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Can initial sarcopenia affect poststroke rehabilitation outcome?
Journal of Clinical Neuroscience xxx (xxxx) xxx
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Clinical study
Can initial sarcopenia affect poststroke rehabilitation outcome? Yongjun Jang a, Sun Im b, Yeonjae Han b, Hyunjung Koo b, Donggyun Sohn b, Geun-Young Park b,⇑ a
Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea Department of Rehabilitation Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327, Sosa-ro, Bucheon-si, Gyeonggi-do 14647, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 9 July 2019 Accepted 24 August 2019 Available online xxxx Keywords: Stroke Sarcopenia Recovery of function Sex Hand strength Hemiplegia
a b s t r a c t This study investigated the association between the presence of sarcopenia, measured by nonhemiplegic grip strength, and the level of functional recovery, measured by the modified Rankin Scale (mRS) at six months after stroke. We performed a retrospective cohort analysis of a prospectively maintained database of 194 hemiplegic poststroke patients, who had been admitted to the Department of Rehabilitation Medicine of a university-affiliated hospital. At 6 months after stroke, 72.2% of patients had mRS score >3, with more women (81.0% vs. 66.0%, p = 0.024) showing poor recovery. Both men (51.3% vs. 35.9%, p = 0.041) and women (42.2% vs. 6.7%, p = 0.022) with mRS score >3 had a higher rate of sarcopenia. Univariate analysis revealed that the presence of sarcopenia was associated with a 2.71fold higher risk of poor recovery at six months. In addition, women had a 2.18-fold higher risk of poor outcome. Multivariable logistic regression analysis revealed that the presence of sarcopenia was associated with poor functional outcome (odds ratio [OR] = 2.61, 95% confidence interval [CI]: 1.14–5.98, p = 0.024) in men, but this association was notably stronger in women (OR = 9.93, 95% CI: 1.22–81.19, p = 0.032). This study suggests that the presence of sarcopenia two weeks after stroke may increase the risk of poor functional outcome six months after stroke. Most notably, women with sarcopenia within 2 weeks from stroke onset were more significantly likely to have a poor modified Rankin Scale after 6 months. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Stroke is one of the leading causes of disability worldwide, and it is expected to increase continuously over the next decades [1]. Hemiparesis is the most noticeable sequelae after stroke and has been regarded as a consequence of brain injury itself. Many factors directly affect the prognosis of stroke. Neurologic severity based on brain lesion, as quantified by the National Institutes of Health Stroke Scale [2], and comorbidities [3] are generally perceived as the most critical poststroke prognostic factors. Also, functional deficits such as dysphagia [4] and decline in functional level (Barthel Index [5] or Functional Independence Measure [6]) at admission are also regarded as crucial prognostic factors [7]. Recently, the literature on this topic has emphasized secondary skeletal muscle abnormalities such as sarcopenia and their clinical relevance in the functional outcome, especially in the geriatric population [8,9]. However, the role of sarcopenia on poststroke functional outcome needs to be determined further.
⇑ Corresponding author. E-mail address: [email protected] (G.-Y. Park).
Sarcopenia is a condition that leads to loss of skeletal muscle mass, quality, and strength usually related to the physiological process of aging [10]. However, irrelevant to age, sarcopenia can be accelerated after specific acute systemic disease such as stroke [11,12]. Vicious cascades of skeletal muscle loss are critical to poststroke patients because the skeletal muscle is the most vulnerable organ that is directly affected by poststroke disability. Since the amount of muscle atrophy corresponds to the patient’s maximal capability of making a volitional effort [11,13], decreased skeletal muscle bulk and weakness may eventually influence the patient’s functional outcome [9]. A recent study by Yoshimura et al. showed that the prevalence of sarcopenia in rehabilitation ward inpatients was up to 53.0% [14]. Seo et al. suggested that grip strength on the unaffected side is an independent predictor of short-term poststroke functional outcome [15]. Nevertheless, the secondary consequences from accelerated sarcopenia after stroke are usually underestimated, and their impact on functional outcome in stroke patients has not yet been determined. Taking into consideration that poor muscle functioning related to sarcopenia increases the risk of functional decline, falls, and mortality [16], clarifying the impact of sarcopenia in stroke patients may have important clinical implications.
https://doi.org/10.1016/j.jocn.2019.08.109 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
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Y. Jang et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
The purpose of the present study was to assess the impact of sarcopenia on functional outcome at the time of stroke onset and 6 months after stroke. We aimed to determine whether the presence of low grip strength of the unaffected side, a marker of sarcopenia [17], could be an independent risk factor of poor functional outcome after stroke. Further, in consideration of sex differences in muscle strength and sex-specific pathophysiological mechanisms for sarcopenia [18], we attempted to elucidate whether the impact of sarcopenia after stroke showed sex differences. 2. Methods 2.1. Subject population We performed a retrospective cohort analysis of a prospectively maintained database of patients who had been admitted to the Department of Rehabilitation of a university-affiliated hospital between January 2012 and August 2016 [19]. Patients with the first-ever stroke who had been diagnosed at the stroke unit of our institution and who had been transferred to our department were included. The study was approved by the Institutional Review Board of our institution (HC16RISI0007). 2.2. Eligibility criteria Hemiplegic poststroke patients aged 45–81 years old, who were physically independent with no previous history of stroke, and who could follow at least one-step commands to fully cooperate with functional assessments, were eligible. These patients were required to have full medical records of their level of functional parameters both at 2 weeks and at up to 6 months poststroke. Patients who had a comorbid disease such as chronic inflammatory disease, active tuberculosis, autoimmune disease, chronic colitis, organ transplantation, immunosuppressive therapy, acquired immunodeficiency syndrome, malignancy, or amputation were excluded, as those conditions can influence muscle mass [12]. 2.3. Definition of sarcopenia Recent guideline of European Working Group on Sarcopenia in Older People (EWGSOP) focused on low muscle strength as a key characteristic of sarcopenia [20]. Therefore, the present study defined sarcopenia based on the grip strength measured from the nonhemiparetic side using a dynamometer (Jamar Hydraulic Hand Dynamometer, Masan, Gyeongsangname-do, Republic of Korea), based on the recommendation of the Southampton protocol [21]. Three trials of grip strength from each hand were performed, with the mean value used for analysis. The grip strength was measured by a single occupational therapist who was blind to the patient’s clinical information. According to the recommendations from the Asian Working Group for Sarcopenia, sarcopenia was defined with cutoff values of the grip strength set at <26 kg for men and <18 kg for women [17].
2.5. Functional outcome parameters and confounding factors The definition of good functional outcome was based on the modified Rankin Scale (mRS), which was recorded 6 months poststroke. A mRS score 3 was defined as a good functional outcome that patients can at least walk without assistance, whereas a mRS score >3 was defined as a poor functional outcome with a profound disability, requiring continuous assistance. The level of functional performance was measured using the following parameters. The patients’ level of independence in daily living was measured by the Korean version of the Modified Barthel Index (K-MBI) [22]. Cognitive function was evaluated with the Korean version of the Mini-Mental Status Examination (K-MMSE) [23]. The level of swallowing performance and oral diet intake was categorized according to the Function Oral Intake Scale [24]. Each functional parameter was measured twice: within 2 weeks from stroke onset (t0) and at 6 months after stroke (t1). 2.6. Laboratory parameters Since nutritional influences are strongly linked to sarcopenia [25], the laboratory assessment was done to evaluate patients’ nutritional status at baseline [26]. Fasting serum venous blood samples were collected at 2 weeks poststroke and malnutrition was defined as a serum albumin level below the cutoff of 3.5 g/ dL [27]. 2.7. Statistical analysis To evaluate factors that affect the poor poststroke functional outcome, demographic characteristics were compared between the groups with poor (mRS >3) and good (mRS 3) functional outcome. Normally distributed continuous variables were described with means (±SD), and intergroup comparisons were performed by two-sample t-tests. Nonnormally distributed data were presented as the median (interquartile range), and between-group comparisons were made using the Mann-Whitney test. Categorical variables were presented as percentages (number, %), and either a Mann-Whitney test (ordinal data) or Fisher’s exact test (dichotomous data) was performed to evaluate the intergroup difference. Univariate and multivariate logistic regressions were performed to identify independent parameters associated with low functional outcome (mRS >3) at 6 months poststroke. To validate sarcopenia as a single prognostic parameter for the low functional outcome at 6 months poststroke, multiple logistic regression was performed, adjusting for age, sex, and significant univariate variables. A multivariable logistic regression model was constructed using stepwise selection with an entry criterion of p < 0.1 and stay criterion of p < 0.05. All statistical tests were analyzed using SAS 9.4 (Statistical Analysis System software, version 9.4, Cary, NC, USA) and were two-tailed, with p < 0.05 considered statistically significant. 3. Results 3.1. Demographic characteristics of the study population
2.4. Demographic characteristics Information on stroke etiology, hemiparetic side, and baseline demographics such as sex, age, hand dominance, and grip strength data were acquired. Height and weight were obtained, and body mass index was calculated. The presence of cerebral vascular disease-related medical comorbidities such as hypertension, diabetes, hyperlipidemia, coronary artery disease, arrhythmia, and other underlying diseases such as osteoporosis and infection history were recorded.
Among 298 patients who had been diagnosed with a first-ever stroke, 194 met the inclusion criteria (Fig. 1). Based on the grip strength from the nonhemiparetic side, 81 (41.8%) satisfied the criteria for sarcopenia. Compared with patients with a mRS score 3, those with a mRS score >3 had a higher rate of sarcopenia (47.1% vs. 27.8%, p < 0.01). Differences in functional level as measured by the MBI and MMSE were observed between the two groups. Those with a mRS score >3 were more likely to be nil per mouth (51.4% vs. 24%, p < 0.000) with evidence of malnutrition (Table 1).
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
Y. Jang et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
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Fig. 1. Flow chart of the study population.
At 6 months poststroke, 72.2% of patients had a mRS score >3, with more women showing poor recovery. 3.2. Predictors of poor functional outcome: univariate analysis Univariate analysis revealed that the presence of sarcopenia was associated with a 2.71-fold higher risk of poor recovery (mRS >3). Also, female was associated with a 2.18-fold higher risk of poor outcome (Table 2). Other independent risk factors were poor Barthel index, nil per mouth, and lower MMSE scores at 2 weeks after stroke. When analyzing only the men, the impact of sarcopenia was still present, with a 2.61-fold higher risk of poor outcome, along with low MBI and nil per mouth. In sharp contrast, in women, the presence of sarcopenia was significantly associated with a 9.93-fold higher risk of poor functional outcome, along with low MBI and the presence of malnutrition. 3.3. Predictors of poor functional outcome: multivariate logistic regression analysis Multivariate regression analysis showed that sarcopenia was associated with a 2.23-fold higher risk of poor outcome, even after adjustment for sex, age, nil per mouth, the presence of malnutrition, and MMSE (Table 3). In the sex-stratified analysis, sarcopenia was associated with a 2.99-fold higher risk of poor outcome in men after adjustment for age and sex. However, this model was no
longer significant after adjustment for the covariables, such as tube feeding malnutrition and MMSE. In women, sarcopenia was associated with a 9.77-fold higher risk of poor outcome, even after adjustment for the covariables of age, sex, and nil per mouth. The odds for poor recovery decreased when the covariate malnutrition was introduced into the model, indicating that malnutrition is a strong confounding factor for sarcopenia that affects women more than men. 4. Discussion Patients with a mRS score >3 at 6 months poststroke showed a higher rate of initial sarcopenia than those with a mRS score 3 (47.1% vs. 27.8%). In addition, this study showed that the presence of sarcopenia was associated with a 2.71-fold higher risk of poor poststroke recovery at 6 months. It also emphasizes the fact that poststroke women with sarcopenia within 2 weeks poststroke are at greator risk of poor outcome compared with men (women: 9.93-fold vs. men: 2.61-fold) at 6 months poststroke. The results of the present study concur with those reported by previous studies. Scherbakov et al. highlighted the biologic alternation of the muscular structure after stroke [11,28]. After the stroke, type II muscle fibers gradually degrade, resulting in a decrement in the cross-sectional area of entire skeletal muscles. These changes in muscle volume eventually lead to mobility deficit [29] and affect the mRS [30]. A particularly significant finding of the present study
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
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Table 1 Demographic, clinical and laboratory parameters of the participants. Total (n = 194)
Poor (mRS > 3) (n = 140)
Good (mRS 3) (n = 54)
p-value
Sarcopenia Yes No
81 (41.8%) 113 (58.2%)
66 (47.1%) 74 (52.9%)
15 (27.8%) 39 (72.2%)
0.022
Demographics Sex Men Women Age BMI
115 (59.3%) 79 (40.7%) 64.3 ± 13.0 24.2 ± 3.4
76 (54.3%) 64 (45.7%) 65.2 ± 12.6 23.9 ± 3.2
39 (72.2%) 15 (27.8%) 61.9 ± 13.5 24.1 ± 2.9
Brain Lesion Etiology Ischemia Hemorrhage Both
111 (57.5%) 69 (35.8%) 13 (6.7%)
74 (53.2%) 55 (39.6%) 10 (7.1%)
37 (68.5%) 14 (25.9%) 3 (5.6%)
29 (5;59) 63 (15;90) 19 (8;25) 22 (16;26) 4 (1; 7) 6 (4; 7)
13 (0;37) 43 (9;70) 15 (4;24) 20 (13;25) 3 (1; 6) 6 (4; 7)
74 (56;87) 90 (80;92) 25 (18;27) 25 (19;29) 5 (4; 7) 7 (5; 7)
0.000 0.000 0.000 0.002 0.002 0.004
85 (43.8%) 49 (25.3%) 6.6 ± 0.6 3.8 ± 0.5 24.9 ± 6.6
72 (51.4%) 44 (31.4%) 6.6 ± 0.6 3.9 ± 0.5 24.9 ± 6.7
13 (24%) 5 (9.3%) 6.8 ± 0.5 4.0 ± 0.4 24.9 ± 6.4
0.000 0.003 0.019 0.875 0.970
0.034
0.072 0.755 0.257
Functional parameters MBI
t0 t1 t0 t1 t0 t1
MMSE FOIS Nutritional parameter Nil per mouth Malnutrition Protein (g/dL) Albumin (g/dL) Prealbumin (g/dL)
Abbreviations: t0 = within two weeks poststroke; t1 = time at poststroke six months. Normally distributed continuous variables were described with means (±SD) and nonnormally distributed data were presented with median (interquartile range, IQR). Categorical variables were presented as percentages (number, %).
Table 2 Predictors of functional outcome at six months by univariate analysis according to sex. Total (n = 194)
Sarcopenia Age Sex (women) Smoking MBI at baseline (<50) MMSE (<24) FOIS (3) Malnutrition (yes) *
Men (n = 115)
Women (n = 79)
OR (95% CI)
p-value*
OR (95% CI)
p-value*
OR (95% CI)
p-value*
2.71 1.02 2.18 0.66 1.95 1.22 2.97 1.16
0.005 0.137 0.001 0.222 0.000 0.001 0.003 0.054
2.61 1.00 NA 1.28 1.87 1.70 4.03 1.21
(1.14–5.98) (0.96–1.03)
0.024 0.843
(1.22–81.19) (0.99–1.09)
0.032 0.107
(0.57–2.88) (1.53–2.29) (0.68–1.93) (1.64–9.89) (0.96–1.53)
0.550 0.000 0.448 0.002 0.107
9.93 1.04 NA 0.16 2.02 1.14 1.95 1.26
(0.02–1.05) (1.56–2.62) (1.04–1.21) (0.55–6.94) (1.05–1.50)
0.056 0.000 0.356 0.301 0.013
(1.35–5.47) (0.99–1.05) (1.12–4.43) (0.34–1.29) (1.68–2.26) (1.07–1.39) (1.44–6.13) (1.00–1.35)
Analyzed by logistic regression analysis(univariate).
Table 3 Predictors of functional outcome at six months by multivariate analysis, according to sex. Total
Crude Model Model Model Model * y à § ||
1y 2à 3§ 4||
Men
Women
OR (95% CI)
p-value*
OR (95% CI)
p-value*
OR (95% CI)
p-value*
2.71 3.33 2.71 2.38 2.23
0.005 0.002 0.011 0.000 0.001
2.61 2.99 2.12 2.01 1.45
0.024 0.016 0.119 0.142 0.116
9.93 9.94 9.77 2.48 1.96
0.032 0.033 0.035 0.037 0.081
(1.35–5.47) (1.57–7.07) (1.25–5.88) (1.48–3.82) (1.38–3.59)
(1.14–5.98) (1.23–7.23) (0.82–5.47) (0.63–4.32) (0.97–1.37)
(1.22–81.19) (1.20–82.15) (1.18–81.03) (1.37–4.50) (0.93–4.13)
Analyzed by logistic regression analysis (multivariate). Adjusted by age and sex. Adjusted by age, sex, and FOIS (p-value <0.05). Adjusted by age, sex, FOIS, and malnutrition (p-value <0.05). Adjusted by age, sex, FOIS, malnutrition, and MMSE (p-value <0.05).
is that the functional decrement as a result of sarcopenia was more distinct among women. Several studies have revealed sex-specific differences regarding the poststroke outcome [31–35]. However, none of the studies
mentioned sex-specific differences in the effect of sarcopenia on the poststroke outcome. Di Carlo et al. showed that women were at 1.5 times higher risk of disability and handicap 3 months after stroke. Sex differences in age distribution, baseline comorbidities,
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
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and sociodemographic factors were cited as possible factors [32]. In another single-hospital–based registry, there was a higher prevalence of atrial fibrillation in women compared with men. In our study, the average age and proportion of those with poor functional ability (mRS >3) were higher in women (women = 81%, men = 66.1%). However, the prevalence of underlying comorbidities including coronary artery disease (p = 0.540), hypertension (p = 0.121), and arrhythmia (p = 0.091) did not show significant gender differences. Therefore, baseline medical comorbidities played a small role in our study. In addition to underlying comorbidities, poststroke swallowing difficulty and malnutrition are also known to affect structural and functional alteration of muscle, resulting in sarcopenia. As high as 42% of poststroke patients manifest with dysphagia, which may accelerate the process of sarcopenia [36]. An insufficient amount of protein intake can also be especially detrimental to muscle protein synthesis [8]. In this study, however, the possible contributing effect of dysphagia and inadequate protein intake were eliminated by the multiple regression analyses. Even after adjustment of these factors, the odds ratio (OR) of poor functional outcome was 2.23fold in the presence of sarcopenia. This indicates that the presence of sarcopenia per se played a negative role in the poststroke functional outcome at 6 months. However, different results were observed between men and women. Whereas the men showed a change in OR from 2.61 to 2.01 after malnutrition adjustment, which was not statistically significant, the women showed more drastic changes from 9.93 to 2.48. The outcome in women was more affected by malnutrition than men. These discrepancies may be attributable to differences in serum prealbumin level, with women showing lower values (women = 22.9 ± 221 6.2 g/dL, men = 26.4 ± 6.5 g/dL). Prealbumin levels, known to have a short turnover rate of 2–3 days, most likely reflect nutritional and protein status immediately after a stroke and exclude the dietary intake in the prestroke period [37,38]. Therefore, the low prealbumin levels in the presence of normal protein and albumin levels indicate that more women, due to their increased age and menopause state, may be more vulnerable to poststroke protein degradation or poor protein synthesis. Two crucial factors may contributed to the decline in muscle mass that makes women more vulnerable. First, women have a higher prevalence of sarcopenia because of the Korean national tendency to show relatively low physical activity [39] and low protein diet [40] compared with men. Second, most women were at the postmenopause stage. Menopause-related biological changes in insulin sensitivity and estrogen receptors could play a role in muscle mass and strength [41] by reducing muscle protein synthesis and disturbing insulin-mediated suppression of proteolysis [42]. Further studies that are designed for sex-specific analyses are needed to draw a clear conclusion on the sex-specific discrepancy in the effect of sarcopenia. A variety of tools are available to measure sarcopenia. The amount of absolute muscle mass can be measured only by using body image techniques such as bioimpedance, dual x-ray absorptiometry, computed tomography, or magnetic resonance imaging [43]. However, a recently revised study from the EWGSOP emphasized the importance of muscle function over quantity and guided that the measurement of muscle function by grip strength is an adequate screening tool for sarcopenia in clinical settings [44]. Therefore, a handheld dynamometry, as used in this study, may be considered as the optimal choice in stroke patients for detecting sarcopenia since this approach can be easily applied in various settings, is inexpensive and quick to administer. Sarcopenia can be reversible with some aerobic and isometric exercise training, such as treadmill exercise, robotic-assisted gait, and strengthening training in poststroke patients [45–47]. Moreover, nutritional support for stroke patients in the hospital within
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the first week of admission was beneficial for maintaining adequate body composition, especially among women [48]. Considering its reversible nature, early detection and intervention are crucial for minimizing the deleterious effect of poststroke sarcopenia on functional outcome. Sarcopenia should be considered in stroke management to arouse physiatrists’ attention to the implication of stroke-related sarcopenia on stroke recovery. 4.1. Study limitations There are a few limitations in this study. First, the subjects of this study were limited to a single center. Therefore, the results of the present study may not represent the generalized population. However, 194 patients with relatively homogenous demographic information were recruited using strict inclusion criteria, which makes this study more trustworthy. Second, the retrospective nature of this study had a limitation on tracing patients’ long-term outcome. When considering the time course of stroke recovery, most neurologic and functional recovery from acute stroke rehabilitation is greatest within the first 3 months and tends to plateau after 6 months [49]. This study includes follow-up results up to 6 months from the onset, which includes the period in which the greatest recovery occurs. Third, sarcopenia was defined primarily by results obtained from the grip strength. Theoretically, additional tools that can provide a quantitative measure of muscle mass is required to confirm the diagnosis of sarcopenia. However, a revised algorithm for sarcopenia case-finding was recently introduced by EWGSOP. According to the guideline, if decreased grip strength is detected, it is considered to be enough evidence to start intervention for sarcopenia in clinical practice [20]. Finally, only of those patients who were able to comply with at least one-step obey commands were recruited, eliminating more severe poststroke patients and those with double hemiplegia. Whether the impact of sarcopenia is more pronounced in these severe stroke patients is a topic that warrants future large-scale prospective studies. 5. Summary and conclusion This study suggests that poststroke patients who show positive evidence of sarcopenia at 2 weeks poststroke, as assessed by the grip strength of the nonhemiplegic hand, may be at increased risk of poor functional outcome at 6 months poststroke. More importantly, the impact of sarcopenia was more pronounced in women than in men. Therefore, early detection of sarcopenia in patients after stroke is necessary to prevent its deleterious effect on poststroke functional outcome. Further studies in various regions are suggested to reach a consensus on the impact of sarcopenia on poststroke functional recovery. Sources of support (1) The statistical consultation was supported by a grant from the Korea Health Technology R&D Project through The Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1062). (2) This work was supported by the Clinical Research Coordinating Center of Bucheon St. Mary’s Hospital, Republic of Korea (Grant number: HC16OISI0028-20161275). References [1] Currie D. Major causes of disability, death shift around the globe: chronic diseases now taking the lead. Nations Health 2013;43:1–22. [2] Weimar C, Konig IR, Kraywinkel K, Ziegler A, Diener HC, German Stroke Study C. Age and National Institutes of Health Stroke Scale Score within 6 hours after
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Clinical study
Can initial sarcopenia affect poststroke rehabilitation outcome? Yongjun Jang a, Sun Im b, Yeonjae Han b, Hyunjung Koo b, Donggyun Sohn b, Geun-Young Park b,⇑ a
Department of Rehabilitation Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 222, Banpo-daero, Seocho-gu, Seoul 06591, Republic of Korea Department of Rehabilitation Medicine, Bucheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 327, Sosa-ro, Bucheon-si, Gyeonggi-do 14647, Republic of Korea b
a r t i c l e
i n f o
Article history: Received 9 July 2019 Accepted 24 August 2019 Available online xxxx Keywords: Stroke Sarcopenia Recovery of function Sex Hand strength Hemiplegia
a b s t r a c t This study investigated the association between the presence of sarcopenia, measured by nonhemiplegic grip strength, and the level of functional recovery, measured by the modified Rankin Scale (mRS) at six months after stroke. We performed a retrospective cohort analysis of a prospectively maintained database of 194 hemiplegic poststroke patients, who had been admitted to the Department of Rehabilitation Medicine of a university-affiliated hospital. At 6 months after stroke, 72.2% of patients had mRS score >3, with more women (81.0% vs. 66.0%, p = 0.024) showing poor recovery. Both men (51.3% vs. 35.9%, p = 0.041) and women (42.2% vs. 6.7%, p = 0.022) with mRS score >3 had a higher rate of sarcopenia. Univariate analysis revealed that the presence of sarcopenia was associated with a 2.71fold higher risk of poor recovery at six months. In addition, women had a 2.18-fold higher risk of poor outcome. Multivariable logistic regression analysis revealed that the presence of sarcopenia was associated with poor functional outcome (odds ratio [OR] = 2.61, 95% confidence interval [CI]: 1.14–5.98, p = 0.024) in men, but this association was notably stronger in women (OR = 9.93, 95% CI: 1.22–81.19, p = 0.032). This study suggests that the presence of sarcopenia two weeks after stroke may increase the risk of poor functional outcome six months after stroke. Most notably, women with sarcopenia within 2 weeks from stroke onset were more significantly likely to have a poor modified Rankin Scale after 6 months. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction Stroke is one of the leading causes of disability worldwide, and it is expected to increase continuously over the next decades [1]. Hemiparesis is the most noticeable sequelae after stroke and has been regarded as a consequence of brain injury itself. Many factors directly affect the prognosis of stroke. Neurologic severity based on brain lesion, as quantified by the National Institutes of Health Stroke Scale [2], and comorbidities [3] are generally perceived as the most critical poststroke prognostic factors. Also, functional deficits such as dysphagia [4] and decline in functional level (Barthel Index [5] or Functional Independence Measure [6]) at admission are also regarded as crucial prognostic factors [7]. Recently, the literature on this topic has emphasized secondary skeletal muscle abnormalities such as sarcopenia and their clinical relevance in the functional outcome, especially in the geriatric population [8,9]. However, the role of sarcopenia on poststroke functional outcome needs to be determined further.
⇑ Corresponding author. E-mail address: [email protected] (G.-Y. Park).
Sarcopenia is a condition that leads to loss of skeletal muscle mass, quality, and strength usually related to the physiological process of aging [10]. However, irrelevant to age, sarcopenia can be accelerated after specific acute systemic disease such as stroke [11,12]. Vicious cascades of skeletal muscle loss are critical to poststroke patients because the skeletal muscle is the most vulnerable organ that is directly affected by poststroke disability. Since the amount of muscle atrophy corresponds to the patient’s maximal capability of making a volitional effort [11,13], decreased skeletal muscle bulk and weakness may eventually influence the patient’s functional outcome [9]. A recent study by Yoshimura et al. showed that the prevalence of sarcopenia in rehabilitation ward inpatients was up to 53.0% [14]. Seo et al. suggested that grip strength on the unaffected side is an independent predictor of short-term poststroke functional outcome [15]. Nevertheless, the secondary consequences from accelerated sarcopenia after stroke are usually underestimated, and their impact on functional outcome in stroke patients has not yet been determined. Taking into consideration that poor muscle functioning related to sarcopenia increases the risk of functional decline, falls, and mortality [16], clarifying the impact of sarcopenia in stroke patients may have important clinical implications.
https://doi.org/10.1016/j.jocn.2019.08.109 0967-5868/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
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The purpose of the present study was to assess the impact of sarcopenia on functional outcome at the time of stroke onset and 6 months after stroke. We aimed to determine whether the presence of low grip strength of the unaffected side, a marker of sarcopenia [17], could be an independent risk factor of poor functional outcome after stroke. Further, in consideration of sex differences in muscle strength and sex-specific pathophysiological mechanisms for sarcopenia [18], we attempted to elucidate whether the impact of sarcopenia after stroke showed sex differences. 2. Methods 2.1. Subject population We performed a retrospective cohort analysis of a prospectively maintained database of patients who had been admitted to the Department of Rehabilitation of a university-affiliated hospital between January 2012 and August 2016 [19]. Patients with the first-ever stroke who had been diagnosed at the stroke unit of our institution and who had been transferred to our department were included. The study was approved by the Institutional Review Board of our institution (HC16RISI0007). 2.2. Eligibility criteria Hemiplegic poststroke patients aged 45–81 years old, who were physically independent with no previous history of stroke, and who could follow at least one-step commands to fully cooperate with functional assessments, were eligible. These patients were required to have full medical records of their level of functional parameters both at 2 weeks and at up to 6 months poststroke. Patients who had a comorbid disease such as chronic inflammatory disease, active tuberculosis, autoimmune disease, chronic colitis, organ transplantation, immunosuppressive therapy, acquired immunodeficiency syndrome, malignancy, or amputation were excluded, as those conditions can influence muscle mass [12]. 2.3. Definition of sarcopenia Recent guideline of European Working Group on Sarcopenia in Older People (EWGSOP) focused on low muscle strength as a key characteristic of sarcopenia [20]. Therefore, the present study defined sarcopenia based on the grip strength measured from the nonhemiparetic side using a dynamometer (Jamar Hydraulic Hand Dynamometer, Masan, Gyeongsangname-do, Republic of Korea), based on the recommendation of the Southampton protocol [21]. Three trials of grip strength from each hand were performed, with the mean value used for analysis. The grip strength was measured by a single occupational therapist who was blind to the patient’s clinical information. According to the recommendations from the Asian Working Group for Sarcopenia, sarcopenia was defined with cutoff values of the grip strength set at <26 kg for men and <18 kg for women [17].
2.5. Functional outcome parameters and confounding factors The definition of good functional outcome was based on the modified Rankin Scale (mRS), which was recorded 6 months poststroke. A mRS score 3 was defined as a good functional outcome that patients can at least walk without assistance, whereas a mRS score >3 was defined as a poor functional outcome with a profound disability, requiring continuous assistance. The level of functional performance was measured using the following parameters. The patients’ level of independence in daily living was measured by the Korean version of the Modified Barthel Index (K-MBI) [22]. Cognitive function was evaluated with the Korean version of the Mini-Mental Status Examination (K-MMSE) [23]. The level of swallowing performance and oral diet intake was categorized according to the Function Oral Intake Scale [24]. Each functional parameter was measured twice: within 2 weeks from stroke onset (t0) and at 6 months after stroke (t1). 2.6. Laboratory parameters Since nutritional influences are strongly linked to sarcopenia [25], the laboratory assessment was done to evaluate patients’ nutritional status at baseline [26]. Fasting serum venous blood samples were collected at 2 weeks poststroke and malnutrition was defined as a serum albumin level below the cutoff of 3.5 g/ dL [27]. 2.7. Statistical analysis To evaluate factors that affect the poor poststroke functional outcome, demographic characteristics were compared between the groups with poor (mRS >3) and good (mRS 3) functional outcome. Normally distributed continuous variables were described with means (±SD), and intergroup comparisons were performed by two-sample t-tests. Nonnormally distributed data were presented as the median (interquartile range), and between-group comparisons were made using the Mann-Whitney test. Categorical variables were presented as percentages (number, %), and either a Mann-Whitney test (ordinal data) or Fisher’s exact test (dichotomous data) was performed to evaluate the intergroup difference. Univariate and multivariate logistic regressions were performed to identify independent parameters associated with low functional outcome (mRS >3) at 6 months poststroke. To validate sarcopenia as a single prognostic parameter for the low functional outcome at 6 months poststroke, multiple logistic regression was performed, adjusting for age, sex, and significant univariate variables. A multivariable logistic regression model was constructed using stepwise selection with an entry criterion of p < 0.1 and stay criterion of p < 0.05. All statistical tests were analyzed using SAS 9.4 (Statistical Analysis System software, version 9.4, Cary, NC, USA) and were two-tailed, with p < 0.05 considered statistically significant. 3. Results 3.1. Demographic characteristics of the study population
2.4. Demographic characteristics Information on stroke etiology, hemiparetic side, and baseline demographics such as sex, age, hand dominance, and grip strength data were acquired. Height and weight were obtained, and body mass index was calculated. The presence of cerebral vascular disease-related medical comorbidities such as hypertension, diabetes, hyperlipidemia, coronary artery disease, arrhythmia, and other underlying diseases such as osteoporosis and infection history were recorded.
Among 298 patients who had been diagnosed with a first-ever stroke, 194 met the inclusion criteria (Fig. 1). Based on the grip strength from the nonhemiparetic side, 81 (41.8%) satisfied the criteria for sarcopenia. Compared with patients with a mRS score 3, those with a mRS score >3 had a higher rate of sarcopenia (47.1% vs. 27.8%, p < 0.01). Differences in functional level as measured by the MBI and MMSE were observed between the two groups. Those with a mRS score >3 were more likely to be nil per mouth (51.4% vs. 24%, p < 0.000) with evidence of malnutrition (Table 1).
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
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Fig. 1. Flow chart of the study population.
At 6 months poststroke, 72.2% of patients had a mRS score >3, with more women showing poor recovery. 3.2. Predictors of poor functional outcome: univariate analysis Univariate analysis revealed that the presence of sarcopenia was associated with a 2.71-fold higher risk of poor recovery (mRS >3). Also, female was associated with a 2.18-fold higher risk of poor outcome (Table 2). Other independent risk factors were poor Barthel index, nil per mouth, and lower MMSE scores at 2 weeks after stroke. When analyzing only the men, the impact of sarcopenia was still present, with a 2.61-fold higher risk of poor outcome, along with low MBI and nil per mouth. In sharp contrast, in women, the presence of sarcopenia was significantly associated with a 9.93-fold higher risk of poor functional outcome, along with low MBI and the presence of malnutrition. 3.3. Predictors of poor functional outcome: multivariate logistic regression analysis Multivariate regression analysis showed that sarcopenia was associated with a 2.23-fold higher risk of poor outcome, even after adjustment for sex, age, nil per mouth, the presence of malnutrition, and MMSE (Table 3). In the sex-stratified analysis, sarcopenia was associated with a 2.99-fold higher risk of poor outcome in men after adjustment for age and sex. However, this model was no
longer significant after adjustment for the covariables, such as tube feeding malnutrition and MMSE. In women, sarcopenia was associated with a 9.77-fold higher risk of poor outcome, even after adjustment for the covariables of age, sex, and nil per mouth. The odds for poor recovery decreased when the covariate malnutrition was introduced into the model, indicating that malnutrition is a strong confounding factor for sarcopenia that affects women more than men. 4. Discussion Patients with a mRS score >3 at 6 months poststroke showed a higher rate of initial sarcopenia than those with a mRS score 3 (47.1% vs. 27.8%). In addition, this study showed that the presence of sarcopenia was associated with a 2.71-fold higher risk of poor poststroke recovery at 6 months. It also emphasizes the fact that poststroke women with sarcopenia within 2 weeks poststroke are at greator risk of poor outcome compared with men (women: 9.93-fold vs. men: 2.61-fold) at 6 months poststroke. The results of the present study concur with those reported by previous studies. Scherbakov et al. highlighted the biologic alternation of the muscular structure after stroke [11,28]. After the stroke, type II muscle fibers gradually degrade, resulting in a decrement in the cross-sectional area of entire skeletal muscles. These changes in muscle volume eventually lead to mobility deficit [29] and affect the mRS [30]. A particularly significant finding of the present study
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
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Table 1 Demographic, clinical and laboratory parameters of the participants. Total (n = 194)
Poor (mRS > 3) (n = 140)
Good (mRS 3) (n = 54)
p-value
Sarcopenia Yes No
81 (41.8%) 113 (58.2%)
66 (47.1%) 74 (52.9%)
15 (27.8%) 39 (72.2%)
0.022
Demographics Sex Men Women Age BMI
115 (59.3%) 79 (40.7%) 64.3 ± 13.0 24.2 ± 3.4
76 (54.3%) 64 (45.7%) 65.2 ± 12.6 23.9 ± 3.2
39 (72.2%) 15 (27.8%) 61.9 ± 13.5 24.1 ± 2.9
Brain Lesion Etiology Ischemia Hemorrhage Both
111 (57.5%) 69 (35.8%) 13 (6.7%)
74 (53.2%) 55 (39.6%) 10 (7.1%)
37 (68.5%) 14 (25.9%) 3 (5.6%)
29 (5;59) 63 (15;90) 19 (8;25) 22 (16;26) 4 (1; 7) 6 (4; 7)
13 (0;37) 43 (9;70) 15 (4;24) 20 (13;25) 3 (1; 6) 6 (4; 7)
74 (56;87) 90 (80;92) 25 (18;27) 25 (19;29) 5 (4; 7) 7 (5; 7)
0.000 0.000 0.000 0.002 0.002 0.004
85 (43.8%) 49 (25.3%) 6.6 ± 0.6 3.8 ± 0.5 24.9 ± 6.6
72 (51.4%) 44 (31.4%) 6.6 ± 0.6 3.9 ± 0.5 24.9 ± 6.7
13 (24%) 5 (9.3%) 6.8 ± 0.5 4.0 ± 0.4 24.9 ± 6.4
0.000 0.003 0.019 0.875 0.970
0.034
0.072 0.755 0.257
Functional parameters MBI
t0 t1 t0 t1 t0 t1
MMSE FOIS Nutritional parameter Nil per mouth Malnutrition Protein (g/dL) Albumin (g/dL) Prealbumin (g/dL)
Abbreviations: t0 = within two weeks poststroke; t1 = time at poststroke six months. Normally distributed continuous variables were described with means (±SD) and nonnormally distributed data were presented with median (interquartile range, IQR). Categorical variables were presented as percentages (number, %).
Table 2 Predictors of functional outcome at six months by univariate analysis according to sex. Total (n = 194)
Sarcopenia Age Sex (women) Smoking MBI at baseline (<50) MMSE (<24) FOIS (3) Malnutrition (yes) *
Men (n = 115)
Women (n = 79)
OR (95% CI)
p-value*
OR (95% CI)
p-value*
OR (95% CI)
p-value*
2.71 1.02 2.18 0.66 1.95 1.22 2.97 1.16
0.005 0.137 0.001 0.222 0.000 0.001 0.003 0.054
2.61 1.00 NA 1.28 1.87 1.70 4.03 1.21
(1.14–5.98) (0.96–1.03)
0.024 0.843
(1.22–81.19) (0.99–1.09)
0.032 0.107
(0.57–2.88) (1.53–2.29) (0.68–1.93) (1.64–9.89) (0.96–1.53)
0.550 0.000 0.448 0.002 0.107
9.93 1.04 NA 0.16 2.02 1.14 1.95 1.26
(0.02–1.05) (1.56–2.62) (1.04–1.21) (0.55–6.94) (1.05–1.50)
0.056 0.000 0.356 0.301 0.013
(1.35–5.47) (0.99–1.05) (1.12–4.43) (0.34–1.29) (1.68–2.26) (1.07–1.39) (1.44–6.13) (1.00–1.35)
Analyzed by logistic regression analysis(univariate).
Table 3 Predictors of functional outcome at six months by multivariate analysis, according to sex. Total
Crude Model Model Model Model * y à § ||
1y 2à 3§ 4||
Men
Women
OR (95% CI)
p-value*
OR (95% CI)
p-value*
OR (95% CI)
p-value*
2.71 3.33 2.71 2.38 2.23
0.005 0.002 0.011 0.000 0.001
2.61 2.99 2.12 2.01 1.45
0.024 0.016 0.119 0.142 0.116
9.93 9.94 9.77 2.48 1.96
0.032 0.033 0.035 0.037 0.081
(1.35–5.47) (1.57–7.07) (1.25–5.88) (1.48–3.82) (1.38–3.59)
(1.14–5.98) (1.23–7.23) (0.82–5.47) (0.63–4.32) (0.97–1.37)
(1.22–81.19) (1.20–82.15) (1.18–81.03) (1.37–4.50) (0.93–4.13)
Analyzed by logistic regression analysis (multivariate). Adjusted by age and sex. Adjusted by age, sex, and FOIS (p-value <0.05). Adjusted by age, sex, FOIS, and malnutrition (p-value <0.05). Adjusted by age, sex, FOIS, malnutrition, and MMSE (p-value <0.05).
is that the functional decrement as a result of sarcopenia was more distinct among women. Several studies have revealed sex-specific differences regarding the poststroke outcome [31–35]. However, none of the studies
mentioned sex-specific differences in the effect of sarcopenia on the poststroke outcome. Di Carlo et al. showed that women were at 1.5 times higher risk of disability and handicap 3 months after stroke. Sex differences in age distribution, baseline comorbidities,
Please cite this article as: Y. Jang, S. Im, Y. Han et al., Can initial sarcopenia affect poststroke rehabilitation outcome?, Journal of Clinical Neuroscience, https://doi.org/10.1016/j.jocn.2019.08.109
Y. Jang et al. / Journal of Clinical Neuroscience xxx (xxxx) xxx
and sociodemographic factors were cited as possible factors [32]. In another single-hospital–based registry, there was a higher prevalence of atrial fibrillation in women compared with men. In our study, the average age and proportion of those with poor functional ability (mRS >3) were higher in women (women = 81%, men = 66.1%). However, the prevalence of underlying comorbidities including coronary artery disease (p = 0.540), hypertension (p = 0.121), and arrhythmia (p = 0.091) did not show significant gender differences. Therefore, baseline medical comorbidities played a small role in our study. In addition to underlying comorbidities, poststroke swallowing difficulty and malnutrition are also known to affect structural and functional alteration of muscle, resulting in sarcopenia. As high as 42% of poststroke patients manifest with dysphagia, which may accelerate the process of sarcopenia [36]. An insufficient amount of protein intake can also be especially detrimental to muscle protein synthesis [8]. In this study, however, the possible contributing effect of dysphagia and inadequate protein intake were eliminated by the multiple regression analyses. Even after adjustment of these factors, the odds ratio (OR) of poor functional outcome was 2.23fold in the presence of sarcopenia. This indicates that the presence of sarcopenia per se played a negative role in the poststroke functional outcome at 6 months. However, different results were observed between men and women. Whereas the men showed a change in OR from 2.61 to 2.01 after malnutrition adjustment, which was not statistically significant, the women showed more drastic changes from 9.93 to 2.48. The outcome in women was more affected by malnutrition than men. These discrepancies may be attributable to differences in serum prealbumin level, with women showing lower values (women = 22.9 ± 221 6.2 g/dL, men = 26.4 ± 6.5 g/dL). Prealbumin levels, known to have a short turnover rate of 2–3 days, most likely reflect nutritional and protein status immediately after a stroke and exclude the dietary intake in the prestroke period [37,38]. Therefore, the low prealbumin levels in the presence of normal protein and albumin levels indicate that more women, due to their increased age and menopause state, may be more vulnerable to poststroke protein degradation or poor protein synthesis. Two crucial factors may contributed to the decline in muscle mass that makes women more vulnerable. First, women have a higher prevalence of sarcopenia because of the Korean national tendency to show relatively low physical activity [39] and low protein diet [40] compared with men. Second, most women were at the postmenopause stage. Menopause-related biological changes in insulin sensitivity and estrogen receptors could play a role in muscle mass and strength [41] by reducing muscle protein synthesis and disturbing insulin-mediated suppression of proteolysis [42]. Further studies that are designed for sex-specific analyses are needed to draw a clear conclusion on the sex-specific discrepancy in the effect of sarcopenia. A variety of tools are available to measure sarcopenia. The amount of absolute muscle mass can be measured only by using body image techniques such as bioimpedance, dual x-ray absorptiometry, computed tomography, or magnetic resonance imaging [43]. However, a recently revised study from the EWGSOP emphasized the importance of muscle function over quantity and guided that the measurement of muscle function by grip strength is an adequate screening tool for sarcopenia in clinical settings [44]. Therefore, a handheld dynamometry, as used in this study, may be considered as the optimal choice in stroke patients for detecting sarcopenia since this approach can be easily applied in various settings, is inexpensive and quick to administer. Sarcopenia can be reversible with some aerobic and isometric exercise training, such as treadmill exercise, robotic-assisted gait, and strengthening training in poststroke patients [45–47]. Moreover, nutritional support for stroke patients in the hospital within
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the first week of admission was beneficial for maintaining adequate body composition, especially among women [48]. Considering its reversible nature, early detection and intervention are crucial for minimizing the deleterious effect of poststroke sarcopenia on functional outcome. Sarcopenia should be considered in stroke management to arouse physiatrists’ attention to the implication of stroke-related sarcopenia on stroke recovery. 4.1. Study limitations There are a few limitations in this study. First, the subjects of this study were limited to a single center. Therefore, the results of the present study may not represent the generalized population. However, 194 patients with relatively homogenous demographic information were recruited using strict inclusion criteria, which makes this study more trustworthy. Second, the retrospective nature of this study had a limitation on tracing patients’ long-term outcome. When considering the time course of stroke recovery, most neurologic and functional recovery from acute stroke rehabilitation is greatest within the first 3 months and tends to plateau after 6 months [49]. This study includes follow-up results up to 6 months from the onset, which includes the period in which the greatest recovery occurs. Third, sarcopenia was defined primarily by results obtained from the grip strength. Theoretically, additional tools that can provide a quantitative measure of muscle mass is required to confirm the diagnosis of sarcopenia. However, a revised algorithm for sarcopenia case-finding was recently introduced by EWGSOP. According to the guideline, if decreased grip strength is detected, it is considered to be enough evidence to start intervention for sarcopenia in clinical practice [20]. Finally, only of those patients who were able to comply with at least one-step obey commands were recruited, eliminating more severe poststroke patients and those with double hemiplegia. Whether the impact of sarcopenia is more pronounced in these severe stroke patients is a topic that warrants future large-scale prospective studies. 5. Summary and conclusion This study suggests that poststroke patients who show positive evidence of sarcopenia at 2 weeks poststroke, as assessed by the grip strength of the nonhemiplegic hand, may be at increased risk of poor functional outcome at 6 months poststroke. More importantly, the impact of sarcopenia was more pronounced in women than in men. Therefore, early detection of sarcopenia in patients after stroke is necessary to prevent its deleterious effect on poststroke functional outcome. Further studies in various regions are suggested to reach a consensus on the impact of sarcopenia on poststroke functional recovery. Sources of support (1) The statistical consultation was supported by a grant from the Korea Health Technology R&D Project through The Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1062). (2) This work was supported by the Clinical Research Coordinating Center of Bucheon St. Mary’s Hospital, Republic of Korea (Grant number: HC16OISI0028-20161275). References [1] Currie D. Major causes of disability, death shift around the globe: chronic diseases now taking the lead. Nations Health 2013;43:1–22. [2] Weimar C, Konig IR, Kraywinkel K, Ziegler A, Diener HC, German Stroke Study C. Age and National Institutes of Health Stroke Scale Score within 6 hours after
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