed and extent of progression may depend on perfusion pressure.

Potential harm of early BP lowering in acute stroke

Within the range of cerebral autoregulation, changes in BP cause minimal alterations in cerebral perfusion. However, in ischemic areas where autoregulation is impaired, cerebral perfusion is dependent on mean BP. High BP may increase the risk of intracerebral hemorrhage, whereas excessively low BP may reduce cerebral perfusion and exacerbate ischemic injury. This has led to the assumption that lowering BP in patients with acute stroke could reduce the risk of early recurrent stroke and intracerebral hemorrhage. However, BP reduction may also decrease perfusion in the ischemic region, potentially worsening ischemic damage.

Many studies have investigated the effects of lowering BP on clinical outcomes across different settings and populations with acute stroke. A meta-analysis of 13 randomized controlled trials including 12,703 participants demonstrated that early BP reduction in acute ischemic stroke had a neutral effect on the risk of death, dependency, or recurrent stroke at 3 months [88]. A similar neutral effect of BP-lowering on functional outcome at 3 months was also observed in a randomized clinical trial of patients with acute stroke who received IV thrombolysis (The International Enhanced Control of Hypertension and Thrombolysis Stroke Study [ENCHANTED]) [89].

In contrast, intensive BP lowering for 24 hours was harmful in patients with acute stroke who underwent endovascular thrombectomy and achieved successful recanalization. The likelihood of functional independence at 3 months was lower in the intensive BP-lowering groups in randomized controlled trials (ENCHANTED2/MT and The Outcome in Patients Treated With Intra-Arterial Thrombectomy—Optimal Blood Pressure Control [OPTIMAL-BP]) [90,91]. The China Antihypertensive Trial in Acute Ischemic Stroke-2 (CATIS-2) compared the effect of early antihypertensive treatment initiated within 24-48 hours of stroke onset with delayed treatment starting on day 8. Overall, the trials yielded neutral results; however, they suggested a potentially harmful effect associated with early initiation of antihypertensive treatment due to an increased OR of 1.18, with a lower 95% CI very close to the null (0.98) [92].

These findings indicate that lowering BP in the acute stage of ischemic stroke provides no clinical benefit and may even be harmful in certain patient groups. In patients undergoing endovascular thrombectomy under general anesthesia, intra-procedural BP reduction was associated with decreased collateral circulation and infarct growth [93]. In a secondary analysis of CATIS-2, early antihypertensive treatment in patients with single subcortical infarction and parent artery disease was associated with an increased risk of functional dependency or death at 3 months [9]4. These results suggest that early BP lowering in the acute phase of infarction may predispose patients with subcortical infarction involving the tract—particularly in areas of incomplete infarction— to progression. Conversely, these findings support the hypothesis that induced hypertension may be beneficial in patients with symptom progression who may have regions of incomplete infarction.

Induced hypertension in END

Cerebral blood flow may be increased by elevating mean arterial pressure via inotropic support or by inducing vasodilation through hypercapnia [95]. Induced hypertension using norepinephrine in patients with large middle cerebral infarction has been shown to increase cerebral perfusion pressure and augment mean flow velocity in the middle cerebral artery without a clinically significant rise in intracranial pressure [96]. More recently, phenylephrine, a selective α1-agonist, has been preferred for induced hypertension because it elevates BP through peripheral vasoconstriction without causing direct cerebral vasoconstriction.

In a retrospective study of 662 patients with small deep subcortical infarctions, 66 (9.97%) experienced motor progression. Among these patients, those treated with induced hypertension using phenylephrine had lower NIHSS scores at discharge [1]6. A randomized clinical trial compared induced hypertension with phenylephrine versus standard care in patients with acute noncardioembolic ischemic stroke with progression. The primary efficacy outcome was defined as an improvement of ≥2 points in the NIHSS score between day 0 and day 7. The induced hypertension group achieved the primary endpoint more frequently (44/76 [57.9%] vs. 24/77 [31.2%]) with an adjusted OR of 2.49 [18].

In a retrospective study of 147 patients with lacunar infarction and END, induced hypertension with phenylephrine was associated with higher rates of END recovery (77.2% vs. 51.5%) and excellent outcomes (34.2% vs. 16.2%) compared with argatroban [97]. However, as the study was neither controlled nor randomized, these findings do not establish the superiority of induced hypertension over argatroban in patients with END. Moreover, because only patients with lacunar infarctions were included, the underlying mechanism of END in most of this population was likely progression rather than recurrence. From a mechanistic standpoint, induced hypertension may be more effective for progression-dominant END, whereas argatroban may be beneficial for recurrence-dominant END.

The timing of induced hypertension in patients with END may be critical. In a cohort of 136 patients with small vessel disease and END, 65 (47.8%) demonstrated early neurological improvement. Notably, the interval between END onset and the initiation of induced hypertension was shorter in patients with early improvement. The benefit of induced hypertension appeared to be confined to initiation within the first 3 hours after END onset [98]. These findings reinforce the concept that “time is brain” also applies to progressive stroke. Induced hypertension should be initiated as early as possible before salvageable tissue progresses to complete infarction.

Although previous studies suggest a potential benefit of induced hypertension in selected patients with END, several issues remain to be addressed. Most notably, large controlled clinical trials are needed, as existing evidence is derived primarily from observational studies or small randomized trials. The optimal target BP, therapeutic time window, and appropriate duration of induced hypertension are yet to be clearly defined. Furthermore, while most prior studies have focused on patients with deep subcortical or lacunar infarctions, it remains uncertain whether induced hypertension is effective in other stroke subtypes. Another unanswered question is whether induced hypertension should be applied prophylactically to prevent END or initiated after progression to improve outcomes.

This review focuses on therapeutic strategies aimed at enhancing cerebral perfusion in the context of infarct growth and progression. While infarct growth is driven not only by perfusion deficits but also by ischemic injury mechanisms, such as inflammation, oxidative stress, and excitotoxicity, interventions targeting these molecular pathways may also hold promise for improving outcomes in patients with END. Although the molecular and cellular mechanisms underlying ischemic injury have been extensively studied, their specific roles in END development and treatment remain unclear and require further investigation.

Co-occurrence of recurrence and progression

Recurrence and progression may occur simultaneously or at different times in the same patient. END is a collective term encompassing the clinical features arising from different mechanisms, most notably recurrence and progression. Early recurrence is a new ischemic event attributable to thrombosis or thrombus growth. In contrast, early progression refers to clinical deterioration resulting from ongoing ischemic injury after the initial event and is typically associated with infarct growth (Figure 5). Thus, recurrence and progression are not mutually exclusive and may manifest concurrently in the same patient (Figure 6).

In cases of larger-artery atherothrombosis or BAD, infarcts may extend into deep subcortical structures, including nerve fiber tracts, which are particularly prone to early progression. However, early recurrence may occur because of thrombosis or thrombus growth within the original atherothrombotic lesions. Distinguishing between recurrence and progression is often difficult.

Recurrence and progression may occur at different times in patients receiving antiplatelet therapy. In such cases, anticoagulants, such as argatroban for recurrence, and induced hypertension for progression, may be used sequentially. However, whether these strategies can be combined remains uncertain in cases of co-occurrence of recurrence and progression. The major concern with adding argatroban and induced hypertension to conventional antithrombotic therapies is the potential risk of intracerebral hemorrhage. Although each strategy has been reported to be safe when used individually, most previous studies have enrolled patients with mild-to-moderate neurological deficits and subcortical or lacunar infarctions. Therefore, the safety of these strategies in other stroke populations remains unclear.

In the Multiarm Optimization of Stroke Thrombolysis (MOST) trial, adjunctive administration of argatroban with IV thrombolysis was associated with higher mortality and an increased risk of symptomatic intracerebral hemorrhage [99]. A potential mechanism is that argatroban-induced thrombin inhibition may enhance fibrinolysis by suppressing thrombin-activatable fibrinolysis inhibitors, thereby increasing the risk of hemorrhage. Although only 50 patients were enrolled in the argatroban group, these findings raise concerns regarding the safety of combining arg-atroban with other treatments that may increase the risk of hemorrhage in certain patient populations. In cases in which it is uncertain whether END results from recurrence or progression, urgent diffusion-weighted imaging may help clarify the underlying mechanism and guide a tailored therapeutic approach.

END in CE

Several studies have investigated END in CE; however, the evidence remains limited. In a cohort of 168 patients with acute ischemic stroke, progressive motor syndrome was most frequently observed in deep perforating artery infarctions (34 of 95 patients, 35.8%), followed by LAA (12 of 44 patients, 27.3%), and was least common in CE (1 of 18 patients, 5.3%). Additionally, progressive motor syndrome occurred far less frequently in cortical infarctions (1 of 25 patients, 4.0%) than in subcortical infarctions (44 of 132 patients, 33.3%) [4].

In another small study of 121 patients with atrial fibrillation- related stroke and diabetes mellitus, END—defined as an increase in NIHSS score of ≥4 points within 7 days of symptom onset—was observed in 16 patients (13.2%). Among these patients, 9 experienced stroke progression, 2 hemorrhagic transformation, and 1 early stroke recurrence; however, lesion topography was not addressed in that study [100].

Most studies on END in CE have focused on factors associated with END rather than on mechanistic subtypes or therapeutic strategies. The reported factors include baseline NIHSS score, prestroke glycemic control, matrix metalloproteinase-9 polymorphisms, hemorrhagic transformation, coronary heart disease, diastolic BP, cystatin C levels, platelet-to-lymphocyte ratio, high D-dimer-to-fibrinogen ratio, and high-sensitivity C-reactive protein [100-105].

Although early recurrence or progression may contribute to END in CE, progressive motor deterioration appears to be less frequent than that in atherothrombotic or perforator infarctions. This may be explained by the fact that CE more commonly involves cortical or large hemispheric territories rather than deep perforating artery regions. Moreover, early recurrence related to thrombus growth may be less common in CE, because the predominant mechanism is embolization of relatively aged thrombi formed within the cardiac chambers, whereas newly formed arterial thrombi in atherothrombotic stroke are more prone to local thrombus growth or rethrombosis.

From a therapeutic perspective, no END-specific management strategy unique to CE has been established. Although induced hypertension may be considered in selected patients with progression or perfusion deficits, its efficacy and safety remain uncertain in patients with large hemispheric infarctions that are often caused by cardioembolism. Future studies focusing on the mechanisms, imaging correlates, and tailored management of END in patients with CE are required.

Clinical perspectives and conclusions

Early recurrence and progression can result in neurological deterioration; however, they arise from distinct pathophysiological mechanisms. Therefore, a tailored approach to END is required. Early recurrence is typically attributed to thrombosis or thrombus growth, which may require more potent antithrombotic strategies. Given the role of clot-bound thrombin in the residual thrombus and the contribution of platelets under high-shear stress conditions to rethrombosis or thrombus growth, a combination strategy of direct thrombin inhibitors and antiplatelet agents may represent a rational option for patients prone to or developing early recurrence (Table 1).

In contrast, a reduction in cerebral blood flow and perfusion is a critical factor in early progression. Ischemic regions are highly vulnerable during the hyperacute stage and undergo time-dependent evolution toward complete infarction. Autoregulation is impaired in these regions, rendering them particularly susceptible to changes in systemic BP. Accordingly, avoiding excessive BP reduction may be crucial during the hyperacute stage. Similarly, in patients with progressive symptoms, induced hypertension may help increase perfusion pressure and halt or even reverse progression (Table 1). The benefit of induced hypertension in progression is likely time-dependent and should be initiated as early as possible. Additionally, the management of systemic conditions, such as infection, metabolic disturbances, and anemia, is essential, as these can further compromise ischemic brain tissue.

In patients with END, clinical differentiation between recurrence and progression is crucial, because END due to recurrence and END due to progression require different treatment strategies. Recurrence typically presents abruptly with new symptoms, whereas progression manifests as the worsening of pre-existing deficits, often in a gradual fashion (Table 1). However, differentiation based solely on the clinical presentation is challenging. For example, recurrent ischemic stroke in an area adjacent to the initial lesion may cause an abrupt worsening of pre-existing symptoms, which can be difficult to distinguish from progression due to infarct growth. Stroke subtypes may provide some clues; recurrence is more likely in patients with atherothrombotic disease, such as LAA or advanced cancer, whereas progression more frequently occurs in small-vessel disease involving the nerve fiber tracts, such as the corona radiata, internal capsule, pons, and deep subcortical white matter. Diffusion-weighted imaging is useful for differentiating between recurrence and progression, as it demonstrates new ischemic lesions in recurrence and the expansion of pre-existing lesions in progression (Table 1). However, when atherothrombotic disease also involves the nerve fiber tracts, both recurrence and progression may coexist. In such situations, immediate diffusion-weighted imaging can offer useful information to distinguish between these mechanisms.

Previous studies have often treated END as a single entity. However, END is more accurately regarded as a clinical syndrome encompassing early neurological worsening owing to diverse underlying mechanisms. Although further studies are needed to identify the key determinants of END and optimize treatment strategies, a mechanism-oriented rather than a uniform management approach should be adopted. Therefore, future studies should stratify END into recurrence- and progression-dominant phenotypes, ideally using prospective clinical and imaging-based designs with serial diffusion, perfusion, or vessel wall imaging. Clinical trials testing individualized treatment strategies, such as intensified antithrombotic regimens for recurrence-dominant END and tailored hemodynamic management, including induced hypertension, for progression-dominant END, are warranted. Currently, no ongoing clinical trials have specifically addressed END using a mechanism-based design that differentiates or simultaneously targets recurrence and progression. Addressing this gap through well-designed prospective and interventional studies may represent a critical step toward the personalized management of END and improved outcomes in patients with acute ischemic stroke. In addition, a standardized definition of END that encompasses the progression of a broader range of neurological deficits is needed, as current definitions vary and are largely focused on motor weakness.

Notes

Funding statement

None

Conflicts of interest

The authors have no financial conflicts of interest.

Author contribution

Conceptualization: Ji Hoe Heo. Study design: Ji Hoe Heo. Methodology: Ji Hoe Heo, Kee Ook Lee, JoonNyung Heo. Data collection: Kee Ook Lee, JoonNyung Heo, Hyun Sook Kim. Investigation: Kee Ook Lee, JoonNyung Heo, Hyun Sook Kim. Writing—original draft: Ji Hoe Heo. Writing—review & editing: Kee Ook Lee, JoonNyung Heo, Hyun Sook Kim, Young Dae Kim, Hyo Suk Nam. Approval of the final manuscript: all authors.

Acknowledgments

We appreciate Medical Illustration & Design (MID), a member of the Medical Research Support Services of Yonsei University College of Medicine, for providing excellent support with medical illustrations.

Figure 1.

Mechanism of thrombus growth or rethrombosis in atherothrombotic occlusion or stenosis. Once a cerebral artery is occluded by a thrombus, the local thrombosis-thrombolysis balance and the intra-arterial milieu undergo profound changes. Distal to the occluded artery, blood flow becomes stagnant, and coagulation factors are not adequately cleared. Consequently, local concentrations of coagulation factors and their substrates increase, predisposing to further thrombosis (A). Thrombus growth or thromboembolism may occur at the distal portion of an arterial bifurcation (B) or within the stenotic segment of a symptomatic atherosclerotic artery (C). At these sites, high shear stress induces conformational changes in von Willebrand factor (vWF), thereby promoting platelet adhesion and aggregation. Endogenous tissue plasminogen activator (tPA) may partially lyse the thrombus, exposing clot-bound thrombin, which in turn contributes to thrombus propagation and recurrent thromboembolism.

Figure 2.

Thrombin binding sites and their roles in thrombosis. PARs, protease-activated receptors; LMWH, low-molecular-weight heparin; TAFI, thrombin-activated fibrinolysis inhibitor.

Figure 3.

Effects of anticoagulants on free and clot-bound thrombin. Direct thrombin inhibitors bind directly to the active sites of both free and clot-bound thrombin. Heparin and low-molecular-weight heparin (LMWH) act indirectly by forming a complex with antithrombin, which inhibits free thrombin. However, heparin-antithrombin or LMWH-antithrombin complexes cannot effectively access thrombin trapped within the fibrin network, leaving clot-bound thrombin largely unaffected.

Figure 4.

Mechanism of thrombosis in cancer-associated stroke. vWF, von Willebrand factor.

Figure 5.

Representative diffusion-weighted imaging (DWI) showing infarct growth. A patient with a history of right pontine infarction presented with dysarthria and mild weakness in the right arm and leg while taking aspirin and clopidogrel. DWI obtained 2 hours after symptom onset shows acute infarctions in the left corona radiata (A). The following day, the patient’s dysarthria worsened, and hypertension was induced with phenylephrine. One day after treatment, the dysarthria showed slight improvement. Follow-up DWI demonstrates infarct growth (B). By the 5th day, dysarthria and right-sided weakness had completely resolved.

Figure 6.

A representative case of progression and recurrence. A patient presented with dysarthria, left arm clumsiness, and left facial weakness and was treated with dual antiplatelet therapy (aspirin and clopidogrel). Magnetic resonance angiography shows right middle cerebral artery occlusion (A), with a blooming artifact on susceptibility-weighted imaging indicating an intraluminal thrombus (B). Baseline diffusion-weighted imaging (DWI) reveals multiple infarctions involving the cerebral cortex and corona radiata (C). The following day, the patient’s left-hand weakness worsened. Induced hypertension with phenylephrine was initiated, resulting in improvement with only mild left thumb weakness. Follow-up DWI shows lesion expansion (arrows) (D). On day 19, the patient abruptly developed complete left-hand weakness and mild left-sided facial hypesthesia. Argatroban was administered, and the neurological deficits improved the next day. DWI demonstrates new ischemic lesions (arrowheads) with further lesion expansion (arrows) (E).

Table 1.

Characteristics of END according to underlying mechanisms

	END-recurrence	END-progression
Mechanism	Thrombus growth	Infarct growth
Main pathophysiological factors	Thrombin, platelets	Perfusion
Predisposing condition	Atherothrombotic disease	Nerve fiber tract involvement
Predisposing condition	Advanced cancer	Nerve fiber tract involvement
Clinical characteristics	New symptoms, abrupt	Aggravation of pre-existing symptoms, often gradual
Diffusion-weighted imaging	New ischemic lesions	Expansion of pre-existing infarct
Therapeutic strategies	Inhibition of thrombin and platelet activity	Induced hypertension

END, early neurologic deterioration.

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