European Journal of Cardiovascular Medicine

Stroke, including both ischemic and hemorrhagic is one of the leading causes of long-term disability and death worldwide. A Middle Cerebral Artery (MCA) infarction is one of the most common manifestations of cerebrovascular disease. The clinical picture with an MCA infarction varies and depends on the site of the occlusion and the extent of collateral blood flow. Intravenous thrombolysis (IVT) therapy at the cerebral flow dose in the first 3 to 4.5 hours of the onset of ischemic stroke has a significant benefit.^1-4

Tenecteplase (TNK) is a genetically modified variant of alteplase and has greater fibrin specificity, slower inactivation by plasminogen activator inhibitor 1 and also has a longer half-life.⁵ Tenecteplase bolus is beneficial compared to the infusion of t-PA. According to the studies, the fixed doses of TNK 0.25/kg had better recanalization and clinical prognosis than alteplase in acute ischemic stroke patients.^6-8

Therefore, we planned to assess the clinical outcomes of IVT TNK 0.2 mg/kg bolus in Middle Cerebral Artery (MCA) ischemic stroke within four and half hours of onset.

Aim: To describe the three-month functional outcome in acute ischemic stroke in Middle Cerebral Artery territory who underwent intravenous thrombolysis with Tenecteplase.

OBJECTIVES:

• To assess the functional outcome at the end of three months with a modified Rankin scale after intravenous thrombolysis with Tenecteplase.
• To assess any intracranial haemorrhage that occurred within 24–48 hours after intravenous thrombolysis with Tenecteplase.

It was a prospective observational study conducted over a period of 12 months from April 2019 to March 2020 at a NABH-accredited South Indian tertiary care teaching hospital.

A study was conducted on 42 stroke patients who underwent IVT with TNK 0.25mg/kg within 4.5 hours of onset of symptoms of Middle Cerebral Artery territory ischemic stroke with measurable neurologic deficit (less than 25) on the National Institute of Health Stroke Scale (NIHSS) and patients with a mismatch between Diffusion-Weighted Imaging (DWI)– Magnetic Resonance Imaging (MRI).

Ethical Considerations:

Patients were informed of the procedure and consent was obtained. This study was approved by the KMCH ethics committee, KOVAI Medical College and Hospital Limited (EC/AP/686/03/2019). Written informed consent was obtained from the patient or legally authorized representative (if the patient is not able to understand the study procedure and the outcomes⁹).

Sample Size:

The improvement in the Tenecteplase group according to Lutsep HL et al.,¹⁰ is 64%. The total number of patients administered IVT at the study hospital was 53 people during 2018-19. Hence, the calculated sample size using Estimation of a Single population based on cluster sampling (Design Effect) - Finite population correction was 41 patients, considering a 20% non-follow-up rate.

Study Procedure:

Neurological deficits were measured through the NIHSS at baseline, at 2 hours, at 24 48 hours, and 7 days after IVT-TKT 0.25 mg/kg (or at discharge if earlier). Functional outcomes were measured with the MRS. The mRS score was assessed on the 7th day of IVT TNK (or at discharge if earlier), and at approximately 3 months as an outpatient consultation. Follow-up imaging consisted preferably of brain MRI, or brain CT, at 24–48 hours after treatment.⁹ Intracranial haemorrhage after thrombolysis was described according to the European Cooperative Acute Stroke Study (ECASS) morphological definition¹¹ and symptomatic intracranial haemorrhage was defined based on ECASS III criteria12 (any intracranial haemorrhage causally related to an increase of 4 points or more in NIHSS score).

NIHSS score:

Patients with acute ischemic stroke with a measurable deficit on NIHSS, who were admitted within 4.5 h of symptoms or those who had symptoms on awakening were judged eligible for intravenous thrombolysis according to the eligibility criteria.

As per Heldner et al¹³, the best cut-off values within 3 hours after symptom onset were NIHSS scores ≥ 9 (positive predictive value 86.4%) and NIHSS scores ≥ 7 within >3 to 6 hours (positive predictive value 84.4%) indicating anterior circulatory occlusion.

Modified Rankin’s Scale^{14, 15}

It is a 6-level ordinal outcome scale used to assess the functional status of patients, the range from no symptoms or functional impairment (mRS = 0) to severe disability requiring constant nursing care (mRS = 5) and Death (mRS = 6).

Alberta stroke program early CT score (ASPECTS)¹⁶

It is a semiquantitative topographic score used to estimate the infarct size. This score was initially developed for the assessment of infarct size in CT. Now, it is also being used for CT angiography, Diffusion-Weighted Imaging (DWI), and perfusion studies.

A score of one is given for each region accounting for a total score of 10. One point is deducted from 10 for hypodensities in each of these regions, giving the final ASPECTS score. There is an increase in dependence and death with ASPECTS of 7 or less.

MRI helps diagnose hyperacute and acute stroke. Several studies have proved that diffusion-weighted MRI is more sensitive in detecting ischemic changes when compared to CT. Sensitivity in identifying acute infarct in DWI is between 60-80% as compared to <50% for CT.^17-20

MRA is a non-invasive technique to find out the large vessel occlusion without the use of contrast, unlike CT perfusion. Time of flight is the most common technique in MR angiography. This technique uses 2D or 3D compensated gradient-echo sequences.²¹

After non-contrast CT of the brain, patients were assessed for thrombolytic treatment eligibility and study inclusion. Patients who have symptoms on awakening or unknown onset were included in the study and treated off-label if the mismatch between DW-MRI and FLAIR-MRI was detected.²²

Statistical Methods:

Socio-demographic variables and other categorical variables are described as percentages. Mean and Standard deviation were used for continuous data; Paired ‘T’ tests were used to compare the improvement in mRS and NIHSS measurements. P-value was considered significant if it is <0.05 and highly significant if it is <0.001.

Distribution of baseline parameters in the study population

Demographics: Among the study population, 12 (29%) patients were from the ≤55 years age group 30 (71%) were of ≥55 years of age; 9 (21%) patients were female, and 33 (76.6%) patients were males.

Social habits: Among the study population, 9 (21%) patients had a habit of smoking, and 6 (14.3%) patients had a habit of consuming alcohol in the study population.

Table 1: Distribution of study participants based on the presenting symptoms

Among the study population, 2 (4.7%) patients have presented with the symptoms of awakening. Other significant presenting symptoms like headache, vomiting, loss of consciousness, aphasia, slurring of speech, upper motor neuron facial weakness, hemiparesis, numbness, and ataxia are analyzed, and the details are depicted in Table 1.

Table 2: Cardiovascular workup findings

The study population has a medical history of hypertension (61.9%), diabetes mellitus (52.4%), dyslipidemia (38.1%), a previous cardiovascular event (14.3%), and Cerebrovascular history (minor CVA before 6 months) (11.9%) and atrial fibrillation (2.4%).

At the time of admission all the participants were assessed for cardiovascular events through 12-Lead ECG and Echo, the details are presented in Table 2.

Table 3: Laboratory analysis workup findings

The study population was assessed for metabolic, hematologic, and biochemical parameters and found that 1 (2.4%) participant with mild impairment of renal function. The details of other assessments are presented in Table 3.

Radiological parameters were assessed in all the study population and 1 (2.4%) had a significantly large infarct volume and the CT and MRI ASPECTS scores were less than 7 and 5, respectively for this participant.

Table 4: NIHSS Assessment Findings

Table 5: Association between NIHSS at admission and 24hrs after IVT‑TNK

All the study patients were assessed for the NIHSS Score both at admission and 24 hours after IVT-TNK. The detailed data along with the statistical Values were depicted in Tables 4 and 5.

Among the study population, there is a significant improvement in NIHSS score as there is a significant difference in mean score between scores between both groups (mean reduction of 4.93) and the P value is highly significant if it is <0.001 (Table 5).

Table 6: Distribution of study population based on the mRS score post-IVT-TNK

Table 7: Association between mRS at discharge and after 90 days

Distribution of study population according to mRS score at discharge and after 90 days. The detailed data along with the statistical values were depicted in Tables 6 and 7.

Among the study population, there is a significant improvement observed between Modified Rankin scale mRS at discharge and after 90 days, as there is a significant difference in mean score between scores between both groups (mean reduction of 1.61) and P-value is highly significant if it is <0.001.

Post dose Hemorrhagic transformation (N=42):  Among the study population, treated with Tenecteplase only 2 (4.7%) participants have developed hemorrhagic transformation.

The occurrence of stroke is higher in men than women worldwide; however, in the US it is reported no significant difference between men and women of 20 to 59 years of age.23 Jukka P et al²⁴ reported that Ischemic stroke is more prevalent in the population with ≤ 55 years of age. The incidence of ischemic stroke in young adults varies globally from 8 per one lakh person-years in Europe to more than 100 per one lakh person-years in sub-Saharan Africa. The prevalence of ischemic stroke among working-aged adults almost doubled from 1990 to 2013 both in high-income and low- to middle-income countries.

According to Kamalakannan S et al¹, the incidence and prevalence of stroke in different parts of India have ranged from 44.29 to 559/100,000 population during the past two decades. In support of the literature, in this study, 42 patients were diagnosed with MCA ischemia out of 298 patients who were admitted with neurological deficits during the study period. Out of 42 patients, 12 (29%) patients aged less than 55 years. The majority of patients i.e., 33 (77%) were men in our study population.

Social habits play an important role in neurological complications and still, debate is going on the impact of the level of alcoholism and neurological complications. In our study, 14% of study participants reported the habituation of alcohol consumption. Susanna et al²⁵ concluded that light and moderate alcohol consumption was inversely associated only with ischemic stroke, whereas heavy drinking was associated with increased risk of all stroke types with a stronger association for hemorrhagic strokes.

According to Biqi Pan et al²⁶ meta-analyses, there is an increased risk of stroke in smokers compared with nonsmokers. An increased risk of stroke associated with current smoking was observed in most subgroups. In addition, there was a dose-dependent relationship between current smoking status and the overall risk of stroke, and the risk was increased by 12% for each increment of 5 cigarettes per day. In our study, a considerable number of patients (21%) have the habit of smoking.

Hypertension is the most prevalent risk factor for stroke, based on data from 30 studies, 64% of stroke patients had a history of hypertension.27, 28 In support of the literature majority of the study patients (62%) have reported hypertension.

Findings from the Emerging Risk Factors Collaboration revealed the risk of ischemic and hemorrhagic stroke with diabetes. In our study, we had 22 (52%) patients with diabetes.

In registries and clinical trials up to 60% of documented patients have high levels of blood lipids including cholesterol.²⁹ The same scenario was observed in our study, the majority of the (38%) patients were diagnosed with dyslipidemia.

In our study group, 5 patients had a history of cerebrovascular events ≥6 months before admission. Patients with a recent ischemic stroke (8% to 14%) are at risk of a second ischemic stroke within a year.^{30, 31}

Cardiac investigations help determine the emboli source and are advised in selected circumstances. Noninvasive cardiac imaging can diagnose a variety of cardiac conditions, which can be a potential cause of TIA and evolving stroke. In our study group, Atrial Fibrillation was noted in 1 (2.3%) patient, regional wall motion abnormality in 8 (19%) patients and left ventricular hypertrophy in 20 (47.6%) patients (through Echocardiography).

A systemic review and meta-analysis by Zilong Hao et al³² revealed that renal dysfunction does not increase the risk of poor outcome and intracranial hemorrhage with intravenous thrombosis using tissue plasminogen activator. Renal dysfunction should not be a contraindication for the administration of intravenous thrombolysis to eligible patients. In our study population, 1 (2.3%) patient was diagnosed with mild renal dysfunction and the outcome of the current intravenous thrombolysis with Tenecteplase was good.

In our study group, one (2.3%) patient had CT ASPECTS 7 and MRI ASPECTS 5, his NIHSS score at arrival was 17 and mRS at discharge was 4, he had a poor outcome due to the large volume of infarct.

NIHSS had good reliability, validity, and a good predictor of the long-term prognosis of stroke.^33-37 However, most studies at home and abroad suggest that NIHSS has relatively poor sensitivity in the disease assessment of patients with posterior circulation stroke.38 A study revealed that NIHSS scores can effectively predict the risk of bleeding in patients with cerebral infarction after emergency intravenous thrombolysis. Studies revealed that NIHSS has an ideal specificity, sensitivity and accuracy in predicting the prognosis, and 13 points could be used as the cut-off value of prognosis for stroke patients^{. 39-43}

Most of the study patients scored ≤5 after IVT-TNK (Pre IV-TNK 5 [13%] vs post-TNK 24 [57%]) with a significant improvement in NIHSS score. In our study group, 2(4.7%) patients had an NIHSS score between 16 and 24 at arrival, after thrombolysis with TNK 3(7%) patients had the same NIHSS score. There is a significant improvement in NIHSS score as there is a significant difference in mean score between pre and post-IV-TNK (mean reduction of 4.93) and the P value is highly significant as it is <0.001.

The higher the NIHSS scores, the more severe the condition is. In our study group, 2 (4.7%) patients developed hemorrhagic transformation, among them 1 (2.3%) had an NIHSS score of more than 13 at arrival. This study revealed that the IV-TNK outcomes were better with a low NIHSS score.

The mRS scores of 0 to 1 were defined as positive (treatment success) whereas scores 2 to 6 were defined as negative. Numerous investigations have reported an increased risk of poor outcome (defined as mRS 2 or 3) from discharge to 6 months for more severe types of strokes. Nedeltchev K et al study in 198 younger ischemic stroke patients showed that total anterior circulation infarction was an independent predictor of mRS grade 2 or death at 3 months.^44-46

Molina CA et al⁴⁷ studies involving 177 patients with acute ischemic stroke found that achieving recanalization within 5 hours after intravenous thrombolytic therapy was an independent predictor of achieving a modified Rankin Scale (mRS) Grade 2 at 3 months post-stroke. The odds ratio was 4.11, with a 95% confidence interval of 2.42 to 6.95, and the result was statistically significant (P = 0.001).

Multivariate regression analyses have shown that acute impairment scores, such as the NIH Stroke Scale (NIHSS), are independent predictors of the modified Rankin Scale (mRS) grade from 2 months to 1 year after a stroke. Demchuk and colleagues found that patients with mild strokes (NIHSS scores 1 to 5) had a higher likelihood of achieving a favourable outcome (mRS grade 0 to 1) compared to those with more severe strokes (NIHSS scores 11 to 15, 16 to 20, and above 20). The confidence intervals and p-values for these comparisons were 95% CI 0.02 to 0.16, P = 0.001; 95% CI 0.13 to 0.56, P = 0.001; and 95% CI 0.20 to 0.79, P = 0.008, respectively.⁴⁸

In this study, at the time of discharge, 6 patients (14.2%) had mRS scores of 0, 11 patients (26%) had mRS scores of 1, and 5 patients (12%) had mRS scores of 2. At the three-month follow-up, 11 patients (26%) had mRS scores of 0, 9 patients (21%) had mRS scores of 1, and 8 patients (19%) had mRS scores of 2. There was a significant improvement in mRS scores, with a mean reduction of 1.61 between the two time points, and the P value was highly significant at <0.001.

The incidence of symptomatic intracranial hemorrhage (sICH) following alteplase administration at the standard dose of 0.9 mg/kg (with a 10% bolus over 1 hour) ranges from 2% to 7% in clinical trials and prospective stroke registries.49 In our study, 4.7% (2 patients) developed sICH after receiving TNK at a dose of 0.25 mg/kg as a bolus.

Here are the observations we have drawn:

1. Intravenous thrombolysis with TNK at a dose of 0.25 mg/kg is safe, with a lower risk of symptomatic intracranial hemorrhage.
2. The functional outcomes for MCA ischemic stroke patients treated with IVT-TNK are satisfactory, with mild stroke patients showing better mRS scores at discharge and after 90 days.
3. Satisfactory improvement in NIHSS scores after IVT-TNK in patients with mild to moderate-severe strokes.

1. Kamalakannan S, Gudlavalleti ASV, Gudlavalleti VSM, Goenka S, Kuper H. Incidence & prevalence of stroke in India: A systematic review. Indian J Med Res. 2017;146(2):175-185. doi:10.4103/ijmr.IJMR_516_15
2. Daroff RB, Jankovic J, Mazziotta JC, Pomeroy SL. Bradley’s Neurology in Clinical Practice 8th edition. Elsevier Health Sciences; 2015. 2348 p.
3. Sacco, Ralph L, Broderick JP, Caplan LR, Connors JJ, et al.An updated definition of stroke for the 21st century: a statement for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2013;44(7): 2064-89. doi: 10.1161/STR.0b013e318296aeca
4. Saver JL. Time is brain-qualified. Stroke. 2006;37(1):263-6. doi: 10.1161/01.STR.0000196957.55928.ab.
5. Parsons M, Spratt N, Bivard A, Campbell B, Chung K, et al. A randomized trial of tenecteplase versus alteplase for acute ischemic stroke. N Engl J Med. 2012;366(12):1099-107. doi: 10.1056/NEJMoa1109842.
6. Ramakrishnan TCR, Kumaravelu S, Narayan SK, Buddha SS, Murali C, et al. Tenecteplase in Stroke Investigators. Efficacy and Safety of Intravenous Tenecteplase Bolus in Acute Ischemic Stroke: Results of Two Open-Label, Multicenter Trials. Am J Cardiovasc Drugs. 2018;18(5):387-95. doi: 10.1007/s40256-018-0284-1.
7. Xu N, Chen Z, Zhao C, Xue T, Wu X, et al. Different doses of tenecteplase vs alteplase in thrombolysis therapy of acute ischemic stroke: evidence from randomized controlled trials. Drug Des Devel Ther. 2018;12:2071-84. doi: 10.2147/DDDT.S170803.
8. Kheiri B, Osman M, Abdalla A, Haykal T, Ahmed S,et al. Tenecteplase versus alteplase for management of acute ischemic stroke: a pairwise and network meta-analysis of randomized clinical trials. J Thromb Thrombolysis. 2018;46(4):440-50. doi: 10.1007/s11239-018-1721-3.
9. Logallo N, Novotny V, Assmus J, Kvistad CE, Alteheld L, et al. Tenecteplase versus alteplase for management of acute ischaemic stroke (NOR-TEST): a phase 3, randomised, open-label, blinded endpoint trial [Internet]. The Lancet Neurology. 2017;16:781–8. Accessed 15 March 2022. http://dx.doi.org/10.1016/s1474-4422(17)30253-3.
10. Lutsep HL, Albers GW, Decrespigny A, Kamat GN, Marks MP, et al. Clinical utility of diffusion-weighted magnetic resonance imaging in the assessment of ischemic stroke [Internet]. Annals of Neurology. 1997;41:574–80. Accessed 15 March 2022. http://dx.doi.org/10.1002/ana.410410505.
11. Wolfgang Fleischhacker W, Brooks DJ. Stroke-VascularDiseases. Springer Science & Business Media. New York; 2013.Journal of neural transmission, Supplementum. 63; ISSN 0303-6995.
12. Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, et al. Thrombolysis with Alteplase 3 to 4.5 Hours after Acute Ischemic Stroke [Internet]. New England Journal of Medicine. 2008;359:1317–29. http://dx.doi.org/10.1056/nejmoa0804656
13. Heldner MR, Zubler C, Mattle HP, Schroth G, Weck A, et al. National Institutes of Health Stroke Scale Score and Vessel Occlusion in 2152 Patients With Acute Ischemic Stroke [Internet]. Stroke. 2013;44:1153–7. http://dx.doi.org/10.1161/strokeaha.111.000604
14. Cheng B, Forkert ND, Zavaglia M, Hilgetag CC, Golsari A, et al. Influence of Stroke Infarct Location on Functional Outcome Measured by the Modified Rankin Scale [Internet].Stroke. 2014;45:1695–702.http://dx.doi.org/10.1161/strokeaha.114.005152
15. Jamie L. Banks, Charles A. Marotta. Outcomes Validity and Reliability of the Modified Rankin Scale: Implications for Stroke Clinical Trials: A Literature Review and Synthesis. Stroke.2007;38(3):1091-96.
16. Olivato S, Nizzoli S, Cavazzuti M, Casoni F, Nichelli PF, Zini A. e-NIHSS: an Expanded National Institutes of Health Stroke Scale Weighted for Anterior and Posterior Circulation Strokes. Journal of Stroke and Cerebrovascular Diseases.2016;25:2953–7.http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2016.08.011
17. Sarkar S. Physical Approximations and Stochastic Processes in Einstein’s 1905 Paper on Brownian Motion. Einstein the Formative Years, 1879–1909. 2000. p. 203–29. Available from: http://dx.doi.org/10.1007/978-1-4612-0311-7_7
18. MRI-guided Thrombolysis for Lenticulostriate Artery Stroke within 12 Hours after the Onset of Symptoms. Available from: http://dx.doi.org/10.21203/rs.2.18226/v1
19. Wall SD, Barnes B, Brant-Zawadzki M. CT Findings Within Twenty-Four Hours of Cerebral Infarction. Vol. 16, Investigative Radiology. 1981. p. 396. Available from: http://dx.doi.org/10.1097/00004424-198109000-00072
20. Liu B, Gao S, Li S. A Comprehensive Comparison of CT, MRI, Positron Emission Tomography or Positron Emission Tomography/CT, and Diffusion-Weighted Imaging-MRI for Detecting the Lymph Nodes Metastases in Patients with Cervical Cancer: A Meta-Analysis Based on 67 Studies. Gynecologic and Obstetric Investigation. 2017;82:209–22. http://dx.doi.org/10.1159/000456006
21. Lee J, Chung T-S, Lee K-Y, Suh SH. Comparison of Non-invasive Imaging Studies in the Evaluation of Carotid Artery Stenosis and Occlusion: CT Angiography, Time-of-Flight MR Angiography and Contrast-Enhanced MR Angiography. Journal of the Korean Society of Magnetic Resonance in Medicine.2011;15:234. http://dx.doi.org/10.13104/jksmrm.2011.15.3.234
22. Thomalla G, Cheng B, Ebinger M, Hao Q, Tourdias T, et al. DWI-FLAIR mismatch for the identification of patients with acute ischaemic stroke within 4·5 h of symptom onset (PRE-FLAIR): a multicentre observational study. Lancet Neurol. 2011;10(11):978–86.
23. Christensen H, Bushnell C. Stroke in Women. Lifelong Learning in Neurology. Continuum. 2020;26:363–85. http://dx.doi.org/10.1212/con.0000000000000836.
24. Putaala J. Ischemic Stroke in Young Adults. Lifelong Learning in Neurology. Continuum. 2020;26:386–414. http://dx.doi.org/10.1212/con.0000000000000833.
25. Larsson SC, Wallin A, Wolk A, Markus HS. Differing association of alcohol consumption with different stroke types: a systematic review and meta-analysis. BMC Medicine. 2016;14. http://dx.doi.org/10.1186/s12916-016-0721-4.
26. Pan B, Jin X, Jun L, Qiu S, Zheng Q, Pan M. The relationship between smoking and stroke: A meta-analysis. Medicine. 2019;98(12): e14872.
27. Feigin VL, Norrving B, Mensah GA. Global Burden of Stroke. Circulation Research. 2017;120:439–48. http://dx.doi.org/10.1161/circresaha.116.308413.
28. Collaboration TERF. The Emerging Risk Factors Collaboration. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. The Lancet. 2010;375:2215–22. http://dx.doi.org/10.1016/s0140-6736(10)60484-9.
29. ElAli A, Doeppner TR, Zechariah A, Hermann DM. Increased Blood–Brain Barrier Permeability and Brain Edema After Focal Cerebral Ischemia Induced by Hyperlipidemia. Stroke. 2011;42:3238–44. http://dx.doi.org/10.1161/strokeaha.111.615559
30. Cámara A la, la Cámara A, Arche J, Vivas P, Guzmán J, del Pozo S, et al. Recurrence after a First-ever Ischemic Stroke Development of a Clinical Prediction Rule. Research in Neurology: An International Journal. 2013:1–13. http://dx.doi.org/10.5171/2013.264063
31. Jc N, Navarro JC. Recurrence Rate of Ischemic Stroke: A Single Center Experience. Austin Journal of Cerebrovascular Disease & Stroke. 2017;4.http://dx.doi.org/10.26420/austinjcerebrovascdisstroke.2017.1057
32. Hao Z, Yang C, Liu M, Wu B. Renal Dysfunction and Thrombolytic Therapy in Patients with Acute Ischemic Stroke: A Systematic Review and Meta-Analysis. Medicine. 2014;93(28): e286.
33. Kwiatkowski TG, Libman RB, Frankel M, Tilley BC, Morgenstern LB, Lu M, et al. Effects of Tissue Plasminogen Activator for Acute Ischemic Stroke at One Year [Internet]. New England Journal of Medicine. 1999;340:1781–7. http://dx.doi.org/10.1056/nejm199906103402302
34. Metz CE. Some Practical Issues of Experimental Design and Data Analysis in Radiological ROC Studies. Investigative Radiology. 1989;340:234–45. http://dx.doi.org/10.1097/00004424-198903000-00012.
35. Kwakkel G, Veerbeek JM, van Wegen EEH, Nijland R, Harmeling-van der B, Dippel DWJ. Predictive value of the NIHSS for ADL outcome after ischemic hemispheric stroke: Does timing of early assessment matter? Journal of the Neurological Sciences. 2010;294:57–61. http://dx.doi.org/10.1016/j.jns.2010.04.004.
36. Young FB, Weir CJ, Lees KR. Comparison of the National Institutes of Health Stroke Scale With Disability Outcome Measures in Acute Stroke Trials. Stroke. 2005;36:2187–92. http://dx.doi.org/10.1161/01.str.0000181089.41324.70.
37. Kellert L, Sykora M, Gumbinger C, Herrmann O, Ringleb PA. Blood pressure variability after intravenous thrombolysis in an acute stroke does not predict intracerebral hemorrhage but a poor outcome. Cerebrovasc Dis. 2012;33(2):135–40.
38. Linfante I, Llinas RH, Schlaug G, Chaves C, Warach S, Caplan LR. Diffusion-Weighted Imaging and National Institutes of Health Stroke Scale in the Acute Phase of Posterior-Circulation Stroke. Archives of Neurology. 2001;58.http://dx.doi.org/10.1001/archneur.58.4.621.
39. Zhao X-J, Li Q-X, Liu T-J, Wang D-L, An Y-C, Zhang J, et al. Predictive values of CSS and NIHSS in the prognosis of patients with acute cerebral infarction: A comparative analysis. Medicine. 2018;97(39): e12419.
40. Yaghi S, Herber C, Boehme AK, Andrews H, Willey JZ, Rostanski SK, et al. The Association between Diffusion MRI-Defined Infarct Volume and NIHSS Score in Patients with Minor Acute Stroke. Journal of Neuroimaging. 2017;27:388–91.http://dx.doi.org/10.1111/jon.12423.
41. Muir KW, Weir CJ, Murray GD, Povey C, Lees KR. Comparison of neurological scales and scoring systems for acute stroke prognosis. Stroke. 1996;27(10):1817–20.
42. Adams HP, Davis PH, Leira EC, Chang K-C, Bendixen BH, Clarke WR, et al. Baseline NIH Stroke Scale score strongly predicts outcome after stroke: A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST) [Internet]. Neurology. 1999;53:126. http://dx.doi.org/10.1212/wnl.53.1.126.
43. Schlegel D, Kolb SJ, Luciano JM, Tovar JM, Cucchiara BL, Liebeskind DS, et al. Utility of the NIH Stroke Scale as a Predictor of Hospital Disposition. Stroke. 2003;34:134–7. http://dx.doi.org/10.1161/01.str.0000048217.44714.02.
44. Banks JL, Marotta CA. Outcomes validity and reliability of the modified Rankin scale: implications for stroke clinical trials: a literature review and synthesis. Stroke. 2007;38(3):1091–6.
45. Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957;2(5):200–15.
46. Nedeltchev K, der Maur TA, Georgiadis D, Arnold M, Caso V, Mattle HP, et al. Ischaemic stroke in young adults: predictors of outcome and recurrence. J Neurol Neurosurg Psychiatry. 2005;76(2):191–5.
47. Molina CA, Alexandrov AV, Demchuk AM, Saqqur M, Uchino K, Alvarez-Sabín J, et al. Improving the predictive accuracy of recanalization on stroke outcome in patients treated with tissue plasminogen activator. Stroke. 2004;35(1):151–6.
48. Demchuk AM, Tanne D, Hill MD, Kasner SE, Hanson S, Grond M, et al. Predictors of good outcome after intravenous tPA for acute ischemic stroke. Neurology. 2001;57(3):474–80.
49. Yaghi S, Willey JZ, Cucchiara B, Goldstein JN, Gonzales NR, Khatri P, et al. Treatment and Outcome of Hemorrhagic Transformation After Intravenous Alteplase in Acute Ischemic Stroke: A Scientific Statement for Healthcare Professionals from the American Heart Association/American Stroke Association. Stroke. 2017;48(12): e343–61.