Identifying the Risk Factors of Early Neurological Deterioration After Thrombolysis in Patients with Acute Ischemic Stroke

Abstract

Objective: The efficacy of intravenous (IV) recombinant tissue plasminogen activator (rt-PA) therapy in the treatment of acute ischemic stroke (AIS) has been demonstrated in many studies and IV rt-PA therapy has been increasingly used all over the world. Early neurological deterioration (END) in AIS is common and potentially associated with a poor clinical outcome. The prevalence of END in AIS ranges from 13% to 37% in studies. The aim of this study is to determine the prevalence and risk factors of END in patients with AIS receiving IV rt-PA therapy.

Materials and Methods: One hundred fifty seven patients who were given IV rt-PA treatment by Bursa Uludag University Faculty of Medicine, Department of Neurology between 01.01.2020 and 01.01.2021 were retrospectively included in this study. It was planned to determine the risk group by comparing patients with END with those without.

Results: Age (p=0.023), serum glucose level (p=0.045), The National Institutes of Health Stroke score at discharge (p<0.01), Alberta Stroke Program Early CT (ASPECT) score (p<0.01) when clinical, radiological and demographic data associated with END were evaluated and, statistically significant correlation was found with the presence of major vessel occlusion (p=0.012), ischemic stroke due to cardioembolism (p=0.002), clinical outcome (p<0.001) and symptomatic intracerebral hemorrhage (p<0.001). When the significant variables associated with END were evaluated with binary logistic regression, the most significant variables were found to be age (p=0.006) and ASPECT score (p<0.001).

Conclusion: The causes of END are multifactorial. The most associated risk factors were found to be advanced age and low ASPECT score. It was understood that the most common cause of END was the inability to perform mechanical thrombectomy for major vessel occlusion. Contrary to popular belief, the most common cause of END in patients with AIS who received IV rt-PA treatment was not considered to be symptomatic intracranial hemorrhage but to inadequate recanalization or late recanalization.

Introduction

Acute ischemic stroke (AIS) is one of the leading causes of disability and death in the world, affecting one in six adults with approximately 3-6 million stroke cases per year (1). The efficacy of intravenous recombinant tissue plasminogen activator thrombolysis (IVT) in the treatment of AIS has been demonstrated in many studies, and IVT has been increasingly applied all over the world (2,3).

Early neurological deterioration (END) is common and associated with poor functional outcome. The prevalence of END in AIS ranges from 13% to 37% (4,5,6,7). This wide range may be due to differences in the definition of END. There are several possible mechanisms such as inadequate collateralization, clot progression, recurrent stroke, brain edema, hemorrhagic transformation, re-occlusion of the recanalized artery and seizures, that may cause END in AIS (8).

AIS is a heterogeneous disease in which many complex mechanisms are involved. In addition, risk factors of ischemic stroke show ethnic and racial differences. The aim of this study is to determine the prevalence and predictors of END in patients with AIS treated with IVT.

Material and Methods

This study retrospectively included 157 patients who were treated with IVT in Bursa Uludag University, Faculty of Medicine, Department of Neurology between 01.01.2020-01.01.2021.

The Clinical Research Ethics Committee of the Bursa Uludag University, Faculty of Medicine approved the study (13 April 2022; 2022-8/7). Since it was a retrospective study, a consent form was not required. Eligible patients were treated with IVT according to international clinical guidelines (9).

Inclusion criteria were as follows: Age ≥18 years and admission within the first 4.5 hours of symptom onset. An upper or a lower “The National Institutes of Health Stroke Scale” (NIHSS) score threshold was not chosen. Exclusion criteria were; intracranial hemorrhage in computed tomography (CT), systemic hemorrhage, the presence of frank hypodensity indicating established brain infarction, and “Alberta Stroke Program Early CT” (ASPECT) score of 4 or less. All patients were monitored hourly by using NIHSS for the first 24 hours after IVT start and twice a day after the first 24 hours. An NIHSS score increase of 2 or more in the first 72 hours was considered END (10). NIHSS scoring was performed by neurologists as part of the clinical routine.

Patients with a non-disabling stroke and with NIHSS score <4 who were admitted within the first 4.5 hours of their symptom onset were observed during the treatment window for progression of symptoms. In our center, CT is the initial preferred imaging modality in patients admitted to the emergency department with focal neurological deficits. If intracranial hemorrhage is not seen in the CT, CT angiography is routinely performed. Signs of early ischemia on CT were evaluated and ASPECT scores were calculated for all included patients. Presence of large vessel occlusion (LVO) was evaluated on CT angiography. The examined large vessels were internal carotid artery, M1 and M2 segments of middle cerebral artery and basilar artery. As recommended in international stroke guidelines; mechanical thrombectomy (MT) was performed in patients with ischemic stroke with LVO with a pre-stroke “modified Rankin Scale” (mRS) score lower than 2, and with an NIHSS score of 6 or more (9). Follow up CT was done either 24 hours after treatment or in case of END, and all imaging studies were evaluated by a neuroradiologist.

Symptomatic intracerebral hemorrhage (SICH) was defined as local or distant type 2 parenchymal hemorrhage occurring <36 hours following treatment and causing NIHSS decrease of ≥4 points according to the criteria of “The Safe Implementation of Thrombolysis in Stroke-Monitoring Study” (11).

In patients without SICH in control brain CT, stroke etiologies were evaluated using the TOAST stroke classification, and treatments for stroke etiology were initiated. The clinical outcome of the patients was evaluated in the neurology outpatient clinic on the 90^th day. Those with mRS of 0.1, 2 were evaluated as good clinical outcome, and those with 3-6 as poor clinical outcome. We sought to identify predictors of END by comparing patients with and without END.

Statistical Analysis

Patients with AIS who received IVT were categorized as those who developed END and who did not. The radiological, demographic and clinical data of both groups were compared. Statistical analysis was performed using the IBM SPSS Statistics 25.0 package (IBM Corp., Armonk, New York, USA). ShapiroWilk test and Q-Q plot were used to determine normality of the distribution of the data. Means and standard deviations or medians (25%-75% quartiles) were then used for analysis of continuous variables. Frequencies and percentages were given for categorical variables. Independent sample t-test or Mann-Whitney U test was used to analyze differences in terms of continuous variables between groups. Fisher Exact test and Pearson chi-square test were used to analyze the differences in terms of categorical variables between groups. Binary logistic regression analysis was used to identify independent risk factors for END in patients with AIS who received IVT. P <0.05 was considered statistically significant. Receiver operating characteristic (ROC) analysis was performed to determine the cut-off values of the ASPECT score and age.

Results

One hundred fifty-seven patients, 65 (41.4%) females and 92 (58.6%) males, were included in this study. One hundred eighteen (75.2%) patients had hypertension, 61 (38.9%) diabetes mellitus, 84 (53.5%) coronary artery disease, 78 (49.7%) atrial fibrillation (AF) and 69 (43.9%) patients were smokers. Twenty-seven (17.2%) patients had ischemic stroke due to large artery atherosclerosis, 84 (53.1%) cardioembolism (CE), 8 (5.1%) small-vessel occlusion, 4 (2.4%) stroke of other determined etiology and 35 (22.2%) stroke of undetermined etiology.

One hundred fifty-seven patients were treated with IVT. The mean onset-to-needle time (OTN) of the patients was 190.41±50.23 minutes. LVO was observed in 77 (49%) patients. MT was performed in 47 (29.9%) patients. MT was not performed in 10 patients with NIHSS score <6, and 20 (12.7%) patients who had a pre-stroke mRS score of >2. The mean NIHSS score of patients with AIS was 16.00±7.45 on admission and 10.51±10.31 at discharge. END was observed in 32 (20%) patients. Fifty-five (35%) patients had poor clinical outcome and 102 (64.9%) had good clinical outcome.

END was associated with age (p=0.023), serum glucose level (p=0.045), NIHSS score at discharge (p<0.01), ASPECT score (p<0.01), the presence of LVO (p=0.012), ischemic stroke due to CE (p=0.002), clinical outcome (p<0.01) and symptomatic intracranial hemorrhage (p<0.001). However, END was not associated with gender, hypertension, diabetes mellitus, coronary artery disease, AF, smoking, systolic blood pressure, diastolic blood pressure, creatinine value, NIHSS score before IVT treatment, severity of leukoaraiosis, stroke due to LVO, OTN and MT (p>0.05) (Table 1).

In binary logistic regression, the most significant variables were found to be age [p=0.006, Odds ratio (OR):1.077] and the ASPECT score (p<0.001, OR: 1.278) (Table 2).

The ROC analysis was performed to determine the cutoff values of age and the ASPECT score. The cut-off value for ASPECT score and END was 7 [p<0.001, area under the curve (AUC): 0.721, sensitivity: 68.7%, specificity: 72.8%]. The cut-off value for age and END was 78 (p<0.020, AUC: 0.630), sensitivity: 43.7%, specificity: 81.6% (Table 3, Figure 1).

Figure 1. Comparison of area under the curve for independent risk factors for early neurological deterioration

The causes of END were as follows: Not undergoing MT due to pre-stroke mRS score >2 in 12 patients, SICH in 9 patients, futile recanalization in 4 patients, concomitant aortic dissection in 1 patient, and END of unknown cause in 6 patients (Table 4).

Discussion

The incidence of END was found to be 20% in patients with AIS treated with IVT, and the incidence of poor functional outcome was increased in patients with END. To date, few studies have analyzed the relationship between END and prognosis (12).

In previous studies, factors associated with END were found to be advanced age, systolic blood pressure at admission, diabetes mellitus, and severity of stroke (4,7,13,14,15,16,17). The causes of END are multifactorial. In our study, factors associated with END in patients with AIS treated with IVT were advanced age, presence of LVO, serum glucose level, ASPECT score, ischemic stroke due to cardioembolism, and symptomatic intracranial hemorrhage. The predictors of END were found to be age and ASPECT score.

Advanced age is the most notable and irreversible risk factor for AIS and is an important predictor of clinical outcome (18). The incidence of ischemic stroke increases rapidly with age in both genders, doubling every decade after the age of 55 (19). More than a third of all acute strokes occur in people aged 80 years, and the incidence of stroke will continue to increase in this age group due to increased life expectancy (20). As we found in line with the literature, the probability of developing AF in elderly patients was found to be significantly higher than in younger patients (21,22). AF is associated with a five-fold increased risk of ischemic stroke, but anticoagulation can reduce the risk of recurrent stroke by 60%. Although more than one-third of patients over the age of 80 have AF, only 13.6% are treated with oral anticoagulants (23,24). In addition, AF is an independent risk factor for LVO (25). Many studies have shown the association of advanced age with symptomatic intracranial hemorrhage and poor clinical outcome. Possible causes of END in elderly patients may include more LVO due to AF, the failure of patients with LVO to benefit from IVT, and not performing MT in patients with mRS score greater than 2.

In our study, one of the factors associated with END in patients with AIS who received IVT was the presence of LVO.

Possibly thanks to good collateralization, some patients with AIS with LVO may present with mild deficits. Although IVT is standard in these patients, the risk of END and poor functional outcome has been emphasized (26,27,28).

In patients with minor deficits and LVOs, it has been shown that the cause of END is not intracranial hemorrhage, but rather the enlargement of the ischemic area due to inadequate recanalization (29).

The variable with highest association with END was found to be the ASPECT score in this study. The ASPECT score was developed to detect early ischemic changes in patients with AIS. The use of the ASPECT score becomes widespread as recanalization treatments are increasingly used. In the international stroke guidelines, recanalization treatments are recommended for patients with AIS with an ASPECT score of 6 or higher. ASPECT score has been associated with END in most studies.

SICH, the most devastating cause of END, occurred in 9 (5.7%) patients. Although the incidence of symptomatic intracranial hemorrhage was found to be 6.2% in the NINDS study and 6.2% in the ECASS 2 study, the incidence of symptomatic intracranial hemorrhage was found to be less than 6% in recent studies (2,3,30).

Conclusion

LVO was present in most of the patients (49.1%) who received IVT in our study. The most common cause of END was considered to be failure to perform MT in patients with LVO. Contrary to popular belief, the most common cause of END in patients with AIS who received IVT was not SICH but it was inadequate recanalization or late recanalization. END is multifactorial and its causes are varied. Advanced age and low ASPECT score are independently associated with END. The major limitation of our study was its retrospective nature and small sample size. Due to multifactorial nature of END, our findings based on a small sample cannot be generalized and national multicenter prospective studies are advised.

Approval for the study was obtained from Bursa Uludag University Faculty of Medicine Clinical Research Ethics Committee with the letter dated 13 April 2022 and numbered 2022-8/7.

Retrospective study.

Externally peer-reviewed.

Surgical and Medical Practices: Y.D., R.Ö., B.H., M.B., Concept: Y.D., R.Ö., Design: Y.D., R.Ö., Data Collection or Processing: Y.D., R.Ö., Analysis or Interpretation: Y.D., R.Ö., B.H., M.B., Literature Search: Y.D., R.Ö., Writing: Y.D., R.Ö.

No conflict of interest was declared by the authors.

The authors declared that this study received no financial support.

References

1. Seshadri S, Wolf PA. Lifetime risk of stroke and dementia: current concepts, and estimates from the Framingham study. Lancet Neurol 2007;6:1106- 1114.
2. National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587.
3. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2008;359:1317-1329.
4. Kwan J, Hand P. Early neurological deterioration in acute stroke: clinical characteristics and impact on outcome. QJM 2006;99:625-633.
5. Mohr JP, Caplan LR, Melski JW, et al. The Harvard Cooperative Stroke Registry: a prospective registry. Neurology 1978;28:754-762.
6. Martí-Vilalta JL, Arboix A. The Barcelona stroke registry. Eur Neurol 1999;41:135-142.
7. Weimar C, Mieck T, Buchthal J, et al. Neurologic worsening during the acute phase of ischemic stroke. Arch Neurol 2005;62:393-397.
8. Thanvi B, Treadwell S, Robinson T. Early neurological deterioration in acute ischaemic stroke: predictors, mechanisms and management. Postgrad Med J 2008;84:412-417.
9. Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the Early Management of Patients With Acute Ischemic Stroke: 2019 Update to the 2018 Guidelines for the Early Management of Acute Ischemic Stroke: A Guideline for Healthcare Professionals From the American Heart Association/American Stroke Association. Stroke 2019;50:e344-e418. Erratum in: Stroke 2019;50:e440-e441.
10. Cuadrado-Godia E. Early neurological deterioration, easy methods to detect it. Indian J Med Res 2015;141:266-268. 11.
11. Köhrmann M, Schellinger PD. Symptomatic intracranial hemorrhage after thrombolysis. Cerebrovasc Dis 2007;23:83-84.
12. Ma Y, Liu L, Pu Y, et al. Predictors of neurological deterioration during hospitalization: results from the Chinese Intracranial Atherosclerosis (CICAS) study. Neurol Res 2015;37:385-390.
13. Dávalos A, Cendra E, Teruel J, Martinez M, Genís D. Deteriorating ischemic stroke: risk factors and prognosis. Neurology 1990;40:1865-1869.
14. Roquer J, Rodríguez-Campello A, Gomis M, et al. Acute stroke unit care and early neurological deterioration in ischemic stroke. J Neurol 2008;255:1012-1017.
15. Barber M, Wright F, Stott DJ, Langhorne P. Predictors of early neurological deterioration after ischaemic stroke: a case-control study. Gerontology 2004;50:102-109.
16. Tei H, Uchiyama S, Ohara Ket al. Deteriorating ischemic stroke in 4 clinical categories classified by the Oxfordshire Community Stroke Project. Stroke 2000;31:2049-2054.
17. Seo WK, Seok HY, Kim JH, et al. C-reactive protein is a predictor of early neurologic deterioration in acute ischemic stroke. J Stroke Cerebrovasc Dis 2012;21:181-186.
18. Heuschmann PU, Kolominsky-Rabas PL, Roether J, et al. Predictors of in-hospital mortality in patients with acute ischemic stroke treated with thrombolytic therapy. JAMA 2004;292:1831-1838.
19. Chong J, Sacco R. Risk factors for stroke, assessing risk, and the mass and high-risk approaches for stroke prevention. In: Gorelick PB, ed. Continuum: Stroke Prevention. Hagerstwon, Maryland: Lippincott Williams and Wilkins; 2005:18-34.
20. Lenti L, Brainin M, Titianova E, et al. Stroke care in Central Eastern Europe: current problems and call for action. Int J Stroke 2013;8:365-371.
21. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 2004;110:1042- 1046.
22. Zoni-Berisso M, Lercari F, Carazza T, Domenicucci S. Epidemiology of atrial fibrillation: European perspective. Clin Epidemiol 2014;6:213-220.
23. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 1991;22:983-988.
24. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007;146:857-867.
25. Pagola J, Juega J, Francisco-Pascual J, et al. Large vessel occlusion is independently associated with atrial fibrillation detection. Eur J Neurol 2020;27:1618-1624.
26. Mazya MV, Cooray C, Lees KR, et al. Minor stroke due to large artery occlusion. When is intravenous thrombolysis not enough? Results from the SITS International Stroke Thrombolysis Register. Eur Stroke J 2018;3:29- 38.
27. Heldner MR, Jung S, Zubler C, et al. Outcome of patients with occlusions of the internal carotid artery or the main stem of the middle cerebral artery with NIHSS score of less than 5: comparison between thrombolysed and non-thrombolysed patients. J Neurol Neurosurg Psychiatry 2015;86:755- 760.
28. Heldner MR, Chaloulos-Iakovidis P, Panos L, et al. Outcome of patients with large vessel occlusion in the anterior circulation and low NIHSS score. J Neurol 2020;267:1651-1662.
29. Seners P, Baron JC. Revisiting 'progressive stroke': incidence, predictors, pathophysiology, and management of unexplained early neurological deterioration following acute ischemic stroke. J Neurol 2018;265:216-225.
30. Eryildiz ES, Özdemir AÖ, Bas DF, Mutlu F. Identifying risk factors for rtpa-related intracerebral hemorrhages in patients with acute stroke. J Neurol Sci 2017;4:301-311.