Journal of Clinical Neuroscience xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short Communication
Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis Christine Kremer a,⇑, Johan Kappelin a, Fabienne Perren b a b
Neurology Department, Skåne University Hospital, University of Lund, Jan Waldenström Gata 15, S-20502 Malmö, Sweden Department of Clinical Neurosciences, Neurology, HUG, University Hospital and Medical Faculty of Geneva, Switzerland
a r t i c l e
i n f o
Article history: Received 26 September 2013 Accepted 28 January 2014 Available online xxxx Keywords: Acute Aphasia Cerebral Ischemia Outcome Stroke Systemic thrombolysis
a b s t r a c t Clinical observation suggested to us that aphasia recovers relatively better than other deficits early after intravenous recombinant tissue plasminogen activator (IV-rtPA) treatment in stroke patients with minor deficits, while the reverse seemed the case in those with severe deficits. Retrospective analysis of acute ischemic stroke patients with aphasia admitted within 3 hours from symptom onset and treated with IV-rtPA was carried out. Stroke severity, aphasia and global neurological impairment were assessed at admission and 24 hours after thrombolysis. Improvement of aphasia (gain of P1 point on the National Institutes of Health Stroke Scale [NIHSS] aphasia score) and global neurological improvement (gain of P4 points on the NIHSS) were compared in minor strokes (NIHSS 67), moderate strokes (NIHSS 8–15), and major strokes (NIH P16). Sixty-nine of 243 stroke patients suffered from aphasia. Improvement of aphasia occurred in 7/16 minor strokes, 11/25 moderate strokes, and 7/28 severe strokes. Improvement of P4 points on the NIHSS occurred in 3/16 minor strokes, 17/25 moderate strokes and 15/28 severe strokes. There is a significant (X2 = 4.073, p < 0.05) dissociation of recovery of aphasia and that of other neurological deficits between minor versus severe strokes. This confirms the clinically suspected dissociation between a good early recovery from aphasia in minor strokes relative to recovery of other neurological deficits, as opposed to a better recovery from other neurological deficits than from aphasia in patients with severe strokes. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Aphasia is diagnosed in 21–38% [1–5] of hospitalized stroke patients and is responsible for high morbidity and mortality [4], decreased functional recovery [7,8] and a higher risk of developing depression [5,9,10]. Informal clinical observation at our and other centers suggested to us that aphasia recovers relatively better than other deficits early after intravenous recombinant tissue plasminogen activator (IV-rtPA) treatment in stroke patients with minor deficits, while the reverse seemed the case in those with severe deficits. It has been shown that patients with minor strokes show favorable outcome after thrombolysis with low intracerebral bleeding risk and thrombolyses should not be withheld [6,11]. Actual guidelines for thrombolytic therapy recommend a National Institutes of Health Stroke Scale (NIHSS) score of P5 with the exception of patients with symptoms that could be potentially disabling such as aphasia, inattention and other cortical signs. ⇑ Corresponding author. Tel.: +46 4033 6945; fax: +46 4033 3055. E-mail address: [email protected] (C. Kremer).
However, little is known about the effect of this treatment on the specific outcome of aphasia in relation to other deficits. Proven beneficial effects of thrombolysis in patients with minor strokes and aphasia may lead to a more deliberate application of IV thrombolysis and therefore to a lower morbidity in this group of patients. Data are lacking concerning the reperfusion pattern in language areas compared to other areas in patients treated by IV-rtPA thrombolysis. We thus retrospectively analyzed the benefit of thrombolytic therapy in evaluating the short term outcome of aphasia compared to the other deficits.
2. Methods A total of 243 acute ischemic stroke patients admitted within 3 hours from symptom onset and treated with IV-rtPA (0.9 mg/kg [maximum of 90 mg] infused over 60 minutes with 10% of the total dose administered as an initial IV bolus over 1 minute) were retrospectively studied over a period of 6 years. Patients with incomplete NIHSS or aphasia scores were excluded. Stroke severity
http://dx.doi.org/10.1016/j.jocn.2014.01.010 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kremer C et al. Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.01.010
2
C. Kremer et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
was assessed according to the NIHSS at admission and at 24 hours after thrombolysis. Only patients who also suffered from aphasia were studied. Aphasia was assessed at admission and after 24 hours. Improvement of aphasia was defined by the gain of P1 point on the aphasia subscale score of the NIHSS and global neurological improvement by the gain of P4 points on the total NIHSS. Patients were divided into three groups based on stroke severity: minor, NIHSS 67; moderate, NIHSS 8–15; and major, NIHSS P16. Baseline CT scans of the brain, including angiographic sequences at admission and a CT scan at 24 hours, were performed in all patients. Symptomatic hemorrhage was considered if there was intracerebral hemorrhage on CT scan within 72 hours from symptom onset associated with an increase in NIHSS score of 4 points. 3. Results Sixty-nine patients with aphasia of 243 stroke patients (28.4%) were included. Nine patients were excluded due to incomplete follow-up data at 24 hours. Baseline data are provided in Table 1. Improvement of aphasia occurred in 7/16 (43%) minor strokes, 11/25 (44%) moderate strokes, and 7/28 (25%) severe strokes. Table 2 shows the NIHSS aphasia subscores in the respective categories. Seven out of 69 (10.1%) patients suffered from intracerebral hemorrhage (after systemic thrombolysis) of whom three were considered symptomatic. Improvement of NIHSS P4 points occurred in 3/16 (18.7%) minor strokes, 17/25 (68%) moderate strokes and 15/28 (53.5%) severe strokes. Including all groups in the analysis the dissociation was not significant (X2 [degrees of freedom = 2] 4.246, p = 0.059, one-tailed). However, when analyzing only the groups with minor versus severe deficits, for which we had a clinical suspicion of difference (X2 [degrees of freedom = 1] 4.073, p = 0.043; p = 0.021; one-tailed) this dissociation was significant. 4. Discussion Our analysis confirms the clinically suspected dissociation between a good early recovery from aphasia in minor strokes relative to the recovery of other NIHSS deficits, and the reverse in patients with severe strokes displaying a better recovery from other deficits than aphasia. It has been demonstrated that administering IV-rtPA to patients with a very mild stroke, NIHSS 66, can lead to improved clinical outcome when compared to patients with similar NIHSS who have not received thrombolytic treatment [12]. Even in the case of mild isolated aphasia with an NIHSS of 1, IV-rtPA seems to be safe and effective [12]. Aphasia is an early marker of unfavorable outcome in mild ischemic stroke patients, and these patients should not be treated on the basis of NIHSS scoring alone [13]. Data concerning the temporal pattern of aphasia improvement after thrombolysis compared to other deficits is lacking. In right hemispheric stroke it could be shown,
Table 1 Data of included stroke patients suffering from aphasia Total, n Men, n (%) Women, n (%) Median age ± SD Minor stroke, n (%) Moderate stroke, n (%) Major stroke, n (%) Patients with ICH after thrombolysis Patients with symptomatic ICH after thrombolysis ICH = intracerebral hemorrhage, SD = standard deviation.
69 39 (56) 30 (43) 60 ± 30 16 (23) 25 (36) 28 (40) 7 3
Table 2 Patients distributed by aphasia severity according to the National Institutes of Health Stroke Scale (NIHSS) in stroke severity categories NIHSS stroke severitya
a
NIHSS aphasia subscale
Minor
Moderate
Major
1 point 2 points 3 points Total
4 9 3 16
7 11 7 25
1 13 14 28
Minor = NIHSS 67, Moderate = NIHSS 8–15, Major = NIHSS P16.
for example, that thrombolysis has a favorable effect on visuoperceptual functions in acute stroke with equal baseline NIHSS [14]. Limitations of this study are its retrospective character and the relatively small number of included patients. Additional examinations by brain MRI and perfusion imaging would have allowed a deeper pathophysiological insight in the topic. However our results might be the basis of further research. Due to the lack of a control group of non-thrombolysed patients it cannot be excluded that the results might not be exclusively applicable to thrombolysed patients. In moderate and major stroke patients with larger penumbra zones, improvement over the first 24 hours could involve other regions, for example visual areas more than language areas, with improvement in general scoring but not aphasia, areas which are also in some cases well collateralized. Conversely, patients with aphasia could benefit from reperfusion in smaller penumbra zones. The size of the neural network supporting language is larger than that of other functions and thus smaller penumbra recovery might lead to greater functional improvement. Our study shows that in patients treated with IV-rtPA thrombolysis there is a dissociation between early recovery of aphasia in patients with mild compared to severe strokes. This could facilitate the decision to treat patients with aphasia with IV-rtPA thrombolyis independently of the baseline NIHSS score. Further studies are needed to explore the nature of the reperfusion pattern in different areas of the brain early after IV-rtPA thrombolysis. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Pedersen PM, Jørgensen HS, Nakayama H, et al. Aphasia in acute stroke: incidence, determinants and recovery. Ann Neurol 1995;38:659–66. [2] Brust JC, Shafer SQ, Richter RW, et al. Aphasia in acute stroke. Stroke 1976;7:167–74. [3] Wade DT, Hewer RL, David RM, et al. Aphasia after stroke: natural history and associated deficits. J Neurol Neurosurg Psychiatry 1986;49:11–6. [4] Laska AC, Hellblom A, Murray V, et al. Aphasia in acute stroke and relation to outcome. J Intern Med 2001;249:413–22. [5] Kauhanen ML, Korpelainen IT, Hiltunen P, et al. Aphasia, depression, and nonverbal cognitive impairment in ischaemic stroke. Cerebrovasc Dis 2000;10:455–61. [6] Engelter ST, Gostynski M, Papa S, et al. Epidemiology of aphasia attributable to first ischemic stroke: incidence, severity, fluency, etiology, and thrombolysis. Stroke 2006;37:1379–84. [7] Tilling K, Sterne JA, Rudd AG. A new method for predicting recovery after stroke. Stroke 2001;32:2867–73. [8] Paolucci S, Antonucci G, Pratesi L, et al. Functional outcome in stroke inpatient rehabilitation: predicting no, low and high response patients. Cerebrovasc Dis 1998;8:228–34. [9] Bullain SS, Chriki LS, Stern TA. Aphasia: associated disturbances in affect, behaviour, and cognition in the setting of speech and language difficulties. Psychosomatics 2007;48:258–64. [10] Åström M, Adolfsson R, Asplund K. Major depression in stroke patients. A 3-year longitudinal study. Stroke 1993;24:976–82.
Please cite this article in press as: Kremer C et al. Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.01.010
C. Kremer et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx [11] Köhrmann M, Nowe T, Huttner HB, et al. Safety and outcome after thrombolysis in stroke patients with mild symptoms. Cerebrovasc Dis 2009;27:160–6. [12] Hassan AE, Hassanzadeh B, Tohidi V, et al. Very mild stroke patients benefit from intravenous tissue plasminogen activator without increase of intracranial hemorrhage. South Med J 2010;103:398–402.
3
[13] Nesi M, Lucente G, Nencini P, et al. Aphasia predicts unfavorable outcome in mild ischemic stroke patients and prompts thrombolytic treatment. J Stroke Cerebrovasc Dis 2014;23:204–8. [14] Laihosalo M, Kettunen JE, Koivisto AM, et al. Thrombolytic therapy and visuoperceptual functions in right hemisphere infarct patients. J Neurol 2011;258:1021–5.
Please cite this article in press as: Kremer C et al. Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.01.010
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Short Communication
Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis Christine Kremer a,⇑, Johan Kappelin a, Fabienne Perren b a b
Neurology Department, Skåne University Hospital, University of Lund, Jan Waldenström Gata 15, S-20502 Malmö, Sweden Department of Clinical Neurosciences, Neurology, HUG, University Hospital and Medical Faculty of Geneva, Switzerland
a r t i c l e
i n f o
Article history: Received 26 September 2013 Accepted 28 January 2014 Available online xxxx Keywords: Acute Aphasia Cerebral Ischemia Outcome Stroke Systemic thrombolysis
a b s t r a c t Clinical observation suggested to us that aphasia recovers relatively better than other deficits early after intravenous recombinant tissue plasminogen activator (IV-rtPA) treatment in stroke patients with minor deficits, while the reverse seemed the case in those with severe deficits. Retrospective analysis of acute ischemic stroke patients with aphasia admitted within 3 hours from symptom onset and treated with IV-rtPA was carried out. Stroke severity, aphasia and global neurological impairment were assessed at admission and 24 hours after thrombolysis. Improvement of aphasia (gain of P1 point on the National Institutes of Health Stroke Scale [NIHSS] aphasia score) and global neurological improvement (gain of P4 points on the NIHSS) were compared in minor strokes (NIHSS 67), moderate strokes (NIHSS 8–15), and major strokes (NIH P16). Sixty-nine of 243 stroke patients suffered from aphasia. Improvement of aphasia occurred in 7/16 minor strokes, 11/25 moderate strokes, and 7/28 severe strokes. Improvement of P4 points on the NIHSS occurred in 3/16 minor strokes, 17/25 moderate strokes and 15/28 severe strokes. There is a significant (X2 = 4.073, p < 0.05) dissociation of recovery of aphasia and that of other neurological deficits between minor versus severe strokes. This confirms the clinically suspected dissociation between a good early recovery from aphasia in minor strokes relative to recovery of other neurological deficits, as opposed to a better recovery from other neurological deficits than from aphasia in patients with severe strokes. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Aphasia is diagnosed in 21–38% [1–5] of hospitalized stroke patients and is responsible for high morbidity and mortality [4], decreased functional recovery [7,8] and a higher risk of developing depression [5,9,10]. Informal clinical observation at our and other centers suggested to us that aphasia recovers relatively better than other deficits early after intravenous recombinant tissue plasminogen activator (IV-rtPA) treatment in stroke patients with minor deficits, while the reverse seemed the case in those with severe deficits. It has been shown that patients with minor strokes show favorable outcome after thrombolysis with low intracerebral bleeding risk and thrombolyses should not be withheld [6,11]. Actual guidelines for thrombolytic therapy recommend a National Institutes of Health Stroke Scale (NIHSS) score of P5 with the exception of patients with symptoms that could be potentially disabling such as aphasia, inattention and other cortical signs. ⇑ Corresponding author. Tel.: +46 4033 6945; fax: +46 4033 3055. E-mail address: [email protected] (C. Kremer).
However, little is known about the effect of this treatment on the specific outcome of aphasia in relation to other deficits. Proven beneficial effects of thrombolysis in patients with minor strokes and aphasia may lead to a more deliberate application of IV thrombolysis and therefore to a lower morbidity in this group of patients. Data are lacking concerning the reperfusion pattern in language areas compared to other areas in patients treated by IV-rtPA thrombolysis. We thus retrospectively analyzed the benefit of thrombolytic therapy in evaluating the short term outcome of aphasia compared to the other deficits.
2. Methods A total of 243 acute ischemic stroke patients admitted within 3 hours from symptom onset and treated with IV-rtPA (0.9 mg/kg [maximum of 90 mg] infused over 60 minutes with 10% of the total dose administered as an initial IV bolus over 1 minute) were retrospectively studied over a period of 6 years. Patients with incomplete NIHSS or aphasia scores were excluded. Stroke severity
http://dx.doi.org/10.1016/j.jocn.2014.01.010 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kremer C et al. Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.01.010
2
C. Kremer et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
was assessed according to the NIHSS at admission and at 24 hours after thrombolysis. Only patients who also suffered from aphasia were studied. Aphasia was assessed at admission and after 24 hours. Improvement of aphasia was defined by the gain of P1 point on the aphasia subscale score of the NIHSS and global neurological improvement by the gain of P4 points on the total NIHSS. Patients were divided into three groups based on stroke severity: minor, NIHSS 67; moderate, NIHSS 8–15; and major, NIHSS P16. Baseline CT scans of the brain, including angiographic sequences at admission and a CT scan at 24 hours, were performed in all patients. Symptomatic hemorrhage was considered if there was intracerebral hemorrhage on CT scan within 72 hours from symptom onset associated with an increase in NIHSS score of 4 points. 3. Results Sixty-nine patients with aphasia of 243 stroke patients (28.4%) were included. Nine patients were excluded due to incomplete follow-up data at 24 hours. Baseline data are provided in Table 1. Improvement of aphasia occurred in 7/16 (43%) minor strokes, 11/25 (44%) moderate strokes, and 7/28 (25%) severe strokes. Table 2 shows the NIHSS aphasia subscores in the respective categories. Seven out of 69 (10.1%) patients suffered from intracerebral hemorrhage (after systemic thrombolysis) of whom three were considered symptomatic. Improvement of NIHSS P4 points occurred in 3/16 (18.7%) minor strokes, 17/25 (68%) moderate strokes and 15/28 (53.5%) severe strokes. Including all groups in the analysis the dissociation was not significant (X2 [degrees of freedom = 2] 4.246, p = 0.059, one-tailed). However, when analyzing only the groups with minor versus severe deficits, for which we had a clinical suspicion of difference (X2 [degrees of freedom = 1] 4.073, p = 0.043; p = 0.021; one-tailed) this dissociation was significant. 4. Discussion Our analysis confirms the clinically suspected dissociation between a good early recovery from aphasia in minor strokes relative to the recovery of other NIHSS deficits, and the reverse in patients with severe strokes displaying a better recovery from other deficits than aphasia. It has been demonstrated that administering IV-rtPA to patients with a very mild stroke, NIHSS 66, can lead to improved clinical outcome when compared to patients with similar NIHSS who have not received thrombolytic treatment [12]. Even in the case of mild isolated aphasia with an NIHSS of 1, IV-rtPA seems to be safe and effective [12]. Aphasia is an early marker of unfavorable outcome in mild ischemic stroke patients, and these patients should not be treated on the basis of NIHSS scoring alone [13]. Data concerning the temporal pattern of aphasia improvement after thrombolysis compared to other deficits is lacking. In right hemispheric stroke it could be shown,
Table 1 Data of included stroke patients suffering from aphasia Total, n Men, n (%) Women, n (%) Median age ± SD Minor stroke, n (%) Moderate stroke, n (%) Major stroke, n (%) Patients with ICH after thrombolysis Patients with symptomatic ICH after thrombolysis ICH = intracerebral hemorrhage, SD = standard deviation.
69 39 (56) 30 (43) 60 ± 30 16 (23) 25 (36) 28 (40) 7 3
Table 2 Patients distributed by aphasia severity according to the National Institutes of Health Stroke Scale (NIHSS) in stroke severity categories NIHSS stroke severitya
a
NIHSS aphasia subscale
Minor
Moderate
Major
1 point 2 points 3 points Total
4 9 3 16
7 11 7 25
1 13 14 28
Minor = NIHSS 67, Moderate = NIHSS 8–15, Major = NIHSS P16.
for example, that thrombolysis has a favorable effect on visuoperceptual functions in acute stroke with equal baseline NIHSS [14]. Limitations of this study are its retrospective character and the relatively small number of included patients. Additional examinations by brain MRI and perfusion imaging would have allowed a deeper pathophysiological insight in the topic. However our results might be the basis of further research. Due to the lack of a control group of non-thrombolysed patients it cannot be excluded that the results might not be exclusively applicable to thrombolysed patients. In moderate and major stroke patients with larger penumbra zones, improvement over the first 24 hours could involve other regions, for example visual areas more than language areas, with improvement in general scoring but not aphasia, areas which are also in some cases well collateralized. Conversely, patients with aphasia could benefit from reperfusion in smaller penumbra zones. The size of the neural network supporting language is larger than that of other functions and thus smaller penumbra recovery might lead to greater functional improvement. Our study shows that in patients treated with IV-rtPA thrombolysis there is a dissociation between early recovery of aphasia in patients with mild compared to severe strokes. This could facilitate the decision to treat patients with aphasia with IV-rtPA thrombolyis independently of the baseline NIHSS score. Further studies are needed to explore the nature of the reperfusion pattern in different areas of the brain early after IV-rtPA thrombolysis. Conflicts of Interest/Disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication. References [1] Pedersen PM, Jørgensen HS, Nakayama H, et al. Aphasia in acute stroke: incidence, determinants and recovery. Ann Neurol 1995;38:659–66. [2] Brust JC, Shafer SQ, Richter RW, et al. Aphasia in acute stroke. Stroke 1976;7:167–74. [3] Wade DT, Hewer RL, David RM, et al. Aphasia after stroke: natural history and associated deficits. J Neurol Neurosurg Psychiatry 1986;49:11–6. [4] Laska AC, Hellblom A, Murray V, et al. Aphasia in acute stroke and relation to outcome. J Intern Med 2001;249:413–22. [5] Kauhanen ML, Korpelainen IT, Hiltunen P, et al. Aphasia, depression, and nonverbal cognitive impairment in ischaemic stroke. Cerebrovasc Dis 2000;10:455–61. [6] Engelter ST, Gostynski M, Papa S, et al. Epidemiology of aphasia attributable to first ischemic stroke: incidence, severity, fluency, etiology, and thrombolysis. Stroke 2006;37:1379–84. [7] Tilling K, Sterne JA, Rudd AG. A new method for predicting recovery after stroke. Stroke 2001;32:2867–73. [8] Paolucci S, Antonucci G, Pratesi L, et al. Functional outcome in stroke inpatient rehabilitation: predicting no, low and high response patients. Cerebrovasc Dis 1998;8:228–34. [9] Bullain SS, Chriki LS, Stern TA. Aphasia: associated disturbances in affect, behaviour, and cognition in the setting of speech and language difficulties. Psychosomatics 2007;48:258–64. [10] Åström M, Adolfsson R, Asplund K. Major depression in stroke patients. A 3-year longitudinal study. Stroke 1993;24:976–82.
Please cite this article in press as: Kremer C et al. Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.01.010
C. Kremer et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx [11] Köhrmann M, Nowe T, Huttner HB, et al. Safety and outcome after thrombolysis in stroke patients with mild symptoms. Cerebrovasc Dis 2009;27:160–6. [12] Hassan AE, Hassanzadeh B, Tohidi V, et al. Very mild stroke patients benefit from intravenous tissue plasminogen activator without increase of intracranial hemorrhage. South Med J 2010;103:398–402.
3
[13] Nesi M, Lucente G, Nencini P, et al. Aphasia predicts unfavorable outcome in mild ischemic stroke patients and prompts thrombolytic treatment. J Stroke Cerebrovasc Dis 2014;23:204–8. [14] Laihosalo M, Kettunen JE, Koivisto AM, et al. Thrombolytic therapy and visuoperceptual functions in right hemisphere infarct patients. J Neurol 2011;258:1021–5.
Please cite this article in press as: Kremer C et al. Dissociation of severity of stroke and aphasia recovery early after intravenous recombinant tissue plasminogen activator thrombolysis. J Clin Neurosci (2014), http://dx.doi.org/10.1016/j.jocn.2014.01.010
