Abstract
Purpose
Endovascular treatment (EVT) for acute ischemic stroke (AIS) with mild symptoms (National Institute of Health Stroke Scale [NIHSS] score of ≤ 5) has a specific concern about early neurological deterioration (END) after the procedure, but its significance remains unclear. This study aims to examine the prognostic impact and characteristics of END in this patient population.
Methods
We conducted a post-hoc analysis of the Japan Registry of NeuroEndovascular Therapy 4, enrolling 13,479 patients who underwent EVT for AIS at 166 participating centers between 2015 and 2019. We included patients with AIS and NIHSS scores ≤ 5 and compared outcomes (modified Rankin Scale [mRS] score at 30 days) between patients with and without END after EVT. Multivariate logistic regression models were used to explore associations between END and outcomes and risk factors for END.
Results
Of 503 patients analyzed, 66 (13%) developed END. Patients who developed END had a lower proportion of mRS scores of 0–2 at 30 days than the No-END group (17% vs. 80%, P < 0.0001), with an adjusted odds ratio (OR) of 0.04 (95% confidence interval [CI], 0.02–0.11). Mortality within 30 days was higher among patients with END (9.1% vs. 0.7%, P < 0.0001). A multivariable logistic regression model identified that factors associated with END included age ≥ 75 years (adjusted OR 3.67; 95% CI, 1.78–7.55), ASPECTS (adjusted OR 0.82; 95% CI, 0.69–0.97), NIHSS scores before EVT of 0–2 compared with those of 3–5 (adjusted OR 2.11; 95% CI, 1.04–4.25), and unsuccessful recanalization (adjusted OR 8.39; 95% CI, 3.90–18.0).
Conclusion
END after EVT for AIS with mild symptoms was relatively common and associated with worse outcomes. Risk stratification for END and successful recanalization would be crucial, particularly for EVT candidates with mild symptoms.
Keywords: Early neurological deterioration, Acute ischemic stroke, Endovascular treatment, NIHSS score
Introduction
Endovascular treatment (EVT) has become a crucial and highly effective treatment for acute ischemic stroke (AIS) due to large vessel occlusion (LVO) [1, 2]. However, its efficacy and safety in patients with mild neurological symptoms (National Institute of Health Stroke Scale [NIHSS] score ≤ 5) remain unclear due to the lack of robust evidence from randomized clinical trials and controversial results from several meta-analyses [3–5].
Medical management of AIS with mild symptoms has been reported to frequently result in the worsening of symptoms, with one-fifth of patients experiencing an increase in NIHSS score of ≥ 4 [6]. Such early neurological deterioration (END) has been demonstrated to frequently occur early after onset and to be associated with worse clinical outcomes in various stroke populations [6–9]. Although EVT is a promising treatment option for mitigating the risk of END, it presents specific concerns such as technical complications or physical burden to patients. Therefore, particularly for patients with AIS with mild symptoms, a careful risk-benefit assessment is essential when considering the indication for EVT. Understanding the characteristics of patients likely to develop END after EVT may be important for the optimal management of AIS with mild symptoms. However, these have not yet been elucidated.
To address this knowledge gap, this study aimed to investigate the clinical characteristics and prognostic impact of END among patients with mild symptoms (NIHSS score of ≤ 5 before EVT) who underwent EVT, utilizing data from a Japanese nationwide EVT registry.
Methods
Study design and patient selection
This is a sub-analysis of the Japan Registry of NeuroEndovascular Therapy (JR-NET) 4, a retrospective, nationwide registry that enrolled 13,479 patients who received EVT for acute ischemic stroke at 166 participating centers in Japan between January 2015 and December 2019. The eligibility criteria for the JR-NET 4 were as follows: patients who underwent EVT (i) performed by Japanese Society for Neuroendovascular Therapy-certified specialists as operators, supervisors, or assistants and (ii) more than 30 days before the day of enrollment, which continued from the JR-NET 1, 2, and 3 [10, 11]. Patients deemed ineligible by the physicians in charge, as well as those whose treatments were not provided by JSNET-certified specialists, were excluded from the registry. The detailed study protocol is available online at http://www.jrnet.umin.jp.
In this study, we included patients with AIS who had an NIHSS score of ≤ 5 before EVT. We excluded patients who lacked data on the NIHSS scores before EVT or within 24 h of EVT, as well as those who did not complete 30 days of follow-up. In addition, patients who developed any intracranial hemorrhage (ICH) after EVT were excluded, in accordance with the definition of END [12, 13].
Ethics approval
This study adhered to the declaration of Helsinki guidelines for medical research involving human participants. The protocol was approved by the institutional review boards at the Kobe City Medical Center General Hospital (zn200107). The requirement for written informed consent was waived in accordance with the Ethical Guidelines for Medical and Health Research Involving Human Subjects in. An opt-out approach was implemented with information publicly disclosed on the participating hospitals. The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Definition of early neurological deterioration; END vs. No-END
We defined END as a worsening of ≥ 4 points in the NIHSS score within 24 h of EVT, without identification of ICH, according to previously reported criteria [12, 13]. In the JR-NET 4, ICH was assessed using computed tomography (CT) or magnetic resonance imaging (MRI) within 24 ± 8 h of admission, as part of the assessment for hemorrhagic complications following EVT. Patients were classified into two groups: END and No-END groups.
Data collection
The clinical data of each patient were anonymized and registered retrospectively on the web using a registration system developed by the Translational Research Informatics Center (TRI, http://www.tri-kobe.org/).
We collected the following clinical data for each patient. Demographic and baseline characteristics included age, sex, and the modified Rankin Scale (mRS) score before stroke onset [14]. Clinical presentation was documented using the time from symptom onset to puncture and the NIHSS score before EVT [15]. Imaging findings included the ischemic volume assessed by the Alberta Stroke Program Early CT Score (ASPECTS) on non-contrasted CT or diffusion-weighted imaging (DWI) on MRI. For patients with posterior circulation stroke, we evaluated the posterior circulation using the Acute Stroke Prognosis Early CT Score (pc-ASPECTS) on non-contrasted CT or DWI [16]. The occluded vessel was classified into three categories: intracarotid artery (ICA) and M1 occlusion, medium-vessel occlusion (MeVO), and vertebrobasilar occlusion. MeVO was defined as occlusions of the M2 or distal segment of the middle cerebral artery, A2 or distal segment of the anterior cerebral artery, and P1, P2, or P3 segment of the posterior cerebral artery. The degree of reperfusion was classified using the modified thrombolysis in cerebral infarction (mTICI) grading system based on digital subtraction angiography findings immediately after the EVT procedures [17]. The stroke subtype was classified according to the Trial of ORG 10,172 in Acute Stroke Treatment (TOAST) classification as cardioembolic, atherothrombotic, or others [18].
Outcome measures
The primary outcome was an mRS score of 0–2 at 30 days after EVT. Secondary outcomes included a one-point improvement on the mRS scale at 30 days, an mRS score of 0–1 at 30 days, and all-cause mortality within 30 days.
Statistical analysis
We primarily compared the characteristics and clinical outcomes between the END and No-END groups. Categorical variables are described as numbers (percentage) and continuous variables as means (standard deviation, [SD]) or medians (25–75% interquartile range [IQR]). We compared the variables between the two groups using the chi-square test for categorical variables and Student’s t-test or the Wilcoxon rank sum test for continuous variables, depending on the distribution of the variables. The number of observed variables was presented in the Tables.
We constructed a multivariate logistic regression model to estimate the adjusted odds ratios (ORs) and 95% confidence intervals (CIs) of the END group relative to the No-END group for the primary and secondary outcomes. Adjusted ORs were estimated using this model, adjusted for the following possible confounders, which were selected based on biological plausibility and pre-existing knowledge: age; sex; mRS score before onset; t-PA administration; onset-to-puncture time (≤ 6 or > 6 h); baseline ASPECTS; type of procedure (stent retriever, aspiration, or combined); occluded vessel (ICA and M1, MeVO, or vertebrobasilar); and mTICI grade after EVT (≥ 2b or < 2b). Cutoff values were selected based on clinical relevance and prior literature. Age ≥ 75 years reflects commonly used definitions of older adults in Japan [19]. For onset-to-puncture time (≥ 6 h vs. <6 h), we adopted the threshold presented in EVT guidelines that were mainly referenced during the registry period [20].
The distribution of ordinal mRS scores at 30 days was presented, and differences in distribution between the two groups were assessed using the chi-squared test. We also constructed an ordinal logistic regression model to estimate the adjusted common ORs with 95% CIs for achieving a one-point lower mRS score at 30 days after the assessment of the proportional odds assumption. To address the potential for overfitting given the limited number of END, we conducted a sensitivity analysis using a multivariate model with reduced number of adjustment variables (age, baseline ASPECTS, and mTICI grade after EVT (≥ 2b or < 2b) for the primary outcome.
Additionally, we constructed the same multivariable logistic regression model for the primary outcome in the subgroups to estimate the adjusted ORs for each subgroup and the interaction P values. The subgroups included age (≥ 75 or < 75 years), sex, onset-to-puncture time (≥ 6 or < 6 h), NIHSS score before EVT (3–5 or 0–2), ASPECTS (< 7 or ≥ 7), tPA administration, the occluded vessel (anterior or posterior circulation), and the etiology of AIS (cardioembolic stroke or not). We used 7 of ASPECTS as the cutoff, as it indicates relatively larger ischemic volume even within the mild stroke population and provided a more balanced distribution.
To explore the possible risk factors for END, we constructed a multivariable logistic regression model. Considering clinical, biological plausibility, and variables showing statistically significant differences or trends between END and no-END groups in univariate comparisons, we included age (< 75 or ≥ 75 years), sex, mRS score before onset, onset-to-puncture time (≥ 6 or < 6 h), baseline ASPECTS, NIHSS score before EVT (0–2 or 3–5), type of procedure (stent retriever, aspiration, or combined), mTICI grade after EVT (≥ 2b or < 2b), and the etiology of AIS (atherothrombotic stroke or not) in the model.
All statistical analyses were conducted using JMP 16.0 (SAS Institute Inc., Cary, NC, USA). All tests were two-sided, and statistical significance was set at P < 0.05.
Results
Patient characteristics
During the study period, 13,479 patients who underwent EVT for AIS were enrolled in the JR-NET 4. After excluding 1,029 patients without data on NIHSS scores before EVT, 11,637 patients with NIHSS scores > 5 before EVT, 274 patients without data on NIHSS scores within 24 h of EVT, 30 patients who developed any ICH after EVT, and 6 patients lost to follow-up, we finally analyzed 503 patients. Of the participants, 66 (13%) and 437 (87%) were classified into the END and No-END groups, respectively (Fig. 1).
Fig. 1.
Study flowchart. JR-NET 4, Japan Registry of NeuroEndovascular Therapy; 4NIHSS, National Institute of Health Stroke Scale; ICH, intracranial hemorrhage
The overall mean age was 71 years, 64% were male, and 89% had an mRS score of 0–1 before onset. Regarding the occluded vessel, 33% had MeVO, while 14% had vertebrobasilar occlusion. The median NIHSS score before EVT was 3 (IQR, 2–5), with 7.5% of patients scoring 0. The median ASPECTS was 9 (IQR, 8–10). Approximately 31% of the patients received t-PA. Successful recanalization after EVT (mTICI ≥ 2b) was achieved in 84% of cases, with the etiology of stroke being atherothrombotic in 21% of patients (Table 1).
Table 1.
Patient characteristics
| Total (N = 509) |
END (N = 67) |
No-END (N = 442) |
P value | N | |
|---|---|---|---|---|---|
| Demographics | |||||
| Age-years, mean (SD) | 71 (13) | 73 (12) | 71 (13) | 0.15 | 509 |
| Age ≥ 75 years, n (%) | 237 (47) | 40 (60) | 197 (45) | 0.02 | 509 |
| Men, n (%) | 324 (64) | 41 (61) | 283 (64) | 0.65 | 509 |
| mRS score before onset, median (IQR) | 0 (0–0) | 0 (0–0) | 0 (0–0) | 0.61 | 506 |
| mRS score before onset < 2, n (%) | 452 (89) | 62 (93) | 390 (89) | 0.36 | 506 |
| Clinical presentation | |||||
| Onset to Puncture time | 0.69 | 494 | |||
| < 180 min, n (%) | 178 (35) | 20 (30) | 158 (36) | ||
| 180–359 min, n (%) | 185 (36) | 24 (36) | 161 (36) | ||
| 360–720 min, n (%) | 77 (15) | 12 (18) | 65 (15) | ||
| > 720 min, n (%) | 54 (11) | 9 (13) | 45 (10) | ||
| Onset to Puncture time < 6 h, n (%) | 363 (73) | 44 (68) | 319 (74) | 0.26 | 494 |
| NIHSS score before EVT, median (IQR) | 3 (2–5) | 3 (2–4) | 4 (2–5) | 0.053 | 509 |
| Distribution | 0.30 | 509 | |||
| 0, n (%) | 38 (7.5) | 7 (10) | 31 (7.0) | ||
| 1, n (%) | 45 (8.8) | 4 (6.0) | 41 (9.3) | ||
| 2, n (%) | 73 (14) | 14 (21) | 59 (13) | ||
| 3, n (%) | 103 (20) | 14 (21) | 89 (20) | ||
| 4, n (%) | 125 (25) | 17 (25) | 108 (24) | ||
| 5, n (%) | 123 (25) | 11 (25) | 114 (26) | ||
| Imaging findings | |||||
| ASPECTS on admission, median (IQR) | 9 (8–10) | 9 (7–10) | 9 (8–10) | 0.047 | 466 |
| ASPECTS ≥ 7, n (%) | 428 (92) | 55 (89) | 373 (92) | 0.33 | 466 |
| Main occlusion site | 0.14 | 506 | |||
| ICA/M1, n (%) | 264 (53) | 40 (61) | 224 (52) | ||
| MeVO, n (%) | 166 (33) | 15 (23) | 151 (35) | ||
| Vertebrobasilar, n (%) | 68 (14) | 11 (17) | 57 (13) | ||
| Treatment and etiologies | |||||
| t-PA use, n (%) | 159 (31) | 22 (33) | 137 (31) | 0.77 | 508 |
| General anesthesia, n (%) | 7 (1.4) | 2 (3.0) | 5 (1.1) | 0.40 | 508 |
| Thrombectomy procedure | 0.53 | 442 | |||
| Stent retriever only, n (%) | 147 (33) | 18 (30) | 129 (34) | ||
| Aspiration catheter, n (%) | 128 (29) | 16 (26) | 112 (29) | ||
| Combined technique, n (%) | 167 (38) | 27 (44) | 140 (38) | ||
| PTA, n (%) | 61 (12) | 11 (16) | 50 (11) | 0.23 | 509 |
| mTICI grade ≥ 2b, n (%) | 423 (84) | 36 (55) | 387 (89) | < 0.0001 | 502 |
| NIHSS score at 24 h at EVT, median (IQR) | 0 (0–4) | 11 (8–18) | 1 (0–3) | < 0.0001 | |
| Etiology of stroke | 0.10 | 509 | |||
| Cardioembolic, n (%) | 283 (56) | 31 (46) | 252 (57) | ||
| Atherothrombotic, n (%) | 108 (21) | 23 (34) | 85 (19) | ||
| Others, n (%) | 105 (23) | 13 (20) | 105 (24) | ||
Data are presented as n (%), mean (SD, standard deviation), or median (IQR, interquartile range). END, early neurological deterioration; mRS, modified Rankin Scale; NIHSS, National Institute of Health Stroke Scale; EVT, endovascular treatment; ASPECTS, Alberta Stroke Program Early Computed Tomography score; t-PA, tissue plasminogen activator; EVT, endovascular treatment; PTA, percutaneous transluminal angioplasty; mTICI, modified thrombolysis in cerebral infarction
The mean age tended to be higher in the END group (73 vs. 71 years, P = 0.15), with a greater proportion of patients aged ≥ 75 years (60% vs. 45%, P = 0.02). No significant differences were observed in mRS scores before onset or the distribution of onset-to-puncture time. Although not statistically significant, MeVO was more prevalent in the No-END group (23% vs. 35%, P = 0.14). The baseline NIHSS score trended to be lower in the END group (3 [2–4] vs. 4 [2–5], P = 0.053), while the distribution of NIHSS scores of 3–5 was similar (71% vs. 70%). Patients in the END group had lower ASPECTS at admission (9 [7–10] vs. 9 [8–10], P = 0.047), while the proportion of those with ASPECTS ≥ 7 was comparable between the two groups (89% vs. 92%, P = 0.33). No significant differences were observed in the proportion of t-PA administration or EVT procedures between the two groups (33% vs. 31%, P = 0.77). However, the achievement of mTICI ≥ 2b was significantly less observed in the END group (55% vs. 89%, P < 0.0001). The NIHSS scores at 24 h after EVT were significantly higher in the END group (11 [8–17] vs. 1 [0–3], P < 0.0001). The atherothrombotic etiology of AIS was more common in the END group (34% vs. 19%), while the cardioembolic cause was more prevalent in the No-END group (46% vs. 57%); however, the difference was not significant (P = 0.10) (Table 1).
Comparison of outcomes
Figure 2 shows that the mRS score at 30 days after EVT was significantly higher in the END group than in the No-END group (P < 0.0001) (Fig. 2).
Fig. 2.
Modified Rankin scale at 30 days. END, early neurological deterioration
Compared with the No-END group, the END group had a lower proportion of patients who achieved an mRS score of 0–2 at 30 days (17% vs. 80%, P < 0.0001), with an adjusted OR of 0.04 (95% CI, 0.02–0.11). The adjusted common OR for achieving a one-point lower mRS score at 30 days in the END group was 0.22 (95% CI, 0.15–0.30). The proportion of mRS scores of 0–1 at 30 days was also lower in the END group (6.1% vs. 66%, P < 0.0001), and the adjusted OR was 0.03 (95% CI, 0.01–0.10). The mortality rate within 30 days was higher in the END group than in the No-END group (9.1% vs. 0.7%, P < 0.0001). Sensitivity analysis using a reduced number of variables showed consistent results with the main model (Table 2).
Table 2.
Comparison of outcomes
| Total (N = 503) |
END group (N = 66) |
No-END group (N = 437) |
Crude OR (95% CI) |
P value | Adjusted OR (95% CI) |
P value | |
|---|---|---|---|---|---|---|---|
| mRS score of 0–2 at 30days, n (%) | 361 (72) | 11 (17) | 350 (80) | 0.05 (0.02–0.10) | < 0.0001 | 0.04 (0.02–0.11) | < 0.0001 |
| 0.07 (0.03–0.14)* | < 0.0001* | ||||||
| One scale better shift of mRS at 30 days | NA | NA | NA | 0.21 (0.16–0.28)a | NA | 0.22 (0.15–0.30)** | NA |
| mRS score of 0–1 at 30 days, n (%) | 291 (58) | 4 (6.1) | 287 (66) | 0.03 (0.01–0.09) | < 0.0001 | 0.03 (0.01–0.10) | < 0.0001 |
| All-cause mortality within 30 days, n (%) | 9 (1.8) | 6 (9.1) | 3 (0.7) | 14.5 (3.53–59.4) | < 0.0001 | NA | NA |
END, early neurological deterioration; OR, odds ratio; CI, confidence interval; mRS, modified Rankin scale
Adjusted for age, sex, mRS score before onset, tPA administration, onset-to-puncture time (≤ 6 h or > 6 h), ASPECTS, procedures during MT (stent retriever, aspiration, or combined), occluded vessel (ICA & M1, MeVO, VA–BA), TICI grade (≥ 2b or < 2b)
* Sensitivity analysis using a multivariable model adjusted for age, ASPECTS, and mTICI grade
** Common ORs calculated using an ordinal logistic regression model, adjusting for the same variables
Subgroup analysis
The subgroup analyses suggested that END within 24 h of EVT was consistently associated with a lower likelihood of mRS scores of 0–2 at 30 days (Fig. 3). In the END group, patients with anterior circulation occlusion tended to have a lower likelihood of achieving mRS scores of 0–2 at 30 days than those with posterior circulation occlusion (interaction P = 0.02). Regarding the etiology of AIS, the association between END and a lower achievement of mRS scores of 0–2 at 30 days was less significant among patients with cardioembolic stroke compared with that among those with other etiologies (interaction P = 0.02).
Fig. 3.
Subgroup analysis. END, early neurological deterioration; OR, odds ratio; CI, confidence interval; NIHSS, National Institute of Health Stroke Scale; t-PA, tissue plasminogen activator; ASPECTS, Alberta Stroke Program Early Computed Tomography Score; ICA, intracarotid artery; M1, M1 segment of middle cerebral artery; MeVO, medium-vessel occlusion
Factors associated with END
The multivariable logistic regression model indicated that the presence of the following variables was associated with END: age ≥ 75 years (adjusted OR 3.67; 95% CI, 1.78–7.55), ASPECTS (adjusted OR 0.82; 95% CI, 0.69–0.97), NIHSS scores before EVT of 0–2 compared with those of 3–5 (adjusted OR 2.11; 95% CI, 1.04–4.25), and mTICI grade ≤ 2a (adjusted OR 8.39; 95% CI, 3.90–18.0) (Table 3).
Table 3.
Factors associated with early neurological deterioration after endovascular treatment
| Variables | Adjusted OR (95% CIs) | P value |
|---|---|---|
| Age ≥ 75 | 3.67 (1.78–7.55) | 0.0004 |
| Men | 1.07 (0.54–2.14) | 0.84 |
| mRS score before onset | 0.64 (0.38–1.07) | 0.06 |
| Onset to puncture time ≥ 6 h | 1.30 (0.57–2.99) | 0.54 |
| ASPECTS | 0.82 (0.69–0.97) | 0.02 |
| t-PA use | 1.41 (0.66–2.99) | 0.37 |
| NIHSS before EVT ≤ 2 | 2.11 (1.04–4.25) | 0.04 |
| Procedures in EVT | ||
| Stent retriever only | Reference | |
| Aspiration catheter only | 1.27 (0.52–3.08) | 0.60 |
| Combined use | 1.45 (0.64–3.25) | 0.37 |
| mTICI grade ≤ 2a | 8.39 (3.90–18.0) | < 0.0001 |
| Atherothrombic etiology | 2.05 (0.88–4.76) | 0.09 |
OR, odds ratio; CI, confidence interval; mRS, modified Rankin scale; ASPECTS, Alberta Stroke Program Early Computed Tomography score; t-PA, tissue plasminogen activator; NIHSS, National Institute of Health Stroke Scale; EVT, endovascular treatment; TICI, thrombolysis in cerebral infarction
Discussion
This sub-analysis of the nationwide EVT registry showed that approximately one in eight patients undergoing EVT for AIS with mild symptoms (NIHSS score ≤ 5) experienced END after EVT. The END group had worse functional outcomes and a higher mortality rate within 30 days after EVT compared with the No-END group. Factors associated with an increased risk of END included older age, lower NIHSS score before EVT, and unsuccessful recanalization during EVT. END was generally associated with worse outcomes in the subgroups, although its adverse effect was more significant in patients with ICA and M1 occlusion and non-cardioembolic stroke.
The association between END and worse outcomes is clinically plausible and has been previously demonstrated, including in recent studies involving patients with acute LVO and M2 occlusion with mild symptoms (NIHSS ≤ 5) [7–9]. Our results were similar to those of these studies but extended the evidence by demonstrating the clinical impact of END in patients undergoing EVT for AIS with mild symptoms, irrespective of the occluded vessels, in a large population. The risk factors for END after EVT have also been explored in several studies in various settings. Regarding patients with acute LVO, the analysis of EVT arms of the HERMES collaboration identified lower baseline NIHSS scores, higher baseline glucose levels, and lower collateral grades as risk factors for END [12]. Other studies found NIHSS scores of ≤ 8 at admission to be a risk factor for END [21]. For isolated M2 occlusion with mild symptoms, atrial fibrillation has been identified as a risk factor for END [9]. A recent meta-analysis considering AIS identified additional factors, including elevated systolic blood pressure, time from onset to treatment, hypertension, diabetes mellitus, and internal cerebral artery occlusion [22]. The present study confirmed known risk factors for END, such as older age and lower baseline NIHSS scores, even in patients with mild symptoms. Additionally, our findings underscore the importance of baseline ASPECTS and successful recanalization during EVT for AIS with NIHSS scores of ≤ 5 before EVT.
In terms of stroke etiology, atherothrombotic stroke was more common in the END group, although it was not identified as an independent risk factor in our analysis. However, the observed trend may indicate that patients with atherosclerotic stroke could be more susceptible to END through mechanisms such as in-situ thrombosis, re-stenosis, or re-occlusion after EVT. Further investigations with larger cohorts are warranted to clarify the potential impact of stroke etiology on END risk.
When excluding patients who developed hemorrhagic complications after EVT, several pathophysiologies of END can be considered. In cases without successful recanalization, the progression of infarction and secondary cerebral edema would be included. Even in scenarios where successful recanalization was achieved, re-occlusion, ischemia-reperfusion injury [23], or systemic complications due to EVT could contribute to worsening of symptoms. In older patients, the clinical impact of END might be exacerbated by age-related changes in the brain, including white matter degeneration or atrophy. This could potentially lead to more significant effects compared with those in younger patients [24, 25]. Patients with very low NIHSS scores (0–2) pose a particular challenge for clinical decision-making for EVT eligibility in daily clinical practice. These patients were included in the present study despite having very low NIHSS scores. However, they would have relatively more serious symptoms, such as paralysis, and likely underwent EVT at an earlier stage after symptom onset. Such patients may be more prone to postoperative worsening, even with relatively small infarct progression or procedure-related effects. Furthermore, because END was defined as a ≥ 4-point increase in NIHSS score, individuals with lower baseline scores were inherently more likely to meet this threshold. This interpretation is consistent with prior reports showing an association between lower initial NIHSS scores and the development of END [12, 21]. It appears obvious that unsuccessful recanalization leads to the expansion of infarction; however, the specific risk factors associated with this outcome remain unclear. In such cases, the burden posed by EVT itself, such as a prolonged procedure time or iatrogenic anemia, may impact outcomes in addition to the infarction [26, 27]. Consequently, for patients at high risk of END, careful assessment of EVT eligibility and technical efforts to maximize the possibility of successful recanalization might be crucial to optimizing the benefits of EVT, particularly in those with mild symptoms. However, to discuss the eligibility of EVT for AIS with mild symptoms, a comparison with patients who received only the best medical treatment is needed. Ongoing randomized controlled trials investigating the efficacy of EVT in patients with low NIHSS scores may provide valuable insights in the future. These include the Endovascular Therapy for Low NIHSS Ischemic Strokes (ENDOLOW, NCT04167527) and Minor Stroke Therapy Evaluation (MOSTE, NCT03796468) trials.
This study has some limitations. First, the eligibility for EVT in patients with AIS with mild symptoms might have differed across facilities or among physicians. Since the JR-NET 4 lacked a standardized treatment protocol, selection bias was inevitable. However, EVT was likely performed for patients deemed suitable candidates for intervention. This suggests that the negative impact of END observed even in such patients holds clinically significant implications. Second, unadjusted factors likely influenced the association between END and clinical outcomes at 30 days. Potential independent variables, including comorbidities, which can independently affect outcomes, and confounding factors, such as the operator’s skill or postoperative management, may have influenced the results. In addition, collateral circulation, admission glucose levels, use of rescue therapies during EVT (e.g., stenting, intra-arterial thrombolysis, or antithrombotics), and intravenous antithrombotic administration after EVT was not assessed in this registry and therefore could not be included in the present analysis. While this unmeasured factor may influence the association between END and outcomes, the observed relationship remained robust, suggesting that the main findings are unlikely to be substantially altered. Third, the follow-up period for the JR-NET 4 was limited to 30 days, which is shorter than the standard 90-day follow-up used in many studies. As a result, 90-day mRS scores were not collected and could not be evaluated in this analysis. This complicates straightforward comparisons of the clinical impact of END with other studies. However, given that the association with poor outcomes was already obvious at 30 days, the interpretation of this study’s findings is unlikely to be weakened by the shorter follow-up period. Previous findings indicating that early neurological symptoms after EVT, including NIHSS scores at 24 h and 7 days, were significantly associated with 90-day outcomes, corroborate our findings [28]. Finally, the JR-NET 4 was conducted in Japan; therefore, caution should be applied when generalizing our findings to other settings.
Conclusions
END after EVT for AIS with mild symptoms was relatively common and significantly associated with poorer 30-day outcomes. For patients with NIHSS scores of ≤ 5, risk stratification methods for END after EVT and optimizing approaches for successful recanalization are warranted.
Author contributions
Study concept: SF, KU, HY, SY, NS.Study design: SF, KU, HY, NS.Acquisition of data: TO, NO, MH, HI. Statistical analysis: SF, KU.Interpretation of data: SF, KU.Drafting of the manuscript: SF, KU.Critical revision of the manuscript for important intellectual content: All authors.Obtained funding: NS.Supervision: NS.
Funding
This study was supported in part by a research grant from the Japanese Society of Neuroendovascular Therapy and by the Kobayashi Foundation, Osaka, Japan.
Data availability
The data supporting the findings of this study are available from the corresponding author upon reasonable request.
Declarations
Competing interests
KU reports lecturer’s fees from Daiichi Sankyo, Bristol-Myers Squibb, Stryker, and Medtronic outside the submitted work.TO reports lecturer’s fees from Medtronic, Daiichi-Sankyo, Johnson & Johnson, Terumo, Stryker Japan, Tokai Medical, Otsuka, Takeda, Eisai, Kaneka, Bristol-Myers Squibb, AstraZeneca, Japan Lifeline, Kowa, Nipro, Century Medical, and Idorsia; a consulting fee for Johnson & Johnson and Tokai Medical outside the submitted work.HY discloses research grants from Bristol-Myers Squibb; lecturer’s fees from Stryker, Medtronic, Johnson & Johnson, and Medico’s Hirata outside the submitted work. AI received a reserach grant from Fuji Film and lecture fees from Medtronic, Stryker, Terumo and Johnson and Johnson outside the submitted work.KI reports a research grant from Idorsia Pharamaceutical Japan outside the submitted work.HI reports the lecturer’s fees from Medtronic, Daiichi Sankyo., Stryker, Terumo, Johnson & Johnson, and Asahi Intecc outside the submitted work.YM discloses lecturer fees from Medtronic, Stryker, Terumo, Kaneka, Biomedical solution, E.P. Medical, B Braun, Daiichi Sankyo and Idorcia outside the submitted work.TS reports research grants from CANON medical systems, lecturer’s fees from Medtronic, and consulting fees from Kaneka Medix outside the submitted work.SY reports research grants from Medico’s Hirata, Medtronic, and Terumo; and lecturer fees from Medtronic, Kaneka, Stryker, Daiichi Sankyo, Bristol-Meyers Squibb, and Johnson & Johnson outside the submitted work.NS reports a research grant from Japan Lifeline, Kaneka, Medtronic, Terumo, and TG Medical; lecturer’s fees from Asahi-Intec, Kaneka, Medtronic, Stryker, and Terumo; membership on the advisory boards for Johnson & Johnson, Medtronic, and Terumo outside the submitted work. Other co-authors have no conflict of interest for this manuscript.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data supporting the findings of this study are available from the corresponding author upon reasonable request.