ARTICLE IN PRESS
24-Hour Alberta Stroke Program Early CT Score Assessment in Post-Stroke Spasticity Development in Patients with a First Documented Anterior Circulation Ischemic Stroke Ondrej Volny, MD, PhD,*,† Maria Justanova, MD,* Petra Cimflova, MD,†,‡ Linda Kasickova, MD,§ Ivana Svobodova, MSc,‖ Jan Muzik, PhD,‖ and Martin Bares, MD, PhD*,¶
Background: Neuroanatomic substrates responsible for development of poststroke spasticity are still poorly understood. The study is focused on identification of brain regions within the territory of the middle cerebral artery associated with spasticity development. Methods: This is a single-center prospective cohort study of first documented anterior circulation ischemic strokes with a neurologic deficit lasting >7 days (from March 2014 to September 2016, all patients are involved in a registry). Ischemic cerebral lesions within the territory of middle cerebral artery were evaluated using the Alberta Stroke Program Early CT Score (ASPECTS) on control 24-hour computed tomography or magnetic resonance imaging. Spasticity was assessed with modified Ashworth scale. Results: Seventy-six patients (mean age 72 years, 45% females; 30% treated with IV tissue plasminogen activator, 6.5% mechanical thrombectomy) fulfilled the study inclusion criteria. Forty-nine (64%) developed early elbow or wrist flexor spasticity defined as modified Ashworth scale >1 (at day 7-10), in 44 (58%) the spasticity remained present at 6 months. There were no differences between the patients who developed spasticity and those who did not when comparing admission stroke severity (National Institutes of Health Stroke Scale 5 [interquartile range {IQR} 4-8] versus 6 [IQR 4-10]) and vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease). Nor was there a difference in 24-hour ASPECTS score (9 [IQR 8-10] versus 9 [IQR 7-10]). No differences were found between the groups with and without the early upper limb flexor spasticity of particular regions (M1, M2, M3, M4, M5, M6, lentiform, insula, caudate, internal capsule) and precentralpostcentral gyrus, premotor cortex, supplementary motor area, posterior limb of
From the *Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic; †International Clinical Research Centre, Stroke Research Program, St. Anne’s University Hospital, Brno, Czech Republic; ‡Department of Medical Imaging, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic; §Department of Neurology, Faculty of Medicine, University Ostrava, Czech Republic; ‖Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic; and ¶Department of Neurology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.Received May 28, 2017; revision received August 16, 2017; accepted August 21, 2017. This study was funded by the National Program of Sustainability II, Czech Republic (grant number LQ1605; O.V., P.C.) and AZV Grant, Czech Republic (grant number 15-31921A; M.J., M.B., J.M., and I.S.). Conflict of interests: The authors declare that there is no conflict of interest. English proofreading: Adam Whitley, MD. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.Address correspondence to Ondrej Volny, MD, PhD, Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 53 Pekarska, 602 00 Brno, Czech Republic. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.08.033
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
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2 internal capsule, and thalamus were compared. Conclusions: We did not find any middle cerebral artery territory associated with post-stroke spasticity development by detailed evaluation of ASPECTS. Key Words: Stroke—post-stroke spasticity—middle cerebral artery territory—modified Ashworth scale. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction Spasticity as a term was defined in 1980s by Lance as a motor disorder characterized by velocity-dependent increase in tonic stretch reflex with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex as 1 component of the upper motor neuron syndrome.1 Post-stroke spasticity (PSS) represents a significant health problem for stroke survivors as it leads to reduced motor function, lower levels of independence, and chronic pain. Furthermore, it is associated with a 4-fold increase in direct care costs during the first year after stroke.2,3 Its prevalence varies between 4% and 27% in the early phase of illness (1-4 weeks after stroke onset) and 17%-43% in the chronic phase (up to 3 months).4 Identification of stroke patients at a high risk of PSS development is necessary for early treatment and outcome improvements. Therefore, the investigation of spasticity predictors is essential.4-7 Our main research question was whether structural stroke neuroimaging has any predictive value for PSS development. So far, there is only limited evidence in terms of lesion location and its extent in association with spasticity development based on widely used neuroimaging methods (computed tomography [CT] and magnetic resonance imaging [MRI] in stroke protocols). One of the aims of our study was to determine a potential role of particular 24-hour Alberta Stroke Program Early CT Score (ASPECTS) regions in spasticity prediction. Additionally, we also focused on evaluation of acute ischemic changes visible on control CT-MRI imaging (>24 hours after the onset) affecting motor precentral and somatosensory postcentral gyrus, posterior limb of internal capsule (PLIC), thalamus, premotor cortex, and supplementary motor area (SMA)—the structures that have been mentioned to be associated with spasticity development in previous studies.6,8-10
Methods This is a single-center prospective cohort study of a first documented middle cerebral artery (MCA) ischemic stroke in patients with a neurologic deficit lasting more than 7 days (from March 2014 to September 2016, all patients are involved in registry Spastic Dystonia Registry in Czech Republic). The study was approved by a local Ethical Committee (St. Anne’s Faculty Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic). Exclusion criteria were as follows: previous stroke in any territory (visible on admission neuroimaging), bilateral stroke, hem-
orrhagic stroke, other neurologic disorders associated with spasticity, musculoskeletal diseases, and previous treatment with antispastic medication for any reason.
Lesion Tracking Acute ischemic changes identifiable on control 24hour non-contrast CT or 24-hour MRI scans (diffusionweighted imaging [DWI]-Apparent diffusion coefficient (ADC), T2-weighted fluid-attenuated inversion recovery imagining [T2 Fluid attenuation inversion recovery (FLAIR)]) were assessed using ASPECTS by consensus of a well-trained neuroradiologist and stroke neurologist (PC and OV) blinded to all clinical data. Briefly, ASPECTS represents a 10-point quantitative topographic scale enabling to score early ischemic changes in MCA strokes. ASPECTS is determined from evaluation in the basal ganglia level, where the thalamus, basal ganglia, and caudate are visible, and the supraganglionic level including the corona radiata and centrum semiovale. Ten regions are defined within the MCA territory: C— caudate, I—insular ribbon, IC—internal capsule, L—lentiform nucleus, M1—anterior MCA cortex, M2—MCA cortex lateral to the insular ribbon, M3—posterior MCA cortex, M4, M5, M6 are the anterior, lateral and posterior MCA territories immediately superior to M1, M2 and M3, rostral to basal ganglia. To compute the ASPECTS, 1 point is subtracted from 10 for any evidence of early ischemic change for each of the defined regions. The abnormality should be visible on at least 2 consecutive cuts.11-13 Additionally, the evaluation of acute ischemic changes was also focused on motor precentral and somatosensory postcentral gyrus, PLIC, thalamus, premotor cortex, and SMA, which have been mentioned in some previous studies focused on PSS.9,10,14
Image Acquisition Non-contrast CT was acquired on multidetector scanner (120-140 kV, 50-125 mAs, LightSpeed VCT 64 Slice; General Electric Healthcare, Waukesha, WI; or 120 kV, 328 mAs [419 mAs per slice], Brilliance iCT 256; Philips Healthcare, Cleveland, OH) with a section thickness of .92.5 mm and image reconstruction of 3-5 mm. MRI sequences (Ingenia 1.5 T, Philips Healthcare, Best, The Netherlands) included axial T2 FLAIR (TR/TE/TI, 6000/120/2000 ms; field of view [FOV], 220 × 180 mm; matrix, 320; section thickness [ST], 4; 1-mm gap),
ARTICLE IN PRESS ASPECTS AND POST-STROKE SPASTICITY DEVELOPMENT
gradient T2-weighted imagining (TR/TE, 676/23 ms; flip angle, 18°; FOV, 250 × 212 mm; matrix, 512; ST, 5; 1-mm gap) and DWI (TR, 2792 ms; TE, 72 ms; FOV, 230 × 230 cm; matrix, 256; ST, 5 mm; 1-mm gap).
Muscle Tone Assessment Upper limb flexor spasticity (elbow and wrist) was evaluated by using a modified Ashworth scale (MAS) at day 7-10 (first visit) and 6 months after (second visit) by 1 well-trained neurologist (movement disorders specialist) in the MAS assessment (MJ). Briefly, the MAS is a 6-point grading scale of relax limb resistance to rapid passive stretch (MAS > 1 was defined as the borderline between patients with spasticity or PSS+ and without spasticity or PSS− groups for the purpose of our analysis).15
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Statistical Analysis Standard descriptive statistics were applied in the analysis; mean supplemented by standard deviation or median supplemented by interquartile range (IQR) for continuous variables and absolute and relative frequencies for categorical variables. Statistical significance of differences between groups of patients was computed using Mann-Whitney U test for continuous variables and Fisher exact test for categorical variables. Analysis was computed using SPSS Statistics 24 (IBM Corp, Armonk, NY).
Results Seventy-six patients from the registry (mean age 72 years, 45% females; 30% treated with IV tissue plasminogen
Table 1. Demographics, treatment, and neuroimaging findings in patients with early development of upper limb flexor spasticity with a first acute anterior circulation ischemic stroke
Demographics and treatment Age, y, mean (SD) Sex, female, n (%) Baseline NIHSS, median (IQR) Atrial fibrillation, n (%) Dyslipidemia, n (%) Coronary artery disease, n (%) Diabetes mellitus, n (%) Hypertension, n (%) IV tPA, n (%) Mechanical thrombectomy, n (%) ASPECTS on control imaging, median (IQR) Regions of the middle cerebral artery† M1, n (%) M2, n (%) M3, n (%) M4, n (%) M5, n (%) M6, n (%) Lentiform, n (%) Insula, n (%) Caudate, n (%) Posterior limb of internal capsule, n (%) Thalamus, n (%) Precentral gyrus (BA 4), n (%) Postcentral gyrus (BA 3, 1, 2), n (%) Supplemental motor area or premotor area, n (%)
Superior limb flexor* spasticity (MAS > 1)
No superior limb spasticity
Day 7-10, n = 49
Day 7-10, n = 27
P
70.9 (14.0) 26 (53.1%) 5 (4; 8) 18 (36.7%) 27 (55.1%) 10 (20.4%) 17 (34.7%) 41 (83.7%) 13 (27.1%) 3 (6.1%) 9 (8; 10)
72.8 (9.8) 8 (29.6%) 6 (4; 10) 7 (25.9%) 21 (77.8%) 5 (18.5%) 14 (51.9%) 27 (100.0%) 10 (37.0%) 2 (7.4%) 9 (7; 10)
.652 .058 .153 .446 .081 1.000 .222 .045 .438 1.000 .928
5 (18.5%) 3 (11.1%) 2 (7.4%) 6 (22.2%) 10 (37.0%) 3 (11.1%) 7 (26.9%) 5 (18.5%) 4 (14.8%) 5 (18.5%) 0 (.0%) 8 (29.6%) 6 (22.2%) 5 (18.5%)
.314 .660 1.000 .328 .191 1.000 1.000 .576 1.000 .266 .536 .786 .786 .124
5 (10.2%) 3 (6.1%) 4 (8.2%) 6 (12.2%) 11 (22.4%) 6 (12.2%) 12 (24.5%) 13 (26.5%) 7 (14.3%) 4 (8.2%) 2 (4.1%) 12 (24.5%) 13 (26.5%) 3 (6.1%)
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; BA, Brodmann area; IQR, interquartile range; MAS, modified Ashworth scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; tPA, tissue plasminogen activator. *does not indicates a statistical significance - it indicates spasticity of biceps brachii or flexor carpi radialis or flexor carpi ulnaris. †Bonferroni-corrected P values for the regions of the middle cerebral artery in post-stroke spasticity development were not significant (data presented as noncorrected).
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Table 2. Demographics, treatment, and neuroimaging findings in patients with upper limb flexor spasticity (MAS assessed after 6 months) with a first acute anterior circulation ischemic stroke Superior limb flexor* spasticity (MAS > 1)
No superior limb spasticity
6 mo, n = 44
6 mo, n = 32
P
70.8 (14.7) 19 (43.2%) 5 (4; 8) 17 (38.6%) 24 (54.5%) 8 (18.2%) 15 (34.1%) 38 (86.4%) 10 (23.3%) 3 (6.8%) 9 (8; 10)
72.7 (9.1) 15 (46.9%) 6 (4; 10) 8 (25.0%) 24 (75.0%) 7 (21.9%) 16 (50.0%) 30 (93.8%) 13 (40.6%) 2 (6.3%) 9 (7; 10)
.760 .817 .063 .229 .093 .774 .237 .455 .132 1.000 .464
4 (9.1%) 3 (6.8%) 4 (9.1%) 5 (11.4%) 10 (22.7%) 4 (9.1%) 10 (22.7%) 8 (18.2%) 7 (15.9%) 10 (22,7%) 2 (4.5%) 9 (20.5%) 14 (31.8%) 2 (4.5%)
6 (18.8%) 3 (9.4%) 2 (6.3%) 7 (21.9%) 11 (34.4%) 5 (15.6%) 9 (29.0%) 10 (31.3%) 4 (12.5%) 7 (21.9%) 0 (.0%) 11 (34.4%) 5 (15.6%) 6 (18.8%)
.306 .692 1.000 .340 .305 .480 .596 .274 .752 .610 .506 .196 .179 .063
Demographics and treatment Age, y, mean (SD) Sex, female, n (%) Baseline NIHSS, median (IQR) Atrial fibrillation, n (%) Dyslipidemia, n (%) Coronary artery disease, n (%) Diabetes mellitus, n (%) Hypertension, n (%) IV tPA, n (%) Mechanical thrombectomy, n (%) ASPECTS on control imaging, median (IQR) Regions of the middle cerebral artery† M1, n (%) M2, n (%) M3, n (%) M4, n (%) M5, n (%) M6, n (%) Lentiform, n (%) Insula, n (%) Caudate, n (%) Posterior limb of internal capsule, n (%) Thalamus, n (%) Precentral gyrus (BA 4), n (%) Postcentral gyrus (BA 3, 1, 2), n (%) Supplemental motor or premotor area, n (%)
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; BA, Brodmann area; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; tPA, tissue plasminogen activator. *Biceps brachii or flexor carpi radialis or ulnaris. †Bonferroni-corrected P values for the regions of the middle cerebral artery in post-stroke spasticity development were not significant (data presented as noncorrected).
activator, 6.5% mechanical thrombectomy) fulfilled the study criteria and were involved into the analysis. Forty-nine (64%) of these patients had developed any level of early flexor spasticity defined as MAS > 1 (at day 7-10); in 44 (58%) patients, spasticity had been present at 6 months. There were no differences between the patients who developed spasticity and who did not in admission stroke severity (National Institutes of Health Stroke Scale 5 [IQR 4-8] versus 6 [IQR 4-10]) and vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease); for details see Tables 1 and 2. There was no difference in 24-hour ASPECTS (9 [IQR 8-10] versus 9 [IQR 7-10]); 30 (40%) patients had followup MRI. No differences were found between the groups with and without spasticity if particular regions of
ASPECTS (M1, M2, M3, M4, M5, M6, lentiform, insula, caudate, internal capsule) and precentral-postcentral gyrus, premotor cortex, SMA, PLIC, thalamus were compared between the 2 groups.
Discussion We did not identify any MCA region that was associated with the development of upper limb wrist or elbow flexors spasticity after ischemic stroke. Additionally to ASPECTS, other regions of interest (cortical and subcortical) associated with spasticity development were assessed.9,10,14 Data regarding neuroimaging findings in patients with PSS are limited. One retrospective study by Picelli et al studied 39 patients with ischemic stroke. In comparison with our study, ischemic lesions were traced on 1.5 T
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MRI images (DWI in acute phase of stroke or FLAIR > 48 hours). The authors pointed out a number of regions of both white and gray matter, which were associated with spasticity development. The gray matter regions included the insula, basal ganglia, and ventral posterolateral nucleus of thalamus, and the white matter regions included the internal capsule, external capsule, superior longitudinal fascicle, and corona radiata. Varying time of spasticity assessment ranging between 3 months and 2 years after stroke, as well as a retrospective design of the study, might be considered as significant limitations of the study.10 Another retrospective study involved 97 patients (51 with upper limb spasticity) and analysis of lesion location across spasticity levels was performed on 28 participants. In comparison with our study, all ischemic strokes with no further specification as well as hemorrhagic strokes were recruited into the analyses (hemorrhagic strokes were excluded in our analysis). In this study, the authors demonstrated only moderate association between ischemic lesion volume and severity of spasticity.9 In terms of spasticity zone, the authors mentioned the putamen as one of the most important structures associated with PSS development. Regarding the methodology used in our study, the putamen represents a part of the “lentiform” region of the ASPECTS. Even though we have focused on this region in the regional rating of acute ischemia extent, we did not prove any association between the upper limb flexor spasticity and the ischemic involvement of putamen. We are aware of some limitations of our study: a relatively small number of patients (to date representing the largest dataset) and assessment of ischemic lesions in the MCA based on the visual rating scale. Nevertheless, we preferred ASPECTS over the volumetric measurements for several reasons. First of all, ASPECTS as a semiquantitative score divides MCA territory into 10 well-defined regions based on neuroanatomy rather than a volume; additionally, ASPECTS reliability and localization-weighted estimation correlating with functional outcome was proved in previous studies.11,16 Second, one of the aims of our study was to determine a potential role of ASPECTS rating on control neuroimaging (representing a standard of care in most centers) in spasticity prediction for everyday clinical practice. Third, ASPECTS represents a useful and validated neuroradiology tool in stroke clinical practice worldwide; it is a fast and easily reproducible method (in comparison with volumetric measurements requiring further post-processing).17
Conclusions We were not able to find any topographical or neuroanatomic brain region within the MCA territory associated with the development of early PSS by using
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ASPECTS on control 24-hour CT or 24-hour MRI. Our results implicate that both non-contrast brain CT and MRI (stroke protocols including ADC-DWI, FLAIR, T1-, T2weighted imaging) are not capable of revealing a morphologic correlate for the development of upper limb flexor spasticity. Acknowledgment: Authors express thanks and gratitude to Prof Robert Jech, MD, PhD, and Prof Petr Kanovsky, MD, PhD, for their contribution to the registry design.
References 1. Lance JW. The control of muscle tone, reflexes, and movement: Robert Wartenberg Lecture. Neurology 1980;30:1303-1313. 2. Lundstrom E, Smits A, Borg J, et al. Four-fold increase in direct costs of stroke survivors with spasticity compared with stroke survivors without spasticity: the first year after the event. Stroke 2010;41:319-324. 3. Sommerfeld DK, Eek EU, Svensson AK, et al. Spasticity after stroke: its occurrence and association with motor impairments and activity limitations. Stroke 2004;35:134139. 4. Wissel J, Manack A, Brainin M. Toward an epidemiology of poststroke spasticity. Neurology 2013;80:S13-S19. 5. Urban PP, Wolf T, Uebele M, et al. Occurrence and clinical predictors of spasticity after ischemic stroke. Stroke 2010;41:2016-2020. 6. Urban PWT, Uebele M, Marx J, et al. Cerebral lesion topography in spasticity following ischemic stroke. Klin Neurophysiol 2010;41:ID57. 7. Opheim A, Danielsson A, Alt Murphy M, et al. Upperlimb spasticity during the first year after stroke: stroke arm longitudinal study at the University of Gothenburg. Am J Phys Med Rehabil 2014;93:884-896. 8. Moura Rde C, Fukujima MM, Aguiar AS, et al. Predictive factors for spasticity among ischemic stroke patients. Arq Neuropsiquiatr 2009;67:1029-1036. 9. Cheung DK, Climans SA, Black SE, et al. Lesion characteristics of individuals with upper limb spasticity after stroke. Neurorehabil Neural Repair 2016;30:6370. 10. Picelli A, Tamburin S, Gajofatto F, et al. Association between severe upper limb spasticity and brain lesion location in stroke patients. Biomed Res Int 2014;2014: 162754. 11. Barber PA, Demchuk AM, Zhang J, et al. Validity and reliability of a quantitative computed tomography score in predicting outcome of hyperacute stroke before thrombolytic therapy. ASPECTS Study Group. Alberta Stroke Programme Early CT Score. Lancet 2000;355:16701674. 12. Pexman JH, Barber PA, Hill MD, et al. Use of the Alberta Stroke Program Early CT Score (ASPECTS) for assessing CT scans in patients with acute stroke. AJNR Am J Neuroradiol 2001;22:1534-1542. 13. Demchuk AM, Coutts SB. Alberta Stroke Program Early CT Score in acute stroke triage. Neuroimaging Clin N Am 2005;15:409-419, xii. 14. Pundik S, Falchook AD, McCabe J, et al. Functional brain correlates of upper limb spasticity and its mitigation following rehabilitation in chronic stroke survivors. Stroke Res Treat 2014;2014:306325.
ARTICLE IN PRESS 6 15. Bohannon RW, Smith MB. Interrater reliability of a modified Ashworth scale of muscle spasticity. Phys Ther 1987;67:206-207. 16. Dzialowski I, Hill MD, Coutts SB, et al. Extent of early ischemic changes on computed tomography (CT) before thrombolysis: prognostic value of the Alberta Stroke
O. VOLNY ET AL. Program Early CT Score in ECASS II. Stroke 2006;37:973978. 17. Coutts SB, Demchuk AM, Barber PA, et al. Interobserver variation of ASPECTS in real time. Stroke 2004;35:e103e105.
24-Hour Alberta Stroke Program Early CT Score Assessment in Post-Stroke Spasticity Development in Patients with a First Documented Anterior Circulation Ischemic Stroke Ondrej Volny, MD, PhD,*,† Maria Justanova, MD,* Petra Cimflova, MD,†,‡ Linda Kasickova, MD,§ Ivana Svobodova, MSc,‖ Jan Muzik, PhD,‖ and Martin Bares, MD, PhD*,¶
Background: Neuroanatomic substrates responsible for development of poststroke spasticity are still poorly understood. The study is focused on identification of brain regions within the territory of the middle cerebral artery associated with spasticity development. Methods: This is a single-center prospective cohort study of first documented anterior circulation ischemic strokes with a neurologic deficit lasting >7 days (from March 2014 to September 2016, all patients are involved in a registry). Ischemic cerebral lesions within the territory of middle cerebral artery were evaluated using the Alberta Stroke Program Early CT Score (ASPECTS) on control 24-hour computed tomography or magnetic resonance imaging. Spasticity was assessed with modified Ashworth scale. Results: Seventy-six patients (mean age 72 years, 45% females; 30% treated with IV tissue plasminogen activator, 6.5% mechanical thrombectomy) fulfilled the study inclusion criteria. Forty-nine (64%) developed early elbow or wrist flexor spasticity defined as modified Ashworth scale >1 (at day 7-10), in 44 (58%) the spasticity remained present at 6 months. There were no differences between the patients who developed spasticity and those who did not when comparing admission stroke severity (National Institutes of Health Stroke Scale 5 [interquartile range {IQR} 4-8] versus 6 [IQR 4-10]) and vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease). Nor was there a difference in 24-hour ASPECTS score (9 [IQR 8-10] versus 9 [IQR 7-10]). No differences were found between the groups with and without the early upper limb flexor spasticity of particular regions (M1, M2, M3, M4, M5, M6, lentiform, insula, caudate, internal capsule) and precentralpostcentral gyrus, premotor cortex, supplementary motor area, posterior limb of
From the *Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic; †International Clinical Research Centre, Stroke Research Program, St. Anne’s University Hospital, Brno, Czech Republic; ‡Department of Medical Imaging, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic; §Department of Neurology, Faculty of Medicine, University Ostrava, Czech Republic; ‖Institute of Biostatistics and Analyses, Masaryk University, Brno, Czech Republic; and ¶Department of Neurology, School of Medicine, University of Minnesota, Minneapolis, Minnesota.Received May 28, 2017; revision received August 16, 2017; accepted August 21, 2017. This study was funded by the National Program of Sustainability II, Czech Republic (grant number LQ1605; O.V., P.C.) and AZV Grant, Czech Republic (grant number 15-31921A; M.J., M.B., J.M., and I.S.). Conflict of interests: The authors declare that there is no conflict of interest. English proofreading: Adam Whitley, MD. Ethical approval: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.Address correspondence to Ondrej Volny, MD, PhD, Department of Neurology, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, 53 Pekarska, 602 00 Brno, Czech Republic. E-mail: [email protected]. 1052-3057/$ - see front matter © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2017.08.033
Journal of Stroke and Cerebrovascular Diseases, Vol. ■■, No. ■■ (■■), 2017: pp ■■–■■
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2 internal capsule, and thalamus were compared. Conclusions: We did not find any middle cerebral artery territory associated with post-stroke spasticity development by detailed evaluation of ASPECTS. Key Words: Stroke—post-stroke spasticity—middle cerebral artery territory—modified Ashworth scale. © 2017 National Stroke Association. Published by Elsevier Inc. All rights reserved.
Introduction Spasticity as a term was defined in 1980s by Lance as a motor disorder characterized by velocity-dependent increase in tonic stretch reflex with exaggerated tendon jerks, resulting from hyperexcitability of the stretch reflex as 1 component of the upper motor neuron syndrome.1 Post-stroke spasticity (PSS) represents a significant health problem for stroke survivors as it leads to reduced motor function, lower levels of independence, and chronic pain. Furthermore, it is associated with a 4-fold increase in direct care costs during the first year after stroke.2,3 Its prevalence varies between 4% and 27% in the early phase of illness (1-4 weeks after stroke onset) and 17%-43% in the chronic phase (up to 3 months).4 Identification of stroke patients at a high risk of PSS development is necessary for early treatment and outcome improvements. Therefore, the investigation of spasticity predictors is essential.4-7 Our main research question was whether structural stroke neuroimaging has any predictive value for PSS development. So far, there is only limited evidence in terms of lesion location and its extent in association with spasticity development based on widely used neuroimaging methods (computed tomography [CT] and magnetic resonance imaging [MRI] in stroke protocols). One of the aims of our study was to determine a potential role of particular 24-hour Alberta Stroke Program Early CT Score (ASPECTS) regions in spasticity prediction. Additionally, we also focused on evaluation of acute ischemic changes visible on control CT-MRI imaging (>24 hours after the onset) affecting motor precentral and somatosensory postcentral gyrus, posterior limb of internal capsule (PLIC), thalamus, premotor cortex, and supplementary motor area (SMA)—the structures that have been mentioned to be associated with spasticity development in previous studies.6,8-10
Methods This is a single-center prospective cohort study of a first documented middle cerebral artery (MCA) ischemic stroke in patients with a neurologic deficit lasting more than 7 days (from March 2014 to September 2016, all patients are involved in registry Spastic Dystonia Registry in Czech Republic). The study was approved by a local Ethical Committee (St. Anne’s Faculty Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic). Exclusion criteria were as follows: previous stroke in any territory (visible on admission neuroimaging), bilateral stroke, hem-
orrhagic stroke, other neurologic disorders associated with spasticity, musculoskeletal diseases, and previous treatment with antispastic medication for any reason.
Lesion Tracking Acute ischemic changes identifiable on control 24hour non-contrast CT or 24-hour MRI scans (diffusionweighted imaging [DWI]-Apparent diffusion coefficient (ADC), T2-weighted fluid-attenuated inversion recovery imagining [T2 Fluid attenuation inversion recovery (FLAIR)]) were assessed using ASPECTS by consensus of a well-trained neuroradiologist and stroke neurologist (PC and OV) blinded to all clinical data. Briefly, ASPECTS represents a 10-point quantitative topographic scale enabling to score early ischemic changes in MCA strokes. ASPECTS is determined from evaluation in the basal ganglia level, where the thalamus, basal ganglia, and caudate are visible, and the supraganglionic level including the corona radiata and centrum semiovale. Ten regions are defined within the MCA territory: C— caudate, I—insular ribbon, IC—internal capsule, L—lentiform nucleus, M1—anterior MCA cortex, M2—MCA cortex lateral to the insular ribbon, M3—posterior MCA cortex, M4, M5, M6 are the anterior, lateral and posterior MCA territories immediately superior to M1, M2 and M3, rostral to basal ganglia. To compute the ASPECTS, 1 point is subtracted from 10 for any evidence of early ischemic change for each of the defined regions. The abnormality should be visible on at least 2 consecutive cuts.11-13 Additionally, the evaluation of acute ischemic changes was also focused on motor precentral and somatosensory postcentral gyrus, PLIC, thalamus, premotor cortex, and SMA, which have been mentioned in some previous studies focused on PSS.9,10,14
Image Acquisition Non-contrast CT was acquired on multidetector scanner (120-140 kV, 50-125 mAs, LightSpeed VCT 64 Slice; General Electric Healthcare, Waukesha, WI; or 120 kV, 328 mAs [419 mAs per slice], Brilliance iCT 256; Philips Healthcare, Cleveland, OH) with a section thickness of .92.5 mm and image reconstruction of 3-5 mm. MRI sequences (Ingenia 1.5 T, Philips Healthcare, Best, The Netherlands) included axial T2 FLAIR (TR/TE/TI, 6000/120/2000 ms; field of view [FOV], 220 × 180 mm; matrix, 320; section thickness [ST], 4; 1-mm gap),
ARTICLE IN PRESS ASPECTS AND POST-STROKE SPASTICITY DEVELOPMENT
gradient T2-weighted imagining (TR/TE, 676/23 ms; flip angle, 18°; FOV, 250 × 212 mm; matrix, 512; ST, 5; 1-mm gap) and DWI (TR, 2792 ms; TE, 72 ms; FOV, 230 × 230 cm; matrix, 256; ST, 5 mm; 1-mm gap).
Muscle Tone Assessment Upper limb flexor spasticity (elbow and wrist) was evaluated by using a modified Ashworth scale (MAS) at day 7-10 (first visit) and 6 months after (second visit) by 1 well-trained neurologist (movement disorders specialist) in the MAS assessment (MJ). Briefly, the MAS is a 6-point grading scale of relax limb resistance to rapid passive stretch (MAS > 1 was defined as the borderline between patients with spasticity or PSS+ and without spasticity or PSS− groups for the purpose of our analysis).15
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Statistical Analysis Standard descriptive statistics were applied in the analysis; mean supplemented by standard deviation or median supplemented by interquartile range (IQR) for continuous variables and absolute and relative frequencies for categorical variables. Statistical significance of differences between groups of patients was computed using Mann-Whitney U test for continuous variables and Fisher exact test for categorical variables. Analysis was computed using SPSS Statistics 24 (IBM Corp, Armonk, NY).
Results Seventy-six patients from the registry (mean age 72 years, 45% females; 30% treated with IV tissue plasminogen
Table 1. Demographics, treatment, and neuroimaging findings in patients with early development of upper limb flexor spasticity with a first acute anterior circulation ischemic stroke
Demographics and treatment Age, y, mean (SD) Sex, female, n (%) Baseline NIHSS, median (IQR) Atrial fibrillation, n (%) Dyslipidemia, n (%) Coronary artery disease, n (%) Diabetes mellitus, n (%) Hypertension, n (%) IV tPA, n (%) Mechanical thrombectomy, n (%) ASPECTS on control imaging, median (IQR) Regions of the middle cerebral artery† M1, n (%) M2, n (%) M3, n (%) M4, n (%) M5, n (%) M6, n (%) Lentiform, n (%) Insula, n (%) Caudate, n (%) Posterior limb of internal capsule, n (%) Thalamus, n (%) Precentral gyrus (BA 4), n (%) Postcentral gyrus (BA 3, 1, 2), n (%) Supplemental motor area or premotor area, n (%)
Superior limb flexor* spasticity (MAS > 1)
No superior limb spasticity
Day 7-10, n = 49
Day 7-10, n = 27
P
70.9 (14.0) 26 (53.1%) 5 (4; 8) 18 (36.7%) 27 (55.1%) 10 (20.4%) 17 (34.7%) 41 (83.7%) 13 (27.1%) 3 (6.1%) 9 (8; 10)
72.8 (9.8) 8 (29.6%) 6 (4; 10) 7 (25.9%) 21 (77.8%) 5 (18.5%) 14 (51.9%) 27 (100.0%) 10 (37.0%) 2 (7.4%) 9 (7; 10)
.652 .058 .153 .446 .081 1.000 .222 .045 .438 1.000 .928
5 (18.5%) 3 (11.1%) 2 (7.4%) 6 (22.2%) 10 (37.0%) 3 (11.1%) 7 (26.9%) 5 (18.5%) 4 (14.8%) 5 (18.5%) 0 (.0%) 8 (29.6%) 6 (22.2%) 5 (18.5%)
.314 .660 1.000 .328 .191 1.000 1.000 .576 1.000 .266 .536 .786 .786 .124
5 (10.2%) 3 (6.1%) 4 (8.2%) 6 (12.2%) 11 (22.4%) 6 (12.2%) 12 (24.5%) 13 (26.5%) 7 (14.3%) 4 (8.2%) 2 (4.1%) 12 (24.5%) 13 (26.5%) 3 (6.1%)
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; BA, Brodmann area; IQR, interquartile range; MAS, modified Ashworth scale; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; tPA, tissue plasminogen activator. *does not indicates a statistical significance - it indicates spasticity of biceps brachii or flexor carpi radialis or flexor carpi ulnaris. †Bonferroni-corrected P values for the regions of the middle cerebral artery in post-stroke spasticity development were not significant (data presented as noncorrected).
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Table 2. Demographics, treatment, and neuroimaging findings in patients with upper limb flexor spasticity (MAS assessed after 6 months) with a first acute anterior circulation ischemic stroke Superior limb flexor* spasticity (MAS > 1)
No superior limb spasticity
6 mo, n = 44
6 mo, n = 32
P
70.8 (14.7) 19 (43.2%) 5 (4; 8) 17 (38.6%) 24 (54.5%) 8 (18.2%) 15 (34.1%) 38 (86.4%) 10 (23.3%) 3 (6.8%) 9 (8; 10)
72.7 (9.1) 15 (46.9%) 6 (4; 10) 8 (25.0%) 24 (75.0%) 7 (21.9%) 16 (50.0%) 30 (93.8%) 13 (40.6%) 2 (6.3%) 9 (7; 10)
.760 .817 .063 .229 .093 .774 .237 .455 .132 1.000 .464
4 (9.1%) 3 (6.8%) 4 (9.1%) 5 (11.4%) 10 (22.7%) 4 (9.1%) 10 (22.7%) 8 (18.2%) 7 (15.9%) 10 (22,7%) 2 (4.5%) 9 (20.5%) 14 (31.8%) 2 (4.5%)
6 (18.8%) 3 (9.4%) 2 (6.3%) 7 (21.9%) 11 (34.4%) 5 (15.6%) 9 (29.0%) 10 (31.3%) 4 (12.5%) 7 (21.9%) 0 (.0%) 11 (34.4%) 5 (15.6%) 6 (18.8%)
.306 .692 1.000 .340 .305 .480 .596 .274 .752 .610 .506 .196 .179 .063
Demographics and treatment Age, y, mean (SD) Sex, female, n (%) Baseline NIHSS, median (IQR) Atrial fibrillation, n (%) Dyslipidemia, n (%) Coronary artery disease, n (%) Diabetes mellitus, n (%) Hypertension, n (%) IV tPA, n (%) Mechanical thrombectomy, n (%) ASPECTS on control imaging, median (IQR) Regions of the middle cerebral artery† M1, n (%) M2, n (%) M3, n (%) M4, n (%) M5, n (%) M6, n (%) Lentiform, n (%) Insula, n (%) Caudate, n (%) Posterior limb of internal capsule, n (%) Thalamus, n (%) Precentral gyrus (BA 4), n (%) Postcentral gyrus (BA 3, 1, 2), n (%) Supplemental motor or premotor area, n (%)
Abbreviations: ASPECTS, Alberta Stroke Program Early CT Score; BA, Brodmann area; IQR, interquartile range; NIHSS, National Institutes of Health Stroke Scale; SD, standard deviation; tPA, tissue plasminogen activator. *Biceps brachii or flexor carpi radialis or ulnaris. †Bonferroni-corrected P values for the regions of the middle cerebral artery in post-stroke spasticity development were not significant (data presented as noncorrected).
activator, 6.5% mechanical thrombectomy) fulfilled the study criteria and were involved into the analysis. Forty-nine (64%) of these patients had developed any level of early flexor spasticity defined as MAS > 1 (at day 7-10); in 44 (58%) patients, spasticity had been present at 6 months. There were no differences between the patients who developed spasticity and who did not in admission stroke severity (National Institutes of Health Stroke Scale 5 [IQR 4-8] versus 6 [IQR 4-10]) and vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, atrial fibrillation, coronary artery disease); for details see Tables 1 and 2. There was no difference in 24-hour ASPECTS (9 [IQR 8-10] versus 9 [IQR 7-10]); 30 (40%) patients had followup MRI. No differences were found between the groups with and without spasticity if particular regions of
ASPECTS (M1, M2, M3, M4, M5, M6, lentiform, insula, caudate, internal capsule) and precentral-postcentral gyrus, premotor cortex, SMA, PLIC, thalamus were compared between the 2 groups.
Discussion We did not identify any MCA region that was associated with the development of upper limb wrist or elbow flexors spasticity after ischemic stroke. Additionally to ASPECTS, other regions of interest (cortical and subcortical) associated with spasticity development were assessed.9,10,14 Data regarding neuroimaging findings in patients with PSS are limited. One retrospective study by Picelli et al studied 39 patients with ischemic stroke. In comparison with our study, ischemic lesions were traced on 1.5 T
ARTICLE IN PRESS ASPECTS AND POST-STROKE SPASTICITY DEVELOPMENT
MRI images (DWI in acute phase of stroke or FLAIR > 48 hours). The authors pointed out a number of regions of both white and gray matter, which were associated with spasticity development. The gray matter regions included the insula, basal ganglia, and ventral posterolateral nucleus of thalamus, and the white matter regions included the internal capsule, external capsule, superior longitudinal fascicle, and corona radiata. Varying time of spasticity assessment ranging between 3 months and 2 years after stroke, as well as a retrospective design of the study, might be considered as significant limitations of the study.10 Another retrospective study involved 97 patients (51 with upper limb spasticity) and analysis of lesion location across spasticity levels was performed on 28 participants. In comparison with our study, all ischemic strokes with no further specification as well as hemorrhagic strokes were recruited into the analyses (hemorrhagic strokes were excluded in our analysis). In this study, the authors demonstrated only moderate association between ischemic lesion volume and severity of spasticity.9 In terms of spasticity zone, the authors mentioned the putamen as one of the most important structures associated with PSS development. Regarding the methodology used in our study, the putamen represents a part of the “lentiform” region of the ASPECTS. Even though we have focused on this region in the regional rating of acute ischemia extent, we did not prove any association between the upper limb flexor spasticity and the ischemic involvement of putamen. We are aware of some limitations of our study: a relatively small number of patients (to date representing the largest dataset) and assessment of ischemic lesions in the MCA based on the visual rating scale. Nevertheless, we preferred ASPECTS over the volumetric measurements for several reasons. First of all, ASPECTS as a semiquantitative score divides MCA territory into 10 well-defined regions based on neuroanatomy rather than a volume; additionally, ASPECTS reliability and localization-weighted estimation correlating with functional outcome was proved in previous studies.11,16 Second, one of the aims of our study was to determine a potential role of ASPECTS rating on control neuroimaging (representing a standard of care in most centers) in spasticity prediction for everyday clinical practice. Third, ASPECTS represents a useful and validated neuroradiology tool in stroke clinical practice worldwide; it is a fast and easily reproducible method (in comparison with volumetric measurements requiring further post-processing).17
Conclusions We were not able to find any topographical or neuroanatomic brain region within the MCA territory associated with the development of early PSS by using
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ASPECTS on control 24-hour CT or 24-hour MRI. Our results implicate that both non-contrast brain CT and MRI (stroke protocols including ADC-DWI, FLAIR, T1-, T2weighted imaging) are not capable of revealing a morphologic correlate for the development of upper limb flexor spasticity. Acknowledgment: Authors express thanks and gratitude to Prof Robert Jech, MD, PhD, and Prof Petr Kanovsky, MD, PhD, for their contribution to the registry design.
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