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Steroid myopathy in patients with chronic respiratory diseases
Journal of the Neurological Sciences 338 (2014) 96–101
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Steroid myopathy in patients with chronic respiratory diseases Oleg S. Levin a, Anna G. Polunina b,c,⁎, Marina A. Demyanova b, Fedor V. Isaev b a b c
Department of Neurology, Russian Medical Academy of Postgraduate Education, Botkinskiy proezd d.5, korp.19, Moscow 125101, Russia Principle Clinical Military Hospital, Federal Security Service of the Russian Federation, Golitzyno, Petrovskoe shosse d.48, Odinzovskiy r-n, Moscow Region 143040, Russia Moscow Research and Practical Center of Narcology, Lyublinskaya ul. 37/1, Moscow 109390, Russia
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Article history: Received 17 September 2013 Received in revised form 19 November 2013 Accepted 11 December 2013 Available online 17 December 2013 Keywords: Asthma Complications of corticosteroid therapy Glucocorticoid-induced myopathy Inhaled corticosteroid Muscle weakness Steroid myopathy
a b s t r a c t Background: Corticosteroid-induced myopathy is a well known clinical entity, and experimental studies showed decreased rate of protein synthesis and increased rate of protein breakdown in muscles of chronically treated animals. Objective: The present observational study was aimed to evaluate skeletal muscle functions in asthmatics and patients with other chronic respiratory diseases treated by inhaled or oral corticosteroids. Methods: Thirty six patients with respiratory diseases were included into the study. The physician-rated peripheral motor deficits scale, stepper test and ankle/wrist index were used for assessment of muscle functions. The effects of length of glucocorticoids intake on muscle functions were evaluated. Results: Sixty five per cent of patients using corticosteroids daily during 1 year and longer reported weakness in legs, and 20% of these patients demonstrated objective signs of the muscle weakness. The performance on the stepper test was significantly worse in patients chronically using corticosteroids in comparison with the control group (10.9 ± 3.4 steps vs 16.1 ± 2.4 steps per 10 s, respectively; F = 21.6, p b 0.001). In addition, a proportion of patients using corticosteroids for at least 18 months were characterized by muscle hypotrophy at a dominant leg. Conclusion: Chronic intake of inhaled corticosteroids induces clinically significant decrease of muscle functions at least after 1-year of daily treatment. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The catabolic effects of glucocorticoids have been well known for many years [1]. In skeletal muscle, glucocorticoids decrease the rate of protein synthesis and increase the rate of protein breakdown contributing to atrophy. Administration of high doses of glucocorticoids to animals caused decrease of muscle mass and induced weakness in a range of studies [1]. In healthy humans, adverse effects of dexamethasone on sarcolemmal excitability (decline of muscle fiber conduction velocity for the biceps brachii, vastus lateralis, vastus medialis, and tibialis anterior) were registered after 1 week of drug administration [2]. Severe cases of acute myopathy complicating status asthmaticus are widely reported in contemporary medical publications [3–5]. Although neuromuscular blockade may contribute to this condition, intensive steroid treatment is considered to be an important factor in these patients. After rapid tapering of systemic steroids, patients tend to quickly regain muscle strength [4]. Electrophysiological tests confirmed the myopathic abnormalities with no evidence of a neuromuscular transmission disorder or generalized neuropathy in the majority of patients with acute myopathy complicating status asthmaticus [3,6]. Electrophysiological improvement paralleled clinical improvement in the study of David ⁎ Corresponding author at: pr-t Vernadskogo 101-8-7, Moscow 119526, Russia. Tel.: + 7 916 1291980; fax: + 7 499 7395727. E-mail address: [email protected] (A.G. Polunina). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.12.023
and colleagues [6] and in the case of Yamaguchi and colleagues [7]. It should be noted, that rhabdomyosis with elevation of creatinine kinase and renal impairment secondary to myoglobinuria may complicate the acute corticosteroid-induced myopathy [3,8]. Myopathy in asthmatic patients chronically taking oral steroids is reported as well. Importantly, the impairment of respiratory muscle functions may manifest as therapy-resistant asthma in these patients as the decrease of the respiratory muscle strength makes inhalations ineffective [7,9,10]. Decramer and Stas [9] reported two patients who developed reductions in PImax and PEmax by 38% and 48% of predicted, respectively, after prolonged treatment with high doses of corticosteroids. Tapering of treatment with corticosteroids resulted in recovery of respiratory muscle force with PImax and PEmax reaching 74% and 92%, respectively, after 3 months. Importantly, animal studies demonstrated diaphragmatic myopathy and atrophy after chronic steroid treatment in rats [11]. Skeletal muscles are commonly dysfunctional in patients with chronic steroid myopathy as well [8]. Patients using glucocorticoids commonly report skeletal muscle weakness and twitching, which the most prominent in legs during walking. Decramer and Stas [9] observed decrease of quadriceps force to 31% of predicted one (range 16 to 46% of predicted) in their chronic patient cohort. The authors noted that improvement of muscle functions in legs was slower in comparison with the respiratory muscles. In six months after reducing steroid intake quadriceps force varied from 31 to 85% of the predicted normative in
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this study. Interestingly, in the study of Minetto and colleagues [12] the muscle fiber conduction velocity was considerably reduced in m. vastus lateralis, m. vastus medialis and m. tibialis anterior in patients with Cushing's disease in comparison with controls (difference: 11.6% to 26.0%). The inhaled corticosteroids are commonly considered by medical practitioners as safer drugs in comparison with oral corticosteroids. However, the scientific data do not confirm this opinion. Borba and colleagues [10] reported similar compromise of respiratory muscle function in asthmatic patients chronically taking either oral or inhaled corticosteroids. Mak and colleagues [13] did not find significant differences in maximal mouth pressure, and quadriceps and sternomastoid strength in asthmatic patient groups according to prednisone or inhaled beclomethasone intake. Moreover, four of 12 patients taking inhaler beclomethasone versus only 1 of 12 patients taking prednisone demonstrated clinical signs of quadriceps weakness. In the similar study of Akkoca and colleagues [14] inhaler group showed somewhat better respiratory muscle function in comparison with oral prednisone group (mean duration of oral steroids: 9.83 ± 9.86 years). Nevertheless, the muscle function was intermediate in inhaler patients in comparison with normal controls and oral steroid group. The present study was aimed to evaluate skeletal muscle functions in patients chronically taking inhaled corticosteroids or low doses of oral corticosteroids. We suggested that duration of chronic steroid treatment would be the important factor of muscle function impairment in patients with respiratory diseases. 2. Methods 2.1. Patients In-patients with respiratory diseases were evaluated at the Principle Clinical Military Hospital of the Federal Security Service of the Russian Federation during the period from the January of 2011 to the February of 2012. The inclusion criteria were: 1) age ≤ 75 years; 2) chronic respiratory disease which is commonly treated by corticosteroids; 3) good compensation of respiratory functions (oxygen saturation by pulse oximetry ≥ 95%). The exclusion criteria were: 1) neurological diseases; 2) diabetes mellitus or hypothyroidism; 3) other serious concomitant diseases. The Medical Council of the Principle Clinical Military Hospital of the Federal Security Service of the Russian Federation considered and approved the design and ethical issues of the study. Patients were informed that the examination of motor functions did not concern the medical management of their disease and was conducted as a part of the scientific research. In addition, the methods of the study were shortly described to the patients. Only patients who gave an oral informed consent (as is customary in Russia) to participate in the study were evaluated. Forty patients were invited, and thirty six gave the informed consent. 2.2. Peripheral Motor Deficits Scale (PMDS) For quantitative evaluation of peripheral motor deficits we developed a physician-rated scale (see the Appendix 1). The scale included three complaints which are the most typical for early stages of myopathy (weakness of the legs during plain walking; problematic walking upstairs or downstairs due to the weakness of the legs; problematic buttoning up or unbuttoning, during sewing or picking up coins). The optional responses were: never (0 points); 2) once or twice during the last month (1 point); 3) one – three times per week (2 points); 4) every day (3 points). When patients reported the subjective motor deficits, we conducted seven traditional clinical tests for evaluation of peripheral motor deficits. Normal performance on a test was evaluated as zero, deficit was evaluated as 1 point, and absence of a function was evaluated as 2
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points. Deficits on motor tests weighted twice as much as deficits on subjective part of the test. Complaints, objective signs and summarized score of the scale were analyzed. 2.3. Stepper test In order to evaluate mild motor deficits in the proximal muscles of lower limbs, we used Mini Stepper Arctix 333-08031. First, we asked patients to train for a while and to find comfortable position on the mini stepper. After that we asked the patient to complete as many steps as possible during 10 s. The number of steps completed during 10 s was included into the analysis. As we started our study without the stepper, only 28 patients completed the test. 2.4. Ankle/wrist index In our previous study we found the ratio between the smallest circumference of leg above an ankle and the smallest circumference of forearm above a wrist of the dominant limbs to be an effective tool for measuring muscle atrophy at early stages of the diabetic neuropathy or steroid myopathy [15]. In patients with mild muscle hypotrophy due to either diabetic neuropathy or steroid myopathy, we observed more prominent atrophic changes in a dominant leg in comparison with a dominant forearm. Therefore, the ankle/wrist index in the present study is the ration between the smallest circumference of dominant leg above an ankle and the smallest circumference of dominant forearm above a wrist (dominant ankle/dominant wrist). As we found significant differences in the values of ankle/wrist index in males and females, sex was included into the analysis as the second between-group factor. Taking off clothes was problematic in 4 patients, therefore only 32 patients were evaluated. 2.5. Neuropathy Disability Score For quantitative evaluation of sensory functions and reflexes we used the modified Neuropathy Disability Score (NDS) [16,17]. Reflexes were graded at the knee and ankle for a maximum of eight points if areflexic. Sensory tests included pinprick sensation and vibration. A sensory score was given according to the anatomic location at which the patient could identify the introduced stimulus. If the patient perceived the stimulus at all levels, a score of 0 was given. A score of 1 was given if the patient failed to perceive the stimulus at the base of the toe, 2 at the midfoot, 3 at the heel, 4 at the lower leg, and 5 if at or above the knee level. The summarized score of pinprick and vibration sensation, and reflexes at both legs was included into the analysis. 2.6. Statistical analysis All analyses were performed using SPSS software for windows (SPSS 17.0, Chicago, IL, USA). Patients were divided into two groups according to the length of steroid treatment. Patients with chronic corticosteroids ≥ 1 year constituted the main group (n = 20), and patients with absent or shortterm steroid treatment were the control group (n = 16). As the PMDS score was nonparametric, we used Mann–Whitney test for evaluation of intergroup differences and Spearman's test for correlative analysis. In addition, we performed ANCOVAs with age, weight and NDS score as covariates. 3. Results 3.1. Patient characteristics The patient characteristics are presented in Table 1. Twenty three males and 13 females were included into the study. The mean age of the patients was 54.1 ± 13.5 years. Bronchial asthma was the most
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Table 1 Clinical characteristics and peripheral motor indexes. Patient
Sex
Age (years)
Diagnosis
Steroids
Duration of steroids (years)
Weight
PMDS
A/W index
Stepper
NDS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
male female male female female female male male male female male female male female female male male female female female male male male male male male female male female male male male male male male male
64 51 54 54 57 70 60 61 74 55 47 57 67 66 61 73 68 71 52 46 51 31 27 52 39 72 55 48 46 39 45 33 42 24 74 62
Asth Asth Asth PuSc Asth Asth COPD Asth Asth Asth PuSc Asth PuSc Asth Asth Asth Asth Asth Asth Asth Sarc Sarc Asth COPD Asth Sarc Asth Asth Asth Sarc Sarc Sarc Sarc Sarc COPD COPD
Flutic Flutic Budes Predn Beclas Flutic Beclas Beclas Flutic Budes Predn Flutic Predn Budes Flutic Beclas Budes Budes Budes Flutic Predn Predn Flutic Flutic Flutic Predn None None None None None None None None None None
6.5 6.5 5 5 4 3.5 3 3 3 3 3 2 2 2 2 2 1.5 1 1 1 0.66 0.5 0.5 0.25 0.15 0.05 0 0 0 0 0 0 0 0 0 0
62 79 80 78 75 70 84 130 89 60 110 60 85 79 124 75 59 73 77 55 99 110 100 88 71 76 58 68 70 82 118 86 90 72 105 62
0 0 8 0 1 1 1 5 2 0 0 4 3 7 0 0 4 5 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1.20 1.21 1.21 1.15 1.15 1.33 1.22 1.06 1.16 1.31 – 1.41 1.30 1.27 1.28 1.16 1.21 1.30 1.29 1.38 – 1.17 1.33 1.13 1.16 1.43 1.41 1.21 – 1.41 1.33 1.21 – 1.27 1.28 1.23
– 9 12 12 – 19 8 10 – 10 – 11 15 5 14 – 9 – 9 9 16 17 18 17 14 19 12 18 – 13 19 18 17 14 13 –
4 8 3 3 6 4 11 10 10 0 6 5 3 1 6 4 2 10 0 0 0 4 1 2 2 8 2 1 2 0 1 0 4 0 5 2
Abbreviations: Asth, asthma; Beclas, beclasone; Budes, budesonite (Symbicort); COPD, chronic obstructive pulmonary disease; Flutic, fluticasone (Seretide or Flixotide); NDS, neuropathy dysfunction score; A/W, Ankle/Wrist index; PMDS, peripheral motor deficits scale; Prednis, prednisone; PuSc, pulmonary sclerosis; Sarc, sarcoidosis.
common diagnosis (21 patients). Sarcoidosis was diagnosed in 8 patients; chronic obstructive pulmonary disease in 4 patients; and pulmonary sclerosis in 3 patients. At the period of the study 26 patients received corticosteroid therapy; 6 more patients never used corticosteroids; and 4 patients were not treated by corticosteroids at least 6 months before evaluation. Patients with bronchial asthma used various corticosteroid inhalers at different periods of their disease. In Table 1 we present corticosteroids which patients were using before hospitalization. Ten asthmatic patients used fluticasone (Seretide or Flixotide), 6 more patients used budesonite (Symbicort), and 4 patients used beclasone before hospitalization. Patients with pulmonary fibrosis received prednisone per os daily for several years before evaluation, and patients with sarcoidosis commonly received prednisone as the 6 month courses. Overall, the duration of corticosteroid therapy varied from 3 weeks (0.05 years) to 6.5 years in our patient cohort, with the mean duration 2.39 ± 1.85 years.
objective signs of peripheral motor dysfunction. None of the patients reported weakness of the hands or showed any decrease of strength in hands. Mann–Whitney test of the PMDS score showed significant intergroup difference with the mean score in chronic steroid group 2.2 ± 2.5 and zero score in patients with none or short-term steroids (z = 3.85, p b 0.001). In addition, motor deficits measured by PMDS
3.2. Motor deficits The individual PMDS scores are presented in Table 1 and group means are presented in Fig. 1. Thirteen of 20 (65%) patients who had received corticosteroids daily for 1 and more years reported weakness in the legs during plain walking and/or walking upstairs or downstairs. Whereas patients, who never received corticosteroids or received these drugs only for several months did not report any motor deficits. Objective evaluation of motor functions showed that 3 patients could not complete the probe with walking on both tiptoes, and another patient could not stand up without support of upper limbs. Overall, 20% of patients who used corticosteroids at least 1 year demonstrated
Fig. 1. Performance on the Peripheral Motor Deficits Scale in two groups of patients: patients with chronic steroid treatment ≥ 1 year showed significantly higher motor deficits in comparison with patients with none or short-term steroid treatment (z = 3.85, p = 0.001).
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significantly and positively correlated with the duration of corticosteroid therapy (Rs = 0.45, p = 0.006). ANCOVAs, which included steroids ≥ 1 year as a grouping factor, and age, weight and NDS score as covariates, showed only significant effects of steroids ≥ 1 year on PMDS score (Fs N 6.5, ps b 0.05). Adding sex as the second grouping factor did not affect significant association between the duration of steroids and motor functions.
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index (Fig. 3). Interaction of the steroid duration and sex was insignificant (F = 0.015, p = 0.904). Both males and females with chronic steroids were characterized by significantly lower ankle/wrist index in comparison with patients with none or short-term steroids. Inclusion of age or weight into the ANOVA model did not change significant effects of the duration of steroids on the ankle/wrist index (Fs N 5.0, ps b 0.05). When NDS was added, the effect of the steroid length became near to be significant (F = 3.84, p = 0.061).
3.3. Stepper test 3.5. Neuropathy Disability Score The individual results of the Stepper test are presented in Table 1 and group means are presented in Fig. 2. The patients who never received corticosteroids or used the drug only for several months (n = 14) completed significantly more steps on the mini stepper during 10 s in comparison with the patients who received corticosteroids daily for 1 – 6.5 years (n = 14; means: 16.1 ± 2.4 vs 10.9 ± 3.4, respectively; z = 3.46, p = 0.001). Additional correlational analysis demonstrated significant and negative correlation between the performance on the mini stepper test and the duration of corticosteroid therapy (Rs = −0.50, p = 0.006). ANCOVAs, which included steroids ≥ 1 year as a grouping factor, and age, weight and NDS score as covariates, showed only significant effects of steroids ≥ 1 year on the performance on the Stepper test (Fs N 17.0, ps b 0.001). Adding sex as the second grouping factor did not affect the significant association between the duration of steroids and motor functions as well (F = 11.0, p = 0.003). 3.4. Ankle/wrist index The primary Mann–Whitney test did not show significant intergroup difference on ankle/wrist index (z = 0.87, p = 0.40). At the same time, ankle/wrist index significantly correlated with chronic steroid length (Rs = − 0.35, p = 0.047), i.e. in patients with prolonged use of corticosteroids ankle/wrist index was lower in comparison with patients with none or short-term steroid drugs. As muscle atrophy appeared to develop in chronic steroid patients somewhat later in comparison with subjective and objective signs of motor deficits, we included three patients with 1-year steroid use into the group with the short-term steroid history. In addition, we included sex as the second fixed factor into ANOVA model. This statistical model showed significant and independent effects of both group (F = 5.66, p = 0.024) and sex factors (F = 5.72, p = 0.024) on ankle/wrist
Fig. 2. Performance on the Stepper Test in two groups of patients: patients with chronic steroid treatment ≥ 1 year performed significantly fewer steps at mini stepper during 10 s in comparison with patients with none or short-term steroid treatment (z = 3.46, p = 0.001).
The NDS was significantly higher in patients using corticosteroids for 1 year and longer in comparison with controls (means: 4.80 ± 3.53 vs 2.13 ± 2.19, respectively; F = 7.0, p = 0.012). However, the significant association between NDS and steroid length was eliminated when age was included into the statistical model as a covariate (F = 1.31, p = 0.26). In the latter model age became a significant predictor of the NDS (F = 5.59, p = 0.024). 4. Discussion The present study evidenced that 65% of patients using corticosteroids daily during 1 year and longer reported weakness in legs, and 20% of these patients demonstrated objective signs of the insufficient muscle strength. The performance on the stepper test was significantly worse in patients chronically using steroids in comparison with the control group. In addition, a proportion of patients using corticosteroids for at least 18 months was characterized by muscle atrophy at dominant leg. The majority of patients who showed signs of steroid myopathy had been chronically using inhaled steroids in our study. Hence, the present results do not support the view that inhaled steroids were absolutely safe. Given the data of a range of studies which showed high frequency of dysphonia and weakness of laryngeal muscles in patients chronically using inhaled corticosteroids [18–20], it may be concluded that the widely accepted opinion concerning safety of inhaled steroids should be reviewed. We could not compare effects of different corticosteroids on muscle functions in our patient cohort, as the majority of patients used inhaler corticosteroids interchangeably. Nevertheless, two patients who had
Fig. 3. Ankle/wrist index in males and females with different length of the steroid treatment. The ANCOVA showed significant and independent effects of both group (F = 5.66, p = 0.024) and sex (F = 5.72, p = 0.024) on the ankle/wrist index.
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been using fluticasone for about 3 years before our study (and overall length of their steroid treatment was 6.5 years) did not report weakness in legs. It may be suggested that inhaled fluticasone is safer in comparison with beclasone, however, further studies are needed to confirm this impression. Although fluticasone appear to be safer in comparison with beclasone, it is not absolutely safe. Severe myopathy was reported in children receiving high-dose inhaled fluticasone [21]. The duration and dose of chronic steroids appear to be the most important risk factors of steroid myopathy. Nevertheless, casuistic cases which showed acute myopathic symptoms after several days of oral steroids were reported as well [22]. Experimental studies showed that glucocorticoids induced most prominent muscle atrophy in elderly animals in comparison with younger ones [1]. In our previous study we observed severe corticosteroid-induced weakness and muscle atrophy in asthmatic patients aged N 70 years [23]. Indeed, sarcopenia and insufficient muscle metabolism are common conditions in elderly people [24], and therefore corticosteroid effects are especially unfavorable in elderly patients. Excessive weight appears to be protective for systemic effects of steroids. The female patient 15 was obese and used high doses of inhaled fluticasone daily for 2 years. She did not demonstrate any signs of myopathy, however, mycotic infection in larynx and esophagus was found during gastroscopy. Her resistance to systemic effects of steroids could be explained by low relative doses of the drugs (although absolute doses were high) and possibly by safer profile of fluticasone in comparison with beclasone profile. The limitations of our study are the absence of electromyographic and creatine phosphokinase (CPK) evaluations. A range of previous studies and case reports showed elevations of CPK in acute steroid myopathy cases and decrease of CPK in patients chronically treated by
corticosteroids or patients with Cushing's disease [2,12]. Some authors recommended measuring creatine in a 24-h urine as the most effective method of evaluation of patients with steroid myopathy [21]. Inclusion of creatine measures and electromyography in further studies would be valuable. Recently European Working Group on Sarcopenia in older People [24] recommended several contemporary neuroimaging and clinical methods for measuring muscle mass, strength and function in research and practice. The experts reported computer tomography and magnetic resonance imaging as gold standards for estimating muscle mass in research, and dual energy X-ray absorptiometry as an alternative method both for research and for clinical use. In addition, the Working Group on Sarcopenia and experts recommended a range of clinical tests for assessment of muscle strength, physical performance and muscle mass [24–26], which may be included into future studies of steroid myopathy and safety profile of steroid drugs. Overall, our study supports the view that side effects of corticosteroids are common and damaging, and these highly active drugs should be used cautiously [27]. It may be concluded, that chronic intake of inhaled corticosteroids induces clinically significant decrease of muscle functions at least after 1-year period of treatment.
Acknowledgments We would like to acknowledge the assistance of our colleagues from the Pulmonology Department, and their informational support concerning pulmonologic diagnosis and anamnesis was very important. We are grateful to all patients who agreed to spend their time on the present study.
Appendix 1. Peripheral Motor Deficits Scale (PMDS)*
I. Complaints How often did you notice the following movement deficits during the last month? I – 1. Weakness of the legs during plain walking. I – 2. Problematic walking upstairs or downstairs due to the weakness of the legs. I – 3. Problematic buttoning up or unbuttoning, sewing or picking up coins. Summarized complaints score:_________________________
Never 0 0 0
1 – 3 times per week 2 2 2
Once or twice 1 1 1
Every day 3 3 3
II. Motor tests
Normal
Deficit
Impossible
II – 1. Stands up without support of upper limbs II – 2. Sits down on the chair without support of upper limbs II – 3. Standing without support. II – 4. Walking without support. II – 5. Walking forward 10 steps on both tiptoes II – 6. Walking forward 10 steps on both heels II – 7. Picking up coins Summarized motor tests score:_________________________
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
PERIPHERAL MOTOR DEFICITS SCORE: Summarized complaints score + 2 X Summarized motor tests score =
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Steroid myopathy in patients with chronic respiratory diseases Oleg S. Levin a, Anna G. Polunina b,c,⁎, Marina A. Demyanova b, Fedor V. Isaev b a b c
Department of Neurology, Russian Medical Academy of Postgraduate Education, Botkinskiy proezd d.5, korp.19, Moscow 125101, Russia Principle Clinical Military Hospital, Federal Security Service of the Russian Federation, Golitzyno, Petrovskoe shosse d.48, Odinzovskiy r-n, Moscow Region 143040, Russia Moscow Research and Practical Center of Narcology, Lyublinskaya ul. 37/1, Moscow 109390, Russia
a r t i c l e
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Article history: Received 17 September 2013 Received in revised form 19 November 2013 Accepted 11 December 2013 Available online 17 December 2013 Keywords: Asthma Complications of corticosteroid therapy Glucocorticoid-induced myopathy Inhaled corticosteroid Muscle weakness Steroid myopathy
a b s t r a c t Background: Corticosteroid-induced myopathy is a well known clinical entity, and experimental studies showed decreased rate of protein synthesis and increased rate of protein breakdown in muscles of chronically treated animals. Objective: The present observational study was aimed to evaluate skeletal muscle functions in asthmatics and patients with other chronic respiratory diseases treated by inhaled or oral corticosteroids. Methods: Thirty six patients with respiratory diseases were included into the study. The physician-rated peripheral motor deficits scale, stepper test and ankle/wrist index were used for assessment of muscle functions. The effects of length of glucocorticoids intake on muscle functions were evaluated. Results: Sixty five per cent of patients using corticosteroids daily during 1 year and longer reported weakness in legs, and 20% of these patients demonstrated objective signs of the muscle weakness. The performance on the stepper test was significantly worse in patients chronically using corticosteroids in comparison with the control group (10.9 ± 3.4 steps vs 16.1 ± 2.4 steps per 10 s, respectively; F = 21.6, p b 0.001). In addition, a proportion of patients using corticosteroids for at least 18 months were characterized by muscle hypotrophy at a dominant leg. Conclusion: Chronic intake of inhaled corticosteroids induces clinically significant decrease of muscle functions at least after 1-year of daily treatment. © 2013 Elsevier B.V. All rights reserved.
1. Introduction The catabolic effects of glucocorticoids have been well known for many years [1]. In skeletal muscle, glucocorticoids decrease the rate of protein synthesis and increase the rate of protein breakdown contributing to atrophy. Administration of high doses of glucocorticoids to animals caused decrease of muscle mass and induced weakness in a range of studies [1]. In healthy humans, adverse effects of dexamethasone on sarcolemmal excitability (decline of muscle fiber conduction velocity for the biceps brachii, vastus lateralis, vastus medialis, and tibialis anterior) were registered after 1 week of drug administration [2]. Severe cases of acute myopathy complicating status asthmaticus are widely reported in contemporary medical publications [3–5]. Although neuromuscular blockade may contribute to this condition, intensive steroid treatment is considered to be an important factor in these patients. After rapid tapering of systemic steroids, patients tend to quickly regain muscle strength [4]. Electrophysiological tests confirmed the myopathic abnormalities with no evidence of a neuromuscular transmission disorder or generalized neuropathy in the majority of patients with acute myopathy complicating status asthmaticus [3,6]. Electrophysiological improvement paralleled clinical improvement in the study of David ⁎ Corresponding author at: pr-t Vernadskogo 101-8-7, Moscow 119526, Russia. Tel.: + 7 916 1291980; fax: + 7 499 7395727. E-mail address: [email protected] (A.G. Polunina). 0022-510X/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jns.2013.12.023
and colleagues [6] and in the case of Yamaguchi and colleagues [7]. It should be noted, that rhabdomyosis with elevation of creatinine kinase and renal impairment secondary to myoglobinuria may complicate the acute corticosteroid-induced myopathy [3,8]. Myopathy in asthmatic patients chronically taking oral steroids is reported as well. Importantly, the impairment of respiratory muscle functions may manifest as therapy-resistant asthma in these patients as the decrease of the respiratory muscle strength makes inhalations ineffective [7,9,10]. Decramer and Stas [9] reported two patients who developed reductions in PImax and PEmax by 38% and 48% of predicted, respectively, after prolonged treatment with high doses of corticosteroids. Tapering of treatment with corticosteroids resulted in recovery of respiratory muscle force with PImax and PEmax reaching 74% and 92%, respectively, after 3 months. Importantly, animal studies demonstrated diaphragmatic myopathy and atrophy after chronic steroid treatment in rats [11]. Skeletal muscles are commonly dysfunctional in patients with chronic steroid myopathy as well [8]. Patients using glucocorticoids commonly report skeletal muscle weakness and twitching, which the most prominent in legs during walking. Decramer and Stas [9] observed decrease of quadriceps force to 31% of predicted one (range 16 to 46% of predicted) in their chronic patient cohort. The authors noted that improvement of muscle functions in legs was slower in comparison with the respiratory muscles. In six months after reducing steroid intake quadriceps force varied from 31 to 85% of the predicted normative in
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this study. Interestingly, in the study of Minetto and colleagues [12] the muscle fiber conduction velocity was considerably reduced in m. vastus lateralis, m. vastus medialis and m. tibialis anterior in patients with Cushing's disease in comparison with controls (difference: 11.6% to 26.0%). The inhaled corticosteroids are commonly considered by medical practitioners as safer drugs in comparison with oral corticosteroids. However, the scientific data do not confirm this opinion. Borba and colleagues [10] reported similar compromise of respiratory muscle function in asthmatic patients chronically taking either oral or inhaled corticosteroids. Mak and colleagues [13] did not find significant differences in maximal mouth pressure, and quadriceps and sternomastoid strength in asthmatic patient groups according to prednisone or inhaled beclomethasone intake. Moreover, four of 12 patients taking inhaler beclomethasone versus only 1 of 12 patients taking prednisone demonstrated clinical signs of quadriceps weakness. In the similar study of Akkoca and colleagues [14] inhaler group showed somewhat better respiratory muscle function in comparison with oral prednisone group (mean duration of oral steroids: 9.83 ± 9.86 years). Nevertheless, the muscle function was intermediate in inhaler patients in comparison with normal controls and oral steroid group. The present study was aimed to evaluate skeletal muscle functions in patients chronically taking inhaled corticosteroids or low doses of oral corticosteroids. We suggested that duration of chronic steroid treatment would be the important factor of muscle function impairment in patients with respiratory diseases. 2. Methods 2.1. Patients In-patients with respiratory diseases were evaluated at the Principle Clinical Military Hospital of the Federal Security Service of the Russian Federation during the period from the January of 2011 to the February of 2012. The inclusion criteria were: 1) age ≤ 75 years; 2) chronic respiratory disease which is commonly treated by corticosteroids; 3) good compensation of respiratory functions (oxygen saturation by pulse oximetry ≥ 95%). The exclusion criteria were: 1) neurological diseases; 2) diabetes mellitus or hypothyroidism; 3) other serious concomitant diseases. The Medical Council of the Principle Clinical Military Hospital of the Federal Security Service of the Russian Federation considered and approved the design and ethical issues of the study. Patients were informed that the examination of motor functions did not concern the medical management of their disease and was conducted as a part of the scientific research. In addition, the methods of the study were shortly described to the patients. Only patients who gave an oral informed consent (as is customary in Russia) to participate in the study were evaluated. Forty patients were invited, and thirty six gave the informed consent. 2.2. Peripheral Motor Deficits Scale (PMDS) For quantitative evaluation of peripheral motor deficits we developed a physician-rated scale (see the Appendix 1). The scale included three complaints which are the most typical for early stages of myopathy (weakness of the legs during plain walking; problematic walking upstairs or downstairs due to the weakness of the legs; problematic buttoning up or unbuttoning, during sewing or picking up coins). The optional responses were: never (0 points); 2) once or twice during the last month (1 point); 3) one – three times per week (2 points); 4) every day (3 points). When patients reported the subjective motor deficits, we conducted seven traditional clinical tests for evaluation of peripheral motor deficits. Normal performance on a test was evaluated as zero, deficit was evaluated as 1 point, and absence of a function was evaluated as 2
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points. Deficits on motor tests weighted twice as much as deficits on subjective part of the test. Complaints, objective signs and summarized score of the scale were analyzed. 2.3. Stepper test In order to evaluate mild motor deficits in the proximal muscles of lower limbs, we used Mini Stepper Arctix 333-08031. First, we asked patients to train for a while and to find comfortable position on the mini stepper. After that we asked the patient to complete as many steps as possible during 10 s. The number of steps completed during 10 s was included into the analysis. As we started our study without the stepper, only 28 patients completed the test. 2.4. Ankle/wrist index In our previous study we found the ratio between the smallest circumference of leg above an ankle and the smallest circumference of forearm above a wrist of the dominant limbs to be an effective tool for measuring muscle atrophy at early stages of the diabetic neuropathy or steroid myopathy [15]. In patients with mild muscle hypotrophy due to either diabetic neuropathy or steroid myopathy, we observed more prominent atrophic changes in a dominant leg in comparison with a dominant forearm. Therefore, the ankle/wrist index in the present study is the ration between the smallest circumference of dominant leg above an ankle and the smallest circumference of dominant forearm above a wrist (dominant ankle/dominant wrist). As we found significant differences in the values of ankle/wrist index in males and females, sex was included into the analysis as the second between-group factor. Taking off clothes was problematic in 4 patients, therefore only 32 patients were evaluated. 2.5. Neuropathy Disability Score For quantitative evaluation of sensory functions and reflexes we used the modified Neuropathy Disability Score (NDS) [16,17]. Reflexes were graded at the knee and ankle for a maximum of eight points if areflexic. Sensory tests included pinprick sensation and vibration. A sensory score was given according to the anatomic location at which the patient could identify the introduced stimulus. If the patient perceived the stimulus at all levels, a score of 0 was given. A score of 1 was given if the patient failed to perceive the stimulus at the base of the toe, 2 at the midfoot, 3 at the heel, 4 at the lower leg, and 5 if at or above the knee level. The summarized score of pinprick and vibration sensation, and reflexes at both legs was included into the analysis. 2.6. Statistical analysis All analyses were performed using SPSS software for windows (SPSS 17.0, Chicago, IL, USA). Patients were divided into two groups according to the length of steroid treatment. Patients with chronic corticosteroids ≥ 1 year constituted the main group (n = 20), and patients with absent or shortterm steroid treatment were the control group (n = 16). As the PMDS score was nonparametric, we used Mann–Whitney test for evaluation of intergroup differences and Spearman's test for correlative analysis. In addition, we performed ANCOVAs with age, weight and NDS score as covariates. 3. Results 3.1. Patient characteristics The patient characteristics are presented in Table 1. Twenty three males and 13 females were included into the study. The mean age of the patients was 54.1 ± 13.5 years. Bronchial asthma was the most
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Table 1 Clinical characteristics and peripheral motor indexes. Patient
Sex
Age (years)
Diagnosis
Steroids
Duration of steroids (years)
Weight
PMDS
A/W index
Stepper
NDS
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
male female male female female female male male male female male female male female female male male female female female male male male male male male female male female male male male male male male male
64 51 54 54 57 70 60 61 74 55 47 57 67 66 61 73 68 71 52 46 51 31 27 52 39 72 55 48 46 39 45 33 42 24 74 62
Asth Asth Asth PuSc Asth Asth COPD Asth Asth Asth PuSc Asth PuSc Asth Asth Asth Asth Asth Asth Asth Sarc Sarc Asth COPD Asth Sarc Asth Asth Asth Sarc Sarc Sarc Sarc Sarc COPD COPD
Flutic Flutic Budes Predn Beclas Flutic Beclas Beclas Flutic Budes Predn Flutic Predn Budes Flutic Beclas Budes Budes Budes Flutic Predn Predn Flutic Flutic Flutic Predn None None None None None None None None None None
6.5 6.5 5 5 4 3.5 3 3 3 3 3 2 2 2 2 2 1.5 1 1 1 0.66 0.5 0.5 0.25 0.15 0.05 0 0 0 0 0 0 0 0 0 0
62 79 80 78 75 70 84 130 89 60 110 60 85 79 124 75 59 73 77 55 99 110 100 88 71 76 58 68 70 82 118 86 90 72 105 62
0 0 8 0 1 1 1 5 2 0 0 4 3 7 0 0 4 5 1 2 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
1.20 1.21 1.21 1.15 1.15 1.33 1.22 1.06 1.16 1.31 – 1.41 1.30 1.27 1.28 1.16 1.21 1.30 1.29 1.38 – 1.17 1.33 1.13 1.16 1.43 1.41 1.21 – 1.41 1.33 1.21 – 1.27 1.28 1.23
– 9 12 12 – 19 8 10 – 10 – 11 15 5 14 – 9 – 9 9 16 17 18 17 14 19 12 18 – 13 19 18 17 14 13 –
4 8 3 3 6 4 11 10 10 0 6 5 3 1 6 4 2 10 0 0 0 4 1 2 2 8 2 1 2 0 1 0 4 0 5 2
Abbreviations: Asth, asthma; Beclas, beclasone; Budes, budesonite (Symbicort); COPD, chronic obstructive pulmonary disease; Flutic, fluticasone (Seretide or Flixotide); NDS, neuropathy dysfunction score; A/W, Ankle/Wrist index; PMDS, peripheral motor deficits scale; Prednis, prednisone; PuSc, pulmonary sclerosis; Sarc, sarcoidosis.
common diagnosis (21 patients). Sarcoidosis was diagnosed in 8 patients; chronic obstructive pulmonary disease in 4 patients; and pulmonary sclerosis in 3 patients. At the period of the study 26 patients received corticosteroid therapy; 6 more patients never used corticosteroids; and 4 patients were not treated by corticosteroids at least 6 months before evaluation. Patients with bronchial asthma used various corticosteroid inhalers at different periods of their disease. In Table 1 we present corticosteroids which patients were using before hospitalization. Ten asthmatic patients used fluticasone (Seretide or Flixotide), 6 more patients used budesonite (Symbicort), and 4 patients used beclasone before hospitalization. Patients with pulmonary fibrosis received prednisone per os daily for several years before evaluation, and patients with sarcoidosis commonly received prednisone as the 6 month courses. Overall, the duration of corticosteroid therapy varied from 3 weeks (0.05 years) to 6.5 years in our patient cohort, with the mean duration 2.39 ± 1.85 years.
objective signs of peripheral motor dysfunction. None of the patients reported weakness of the hands or showed any decrease of strength in hands. Mann–Whitney test of the PMDS score showed significant intergroup difference with the mean score in chronic steroid group 2.2 ± 2.5 and zero score in patients with none or short-term steroids (z = 3.85, p b 0.001). In addition, motor deficits measured by PMDS
3.2. Motor deficits The individual PMDS scores are presented in Table 1 and group means are presented in Fig. 1. Thirteen of 20 (65%) patients who had received corticosteroids daily for 1 and more years reported weakness in the legs during plain walking and/or walking upstairs or downstairs. Whereas patients, who never received corticosteroids or received these drugs only for several months did not report any motor deficits. Objective evaluation of motor functions showed that 3 patients could not complete the probe with walking on both tiptoes, and another patient could not stand up without support of upper limbs. Overall, 20% of patients who used corticosteroids at least 1 year demonstrated
Fig. 1. Performance on the Peripheral Motor Deficits Scale in two groups of patients: patients with chronic steroid treatment ≥ 1 year showed significantly higher motor deficits in comparison with patients with none or short-term steroid treatment (z = 3.85, p = 0.001).
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significantly and positively correlated with the duration of corticosteroid therapy (Rs = 0.45, p = 0.006). ANCOVAs, which included steroids ≥ 1 year as a grouping factor, and age, weight and NDS score as covariates, showed only significant effects of steroids ≥ 1 year on PMDS score (Fs N 6.5, ps b 0.05). Adding sex as the second grouping factor did not affect significant association between the duration of steroids and motor functions.
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index (Fig. 3). Interaction of the steroid duration and sex was insignificant (F = 0.015, p = 0.904). Both males and females with chronic steroids were characterized by significantly lower ankle/wrist index in comparison with patients with none or short-term steroids. Inclusion of age or weight into the ANOVA model did not change significant effects of the duration of steroids on the ankle/wrist index (Fs N 5.0, ps b 0.05). When NDS was added, the effect of the steroid length became near to be significant (F = 3.84, p = 0.061).
3.3. Stepper test 3.5. Neuropathy Disability Score The individual results of the Stepper test are presented in Table 1 and group means are presented in Fig. 2. The patients who never received corticosteroids or used the drug only for several months (n = 14) completed significantly more steps on the mini stepper during 10 s in comparison with the patients who received corticosteroids daily for 1 – 6.5 years (n = 14; means: 16.1 ± 2.4 vs 10.9 ± 3.4, respectively; z = 3.46, p = 0.001). Additional correlational analysis demonstrated significant and negative correlation between the performance on the mini stepper test and the duration of corticosteroid therapy (Rs = −0.50, p = 0.006). ANCOVAs, which included steroids ≥ 1 year as a grouping factor, and age, weight and NDS score as covariates, showed only significant effects of steroids ≥ 1 year on the performance on the Stepper test (Fs N 17.0, ps b 0.001). Adding sex as the second grouping factor did not affect the significant association between the duration of steroids and motor functions as well (F = 11.0, p = 0.003). 3.4. Ankle/wrist index The primary Mann–Whitney test did not show significant intergroup difference on ankle/wrist index (z = 0.87, p = 0.40). At the same time, ankle/wrist index significantly correlated with chronic steroid length (Rs = − 0.35, p = 0.047), i.e. in patients with prolonged use of corticosteroids ankle/wrist index was lower in comparison with patients with none or short-term steroid drugs. As muscle atrophy appeared to develop in chronic steroid patients somewhat later in comparison with subjective and objective signs of motor deficits, we included three patients with 1-year steroid use into the group with the short-term steroid history. In addition, we included sex as the second fixed factor into ANOVA model. This statistical model showed significant and independent effects of both group (F = 5.66, p = 0.024) and sex factors (F = 5.72, p = 0.024) on ankle/wrist
Fig. 2. Performance on the Stepper Test in two groups of patients: patients with chronic steroid treatment ≥ 1 year performed significantly fewer steps at mini stepper during 10 s in comparison with patients with none or short-term steroid treatment (z = 3.46, p = 0.001).
The NDS was significantly higher in patients using corticosteroids for 1 year and longer in comparison with controls (means: 4.80 ± 3.53 vs 2.13 ± 2.19, respectively; F = 7.0, p = 0.012). However, the significant association between NDS and steroid length was eliminated when age was included into the statistical model as a covariate (F = 1.31, p = 0.26). In the latter model age became a significant predictor of the NDS (F = 5.59, p = 0.024). 4. Discussion The present study evidenced that 65% of patients using corticosteroids daily during 1 year and longer reported weakness in legs, and 20% of these patients demonstrated objective signs of the insufficient muscle strength. The performance on the stepper test was significantly worse in patients chronically using steroids in comparison with the control group. In addition, a proportion of patients using corticosteroids for at least 18 months was characterized by muscle atrophy at dominant leg. The majority of patients who showed signs of steroid myopathy had been chronically using inhaled steroids in our study. Hence, the present results do not support the view that inhaled steroids were absolutely safe. Given the data of a range of studies which showed high frequency of dysphonia and weakness of laryngeal muscles in patients chronically using inhaled corticosteroids [18–20], it may be concluded that the widely accepted opinion concerning safety of inhaled steroids should be reviewed. We could not compare effects of different corticosteroids on muscle functions in our patient cohort, as the majority of patients used inhaler corticosteroids interchangeably. Nevertheless, two patients who had
Fig. 3. Ankle/wrist index in males and females with different length of the steroid treatment. The ANCOVA showed significant and independent effects of both group (F = 5.66, p = 0.024) and sex (F = 5.72, p = 0.024) on the ankle/wrist index.
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been using fluticasone for about 3 years before our study (and overall length of their steroid treatment was 6.5 years) did not report weakness in legs. It may be suggested that inhaled fluticasone is safer in comparison with beclasone, however, further studies are needed to confirm this impression. Although fluticasone appear to be safer in comparison with beclasone, it is not absolutely safe. Severe myopathy was reported in children receiving high-dose inhaled fluticasone [21]. The duration and dose of chronic steroids appear to be the most important risk factors of steroid myopathy. Nevertheless, casuistic cases which showed acute myopathic symptoms after several days of oral steroids were reported as well [22]. Experimental studies showed that glucocorticoids induced most prominent muscle atrophy in elderly animals in comparison with younger ones [1]. In our previous study we observed severe corticosteroid-induced weakness and muscle atrophy in asthmatic patients aged N 70 years [23]. Indeed, sarcopenia and insufficient muscle metabolism are common conditions in elderly people [24], and therefore corticosteroid effects are especially unfavorable in elderly patients. Excessive weight appears to be protective for systemic effects of steroids. The female patient 15 was obese and used high doses of inhaled fluticasone daily for 2 years. She did not demonstrate any signs of myopathy, however, mycotic infection in larynx and esophagus was found during gastroscopy. Her resistance to systemic effects of steroids could be explained by low relative doses of the drugs (although absolute doses were high) and possibly by safer profile of fluticasone in comparison with beclasone profile. The limitations of our study are the absence of electromyographic and creatine phosphokinase (CPK) evaluations. A range of previous studies and case reports showed elevations of CPK in acute steroid myopathy cases and decrease of CPK in patients chronically treated by
corticosteroids or patients with Cushing's disease [2,12]. Some authors recommended measuring creatine in a 24-h urine as the most effective method of evaluation of patients with steroid myopathy [21]. Inclusion of creatine measures and electromyography in further studies would be valuable. Recently European Working Group on Sarcopenia in older People [24] recommended several contemporary neuroimaging and clinical methods for measuring muscle mass, strength and function in research and practice. The experts reported computer tomography and magnetic resonance imaging as gold standards for estimating muscle mass in research, and dual energy X-ray absorptiometry as an alternative method both for research and for clinical use. In addition, the Working Group on Sarcopenia and experts recommended a range of clinical tests for assessment of muscle strength, physical performance and muscle mass [24–26], which may be included into future studies of steroid myopathy and safety profile of steroid drugs. Overall, our study supports the view that side effects of corticosteroids are common and damaging, and these highly active drugs should be used cautiously [27]. It may be concluded, that chronic intake of inhaled corticosteroids induces clinically significant decrease of muscle functions at least after 1-year period of treatment.
Acknowledgments We would like to acknowledge the assistance of our colleagues from the Pulmonology Department, and their informational support concerning pulmonologic diagnosis and anamnesis was very important. We are grateful to all patients who agreed to spend their time on the present study.
Appendix 1. Peripheral Motor Deficits Scale (PMDS)*
I. Complaints How often did you notice the following movement deficits during the last month? I – 1. Weakness of the legs during plain walking. I – 2. Problematic walking upstairs or downstairs due to the weakness of the legs. I – 3. Problematic buttoning up or unbuttoning, sewing or picking up coins. Summarized complaints score:_________________________
Never 0 0 0
1 – 3 times per week 2 2 2
Once or twice 1 1 1
Every day 3 3 3
II. Motor tests
Normal
Deficit
Impossible
II – 1. Stands up without support of upper limbs II – 2. Sits down on the chair without support of upper limbs II – 3. Standing without support. II – 4. Walking without support. II – 5. Walking forward 10 steps on both tiptoes II – 6. Walking forward 10 steps on both heels II – 7. Picking up coins Summarized motor tests score:_________________________
0 0 0 0 0 0 0
1 1 1 1 1 1 1
2 2 2 2 2 2 2
PERIPHERAL MOTOR DEFICITS SCORE: Summarized complaints score + 2 X Summarized motor tests score =
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