Research National Institutes of Health Stroke Scale score is an unreliable predictor of perfusion deficits in acute stroke Victor Choi1, Mahesh Kate1, Jayme C. Kosior1, Brian Buck1, Trevor Steve1, Rebecca McCourt1, Thomas Jeerakathil1, Ashfaq Shuaib1, Derek Emery2, and Ken Butcher1* Background Perfusion-weighted magnetic resonance imaging is not routinely used to investigate stroke/transient ischemic attack. Many clinicians use perfusion-weighted magnetic resonance imaging selectively in patients with more severe neurological deficits, but optimal selection criteria have never been identified. Aims and/or Hypothesis We tested the hypothesis that a National Institutes of Health Stroke Scale score threshold can be used to predict the presence of perfusion-weighted magnetic resonance imaging deficits in patients with acute ischemic stroke/transient ischemic attack. Methods National Institutes of Health Stroke Scale scores were prospectively assessed in 131 acute stroke/transient ischemic attack patients followed by magnetic resonance imaging, including perfusion-weighted magnetic resonance imaging within 72 h of symptom onset. Patients were dichotomized based on the presence or absence of perfusion deficits using a threshold of Tmax (time to peak maps after the impulse response) delay ≥four-seconds and a hypoperfused tissue volume of ≥1 ml. Results Patients with perfusion deficits (77/131, 59%) had higher median (interquartile range) National Institutes of Health Stroke Scale scores (8 [12]) than those without perfusion deficits (3 [4], P < 0·001). A receiver operator characteristic analysis indicated poor to moderate sensitivity of National Institutes of Health Stroke Scale scores for predicting perfusion deficits (area under the curve = 0·787). A National Institutes of Health Stroke Scale score of ≥6 was associated with specificity of 85%, but sensitivity of only 69%. No National Institutes of Health Stroke Scale score threshold identified all cases of perfusion-weighted magnetic resonance imaging deficits with sensitivity >94%. Conclusions Although higher National Institutes of Health Stroke Scale scores are predictive of perfusion deficits, many patients with no clinically detectable signs have persisting cerebral blood flow changes. A National Institutes of Health Stroke Scale score threshold should therefore not be used to select patients for perfusion-weighted magnetic resonance imaging. Perfusion-weighted magnetic resonance imaging should be considered in all patients presenting with acute focal neurological deficits, even if these deficits are transient. Correspondence: Ken Butcher*, 2E3 WMC Health Sciences Centre, University of Alberta, 8440 112th Street, Edmonton, Alberta T6G 2B7, Canada. E-mail: ken.butcher@ualberta 1 Division of Neurology, University of Alberta, Edmonton, Alberta, Canada 2 Department of Diagnostic Imaging, University of Alberta, Edmonton, Alberta, Canada
Key words: ischemic stroke, MRI, stroke, cerebral infarction, acute stroke therapy, acute
Received: 28 March 2014; Accepted: 14 November 2014; Published online 6 April 2015
Patients This was a retrospective analysis of data collected between March 2008 and February 2010 as part of an ongoing observational magnetic resonance imaging (MRI) study of TIA/stroke (19,20). The study protocol was approved by our local human research ethics committee and informed consent was obtained. Patients were imaged acutely, at day 7 and on day 30 with MRI. A PWI
Conflicts of interest: None declared. Funding: Dr. Ken Butcher is supported by Heart and Stroke Foundation of Alberta, NWT and Nunavut Professorship in Stroke Medicine. DOI: 10.1111/ijs.12438
582
Vol 10, June 2015, 582–588
Introduction Perfusion-weighted magnetic resonance imaging (PWI) in patients with acute cerebrovascular symptoms provides important diagnostic information beyond brain parenchymal imaging alone (1,2). PWI increases diagnostic accuracy in patients with focal neurological deficits (3). It remains the most reliable method of determining the presence/absence of the ischemic penumbral tissue (4–7). Although penumbral selection of patients for delayed thrombolysis requires further validation, PWI has also been shown to improve prediction of final infarct size and clinical outcomes (8,9). Perfusion imaging has also been shown to result in changes in management, beyond thrombolysis based on penumbral patterns (3,10). Several studies have indicated that perfusion deficits are present in transient ischemic attack (TIA) patients, even after the symptoms have resolved (11–13). PWI may aid in the diagnosis and management of TIA patients, who are at higher risk of recurrent strokes (14,15). Despite the advantages of perfusion imaging, PWI is not routine in many centers due to increased time and cost. Many clinicians will selectively use PWI in patients who present with more severe neurological deficits, but the optimal selection criteria for PWI has never been established. The National Institutes of Health Stroke Scale (NIHSS) is a reliable assessment tool used to quantify the severity of deficits in stroke patients (16,17). Although a positive correlation between increasing NIHSS score and perfusion deficits volume has been described (18), no threshold for predicting the presence of perfusion deficits has ever been identified.
Aims and/or hypothesis We tested the hypothesis that an NIHSS score threshold can be used to predict the presence of perfusion deficits in patients with acute ischemic stroke/TIA.
Methods
© 2015 World Stroke Organization
Research
V. Choi et al. sequence was included at baseline in all patients without contraindications to gadolinium contrast. An NIHSS score was calculated at admission in all patients. Eligible patients were ≥18 years of age and functionally independent (defined as a modified Rankin Scale score ≤2). All patients were imaged with MRI within 72 h of onset of stroke symptoms. Exclusion criteria included contraindications to MRI or gadolinium contrast (renal failure as defined by creatinine >160 μmol/l, or estimated glomerular filtration rate 1 resulted in 7% of the perfusion deficits in our study remaining undetected. The lower threshold for prediction of perfusion deficits likely reflects the fact that PWI can demonstrate areas of decreased blood flow, even when a large artery occlusion is not visible, as was the case in the majority of our patients (Table 1). While an NIHSS score threshold of >1 had predicted perfusion deficits with good sensitivity (93%), 38% (5/13) of patients with an NIHSS score of 0, i.e. TIA patients, had perfusion deficits in our study. Thus, perfusion deficits would be missed in many TIA patients using an NIHSS score threshold >1. It has been demonstrated that up to 34% of patients with TIA exhibit PWI deficits, which persist after resolution of neurological symptoms (13,27). These are clinically relevant changes, as the presence of focal hypoperfusion following TIA/minor stroke is highly predictive of recurrent DWI lesion formation and its location within 30 days (19). Furthermore, MR DWI/PWI mismatch volume has been demonstrated to predict infarct growth and clinical deterioration in patients with minor stroke/TIA (28). These data suggest that stroke ‘recurrence’ in TIA may © 2015 World Stroke Organization
Research
V. Choi et al. actually be a completion of the original cerebrovascular syndrome. In addition, an NIHSS score of zero does not imply that patients are neurologically intact as the NIHSS is insensitive to more subtle neurological changes, including pronator drift and cognitive impairment. Thus, MRI, including PWI, may therefore ultimately be useful in identification and aggressive treatment of TIA patients at highest risk for early stroke recurrence (29). This study has several limitations, including the relatively small sample size and a wide range of NIHSS scores (0–27). The inclusion of a range of patients makes the data ‘real life’, but can also add significant noise within which important messages may be lost. However, our sample includes many patients with low NIHSS scores, which is crucial in identifying an NIHSS score threshold for perfusion deficit prediction with high precision. Another limitation is the relatively long inclusion period for PWI. Although we tried to image as close to symptom onset as possible, these scans (PWI) were performed in a research scanner during daytime hours, after consent was obtained, resulting in delayed time to imaging. However, more than half the patients were imaged within 18·7 h, and only 12 were imaged >48 h after onset. Furthermore, inclusion of patients imaged with PWI at later time-points will only decrease the likelihood of demonstrating perfusion deficits, due to the increasing likelihood of spontaneous reperfusion. Indeed, there was a trend to longer time to MRI in the group without perfusion deficits. Finally, the inclusion of thrombolysed patients (7%) increases the heterogeneity of our sample. However, all patients treated with tPA had high NIHSS scores (≥6), and all had persisting perfusion deficits following treatment, making it unlikely that this affected our results. Both clinical assessment (NIHSS scores) and radiological imaging are imperfect, but complimentary tools in the assessment and management of patients with acute neurovascular syndromes. In conclusion, the NIHSS score is an unreliable predictor of perfusion deficits in acute ischemic stroke/TIA and should not be used as a screening tool for PWI. The exclusion of patients from PWI based on low NIHSS scores, particularly in TIA patients, will result in a failure to recognize persisting perfusion deficits in many cases. Perfusion imaging should be considered in patients presenting with symptoms of acute ischemic stroke/TIA.
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References 1 Parsons MW, Yang Q, Barber PA et al. Perfusion magnetic resonance imaging maps in hyperacute stroke: relative cerebral blood flow most accurately identifies tissue destined to infarct. Stroke 2001; 32:1581–7. 2 Barber PA, Darby DG, Desmond PM et al. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI. Neurology 1998; 51:418–26. 3 Sunshine JL, Bambakidis N, Tarr RW et al. Benefits of perfusion MR imaging relative to diffusion MR imaging in the diagnosis and treatment of hyperacute stroke. AJNR Am J Neuroradiol 2001; 22:915– 21. 4 Karonen JO, Liu Y, Vanninen RL et al. Combined perfusionand diffusion-weighted MR imaging in acute ischemic stroke © 2015 World Stroke Organization
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during the 1st week: a longitudinal study. Radiology 2000; 217: 886–94. Davis SM, Chua MG, Lichtenstein M, Rossiter SC, Binns D, Hopper JL. Cerebral hypoperfusion in stroke prognosis and brain recovery. Stroke 1993; 24:1691–6. Karonen JO, Vanninen RL, Liu Y et al. Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke. Ischemic penumbra predicts infarct growth. Stroke 1999; 30:1583–90. Butcher K, Parsons M, Baird T et al. Perfusion thresholds in acute stroke thrombolysis. Stroke 2003; 34:2159–64. Davis SM, Donnan GA, Parsons MW et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; 7:299–309. Albers GW, Thijs VN, Wechsler L et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006; 60:508–17. Heidenreich JO, Hsu D, Wang G et al. Magnetic resonance imaging results can affect therapy decisions in hyperacute stroke care. Acta Radiol 2008; 49:550–7. Ide C, De Coene B, Trigaux JP et al. Discrepancy between diffusion and perfusion imaging in a patient with transient ischaemic attack. J Neuroradiol 2001; 28:118–22. Neumann-Haefelin T, Wittsack HJ, Wenserski F et al. Diffusionand perfusion-weighted MRI in a patient with a prolonged reversible ischaemic neurological deficit. Neuroradiology 2000; 42: 444–7. Restrepo L, Jacobs MA, Barker PB, Wityk RJ. Assessment of transient ischemic attack with diffusion- and perfusion-weighted imaging. AJNR Am J Neuroradiol 2004; 25:1645–52. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000; 284:2901–6. Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004; 328: 326. Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non-neurologists in the context of a clinical trial. Stroke 1997; 28:307–10. Dewey HM, Donnan GA, Freeman EJ et al. Interrater reliability of the National Institutes of Health Stroke Scale: rating by neurologists and nurses in a community-based stroke incidence study. Cerebrovasc Dis 1999; 9:323–7. Tong DC, Yenari MA, Albers GW, O’Brien M, Marks MP, Moseley ME. Correlation of perfusion- and diffusion-weighted MRI with NIHSS score in acute (
Key words: ischemic stroke, MRI, stroke, cerebral infarction, acute stroke therapy, acute
Received: 28 March 2014; Accepted: 14 November 2014; Published online 6 April 2015
Patients This was a retrospective analysis of data collected between March 2008 and February 2010 as part of an ongoing observational magnetic resonance imaging (MRI) study of TIA/stroke (19,20). The study protocol was approved by our local human research ethics committee and informed consent was obtained. Patients were imaged acutely, at day 7 and on day 30 with MRI. A PWI
Conflicts of interest: None declared. Funding: Dr. Ken Butcher is supported by Heart and Stroke Foundation of Alberta, NWT and Nunavut Professorship in Stroke Medicine. DOI: 10.1111/ijs.12438
582
Vol 10, June 2015, 582–588
Introduction Perfusion-weighted magnetic resonance imaging (PWI) in patients with acute cerebrovascular symptoms provides important diagnostic information beyond brain parenchymal imaging alone (1,2). PWI increases diagnostic accuracy in patients with focal neurological deficits (3). It remains the most reliable method of determining the presence/absence of the ischemic penumbral tissue (4–7). Although penumbral selection of patients for delayed thrombolysis requires further validation, PWI has also been shown to improve prediction of final infarct size and clinical outcomes (8,9). Perfusion imaging has also been shown to result in changes in management, beyond thrombolysis based on penumbral patterns (3,10). Several studies have indicated that perfusion deficits are present in transient ischemic attack (TIA) patients, even after the symptoms have resolved (11–13). PWI may aid in the diagnosis and management of TIA patients, who are at higher risk of recurrent strokes (14,15). Despite the advantages of perfusion imaging, PWI is not routine in many centers due to increased time and cost. Many clinicians will selectively use PWI in patients who present with more severe neurological deficits, but the optimal selection criteria for PWI has never been established. The National Institutes of Health Stroke Scale (NIHSS) is a reliable assessment tool used to quantify the severity of deficits in stroke patients (16,17). Although a positive correlation between increasing NIHSS score and perfusion deficits volume has been described (18), no threshold for predicting the presence of perfusion deficits has ever been identified.
Aims and/or hypothesis We tested the hypothesis that an NIHSS score threshold can be used to predict the presence of perfusion deficits in patients with acute ischemic stroke/TIA.
Methods
© 2015 World Stroke Organization
Research
V. Choi et al. sequence was included at baseline in all patients without contraindications to gadolinium contrast. An NIHSS score was calculated at admission in all patients. Eligible patients were ≥18 years of age and functionally independent (defined as a modified Rankin Scale score ≤2). All patients were imaged with MRI within 72 h of onset of stroke symptoms. Exclusion criteria included contraindications to MRI or gadolinium contrast (renal failure as defined by creatinine >160 μmol/l, or estimated glomerular filtration rate 1 resulted in 7% of the perfusion deficits in our study remaining undetected. The lower threshold for prediction of perfusion deficits likely reflects the fact that PWI can demonstrate areas of decreased blood flow, even when a large artery occlusion is not visible, as was the case in the majority of our patients (Table 1). While an NIHSS score threshold of >1 had predicted perfusion deficits with good sensitivity (93%), 38% (5/13) of patients with an NIHSS score of 0, i.e. TIA patients, had perfusion deficits in our study. Thus, perfusion deficits would be missed in many TIA patients using an NIHSS score threshold >1. It has been demonstrated that up to 34% of patients with TIA exhibit PWI deficits, which persist after resolution of neurological symptoms (13,27). These are clinically relevant changes, as the presence of focal hypoperfusion following TIA/minor stroke is highly predictive of recurrent DWI lesion formation and its location within 30 days (19). Furthermore, MR DWI/PWI mismatch volume has been demonstrated to predict infarct growth and clinical deterioration in patients with minor stroke/TIA (28). These data suggest that stroke ‘recurrence’ in TIA may © 2015 World Stroke Organization
Research
V. Choi et al. actually be a completion of the original cerebrovascular syndrome. In addition, an NIHSS score of zero does not imply that patients are neurologically intact as the NIHSS is insensitive to more subtle neurological changes, including pronator drift and cognitive impairment. Thus, MRI, including PWI, may therefore ultimately be useful in identification and aggressive treatment of TIA patients at highest risk for early stroke recurrence (29). This study has several limitations, including the relatively small sample size and a wide range of NIHSS scores (0–27). The inclusion of a range of patients makes the data ‘real life’, but can also add significant noise within which important messages may be lost. However, our sample includes many patients with low NIHSS scores, which is crucial in identifying an NIHSS score threshold for perfusion deficit prediction with high precision. Another limitation is the relatively long inclusion period for PWI. Although we tried to image as close to symptom onset as possible, these scans (PWI) were performed in a research scanner during daytime hours, after consent was obtained, resulting in delayed time to imaging. However, more than half the patients were imaged within 18·7 h, and only 12 were imaged >48 h after onset. Furthermore, inclusion of patients imaged with PWI at later time-points will only decrease the likelihood of demonstrating perfusion deficits, due to the increasing likelihood of spontaneous reperfusion. Indeed, there was a trend to longer time to MRI in the group without perfusion deficits. Finally, the inclusion of thrombolysed patients (7%) increases the heterogeneity of our sample. However, all patients treated with tPA had high NIHSS scores (≥6), and all had persisting perfusion deficits following treatment, making it unlikely that this affected our results. Both clinical assessment (NIHSS scores) and radiological imaging are imperfect, but complimentary tools in the assessment and management of patients with acute neurovascular syndromes. In conclusion, the NIHSS score is an unreliable predictor of perfusion deficits in acute ischemic stroke/TIA and should not be used as a screening tool for PWI. The exclusion of patients from PWI based on low NIHSS scores, particularly in TIA patients, will result in a failure to recognize persisting perfusion deficits in many cases. Perfusion imaging should be considered in patients presenting with symptoms of acute ischemic stroke/TIA.
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References 1 Parsons MW, Yang Q, Barber PA et al. Perfusion magnetic resonance imaging maps in hyperacute stroke: relative cerebral blood flow most accurately identifies tissue destined to infarct. Stroke 2001; 32:1581–7. 2 Barber PA, Darby DG, Desmond PM et al. Prediction of stroke outcome with echoplanar perfusion- and diffusion-weighted MRI. Neurology 1998; 51:418–26. 3 Sunshine JL, Bambakidis N, Tarr RW et al. Benefits of perfusion MR imaging relative to diffusion MR imaging in the diagnosis and treatment of hyperacute stroke. AJNR Am J Neuroradiol 2001; 22:915– 21. 4 Karonen JO, Liu Y, Vanninen RL et al. Combined perfusionand diffusion-weighted MR imaging in acute ischemic stroke © 2015 World Stroke Organization
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during the 1st week: a longitudinal study. Radiology 2000; 217: 886–94. Davis SM, Chua MG, Lichtenstein M, Rossiter SC, Binns D, Hopper JL. Cerebral hypoperfusion in stroke prognosis and brain recovery. Stroke 1993; 24:1691–6. Karonen JO, Vanninen RL, Liu Y et al. Combined diffusion and perfusion MRI with correlation to single-photon emission CT in acute ischemic stroke. Ischemic penumbra predicts infarct growth. Stroke 1999; 30:1583–90. Butcher K, Parsons M, Baird T et al. Perfusion thresholds in acute stroke thrombolysis. Stroke 2003; 34:2159–64. Davis SM, Donnan GA, Parsons MW et al. Effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-controlled randomised trial. Lancet Neurol 2008; 7:299–309. Albers GW, Thijs VN, Wechsler L et al. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the diffusion and perfusion imaging evaluation for understanding stroke evolution (DEFUSE) study. Ann Neurol 2006; 60:508–17. Heidenreich JO, Hsu D, Wang G et al. Magnetic resonance imaging results can affect therapy decisions in hyperacute stroke care. Acta Radiol 2008; 49:550–7. Ide C, De Coene B, Trigaux JP et al. Discrepancy between diffusion and perfusion imaging in a patient with transient ischaemic attack. J Neuroradiol 2001; 28:118–22. Neumann-Haefelin T, Wittsack HJ, Wenserski F et al. Diffusionand perfusion-weighted MRI in a patient with a prolonged reversible ischaemic neurological deficit. Neuroradiology 2000; 42: 444–7. Restrepo L, Jacobs MA, Barker PB, Wityk RJ. Assessment of transient ischemic attack with diffusion- and perfusion-weighted imaging. AJNR Am J Neuroradiol 2004; 25:1645–52. Johnston SC, Gress DR, Browner WS, Sidney S. Short-term prognosis after emergency department diagnosis of TIA. JAMA 2000; 284:2901–6. Coull AJ, Lovett JK, Rothwell PM. Population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services. BMJ 2004; 328: 326. Goldstein LB, Samsa GP. Reliability of the National Institutes of Health Stroke Scale. Extension to non-neurologists in the context of a clinical trial. Stroke 1997; 28:307–10. Dewey HM, Donnan GA, Freeman EJ et al. Interrater reliability of the National Institutes of Health Stroke Scale: rating by neurologists and nurses in a community-based stroke incidence study. Cerebrovasc Dis 1999; 9:323–7. Tong DC, Yenari MA, Albers GW, O’Brien M, Marks MP, Moseley ME. Correlation of perfusion- and diffusion-weighted MRI with NIHSS score in acute (
