Pediatric Neurology 53 (2015) 73e77
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Movement Disorder-Childhood Rating Scale: A Sensitive Tool to Evaluate Movement Disorders Roberta Battini MD, PhD a, *, Ilaria Olivieri MD a, b, Roberta Di Pietro PT a, Manuela Casarano MD, PhD a, Giuseppina Sgandurra MD, PhD a, Domenico M. Romeo MD c, Giovanni Cioni MD a, b a
Department of Developmental Neuroscience, Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Stella Maris, Pisa, Italy Department of Clinical and Experimental Medicine, University of Pisa, Italy c Department of Paediatric Neurology, Catholic University, Rome, Italy b
abstract BACKGROUND: The Movement Disorder-Childhood Rating Scale represents a new tool for assessment of movement disorders during developmental age. In this study, we evaluated a cohort of 68 patients affected by various types of movement disorders and treated with specific drugs over one year to verify the usefulness of the Movement Disorder-Childhood Rating Scale. METHOD: The participants were divided into two groups according to their ages (0-3 years; 4-18 years) and were evaluated using Movement Disorder-Childhood Rating Scale 0-3 or 4-18 at baseline (i.e., before starting pharmacological treatment [T0], after 6 months [T1], and after 12 months [T2] of treatment. Univariate repeated measures analysis of variance with a Greenhouse-Geisser correction by SPSS 20 was performed to analyze the scale responsiveness for the three indices (e.g., Index I, Index II, Global Index) in each group with time (T0, T1, and T2). In addition, the Bonferroni test was performed to identify the source of significant differences among means. RESULTS: Significant differences were found between time points (T1 versus T0, T2 versus T0, and T2 versus T1) in both scales for all indexes with the exception for T2 versus T1 for Index II in both scales and for T2 versus T1 for the Global Index in the older age group. There was no significant correlation between observed changes in the scores and the age of the children, either for Movement Disorder-Childhood Rating Scale 0-3 or 4-18. CONCLUSION: Our results suggest that Movement Disorder-Childhood Rating Scale is a suitable tool to detect changes independently from age and could be used as outcome measure for clinical trials. Keywords: pediatric movement disorder, MD-CRS, movement disorders treatment, movement disorders assessment tool
Pediatr Neurol 2015; 53: 73-77 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Movement disorders are a clinically, pathologically, and genetically heterogeneous group of neurological conditions, considered as common cause of disability in childhood.1-4 Consent: Written informed consent was obtained from the patients. A copy of the written consent is available for review by the Editor of this journal. Competing interests: All authors declare that they have no competing interests.
Article History: Received November 23, 2014; Accepted in final form February 17, 2015 * Communications should be addressed to: Dr. Battini; Department of Developmental Neuroscience; IRCCS Stella Maris; Viale del Tirreno 331; 56128 Calambrone; Pisa, Italy. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.02.014
Interest in pediatric movement disorders has recently increased because of the advances in diagnosis and treatment that have occurred in the past few years. Clinical presentation, outcome, and management of many of these neurological disorders in children differ substantially from adults, so there has been the need to develop rating scales specifically designed for children affected by dyskinetic cerebral palsy5 and by movement disorders resulting from various neurological causes.6,7 The Movement Disorder-Childhood Rating Scale (MD-CRS) is a scale created in 2008-2009 at Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Stella Maris to evaluate the influence of various movement disorders on daily living activities, motor function, and the effect on the
74
R. Battini et al. / Pediatric Neurology 53 (2015) 73e77
development of children and adolescents; it is divided in two forms, one for age 4-18 years7 and another for the first 3 years of life6 (see Appendix 1 and 2 in supplementary material). The scale responsiveness of the MD-CRS has been evaluated in the two preliminary pilot studies on dystonic patients, aged 4-18 years and aged 0-3 years, before and after 3 and 6 months of a specific drug treatment.6,7 Other authors have assessed changes following L-DOPA treatment in a patient affected by nonprogressive chorea8 and have evaluated the clinical response during specific treatment in a study using EPI-743 in 10 patients aged 1-13 years affected by Leigh syndrome and other mitochondrial diseases.9 More recently, our group reported our experience of MDCRS assessment in patients affected by dyskinetic cerebral palsy treated with anticholinergic drug for one year,10 confirming the MD-CRS as a sensitive tool to detect changes and as a possible outcome measure during natural history data collection or during clinical trials in children with movement disorders. In this article, we discuss the results of a study aimed to: (1) evaluate the responsiveness of the MD-CRS scale during 1 year of follow-up in a wider cohort of patients affected by various movement disorders, before and after specific pharmacological treatment and (2) establish whether the changes on the scales were related to the age at testing and/or to different etiology of movement disorders. Methods The study was performed on 68 children and adolescents aged 0-18 years with various types of movement disorders of different etiology at the time of starting treatment with oral drugs specific for movement disorders and followed for 1 year. The subjects affected by movement disorders consecutively admitted between 2011 and 2013 to the Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy, and to the Department of Paediatric Neurology, Catholic University, Rome, Italy, were included and enrolled in the study. We excluded patients who had not completed the 1-year follow-up within 2013 and those who did not take therapy regularly or treated with intrathecal baclofen pump or deep brain stimulation to ensure the same type of treatment for all the subjects and to avoid for example surgical biases (different steady-state or possible surgical complications). All the enrolled patients were assessed by child neurologists to classify the movement disorders and underwent to a comprehensive diagnostic protocol in an attempt to identify the movement disorders’ etiologies.6 The patients were divided into two groups according to the age (0-3 and 4-18 years) and were evaluated using MD-CRS 0-3 or 4-18, respectively, before starting pharmacological treatment (T0), after 6 months (T1), and after 12 months (T2) of therapy. We defined the followup timing at 6 months because this could be the necessary time for steady-state achievement, in particular for the youngest patients when the incremental dosage is lower. If patients were affected by more than one movement disorder (i.e., myoclonus-dystonia), we decided to score and treat the prevalent one, as described in MD-CRS. The changes in Index I (general assessment), Index II (movement disorder severity), and the Global Index were calculated to quantify the responsiveness of each section of the scale. Each index could range from 0 to 1 and was divided into five classes, according to severity of movement disorder. Class 1 included a 0-0.2 index (healthy), class 2 a 0.2-0.4 index (mildly affected), class 3 a 0.4-0.6 index (moderately affected), class 4 a 0.6-0.8 index (severely affected), and Class 5 a 0.8-1 index
(profoundly affected). In each patient, a class for part I (class I) and a class for part II (class II) was obtained. On the basis of the Global Index, a Global Class was obtained in each patient, according to the ranges previously described.6,7 All assessments were recorded on video of an average duration of 25 minutes; the videotapes collected in all patients were independently rated by three clinicians with significant experience in the field of movement disorders; if different score were obtained, the results were discussed to achieve a consensus on the score. Five percent of the scores (about 10 patients) were evaluated again to achieve agreement; overall, the interrater reliability was very high (MD-CRS 0-3: 0.95-0.98; MD-CRS 4-18: 0.96-0.99) in line with the data already published.6,7 The study was approved by the Ethical Committee of IRCCS Stella Maris and informed written consent for treatment was obtained from the parents of each patient, with particular attention to drugs used for off-label treatment either for age or for type of disease.
Participants The subjects were divided in two groups according to the age related to the two versions of the scale. The first group included 25 children (21 boys, 4 girls) aged 0.6-3.1 years at T0 (mean age, 1.97 years; standard deviation [SD] 0.76) with various types of movement disorders: dystonia (n ¼ 21), chorea (n ¼ 2), chorea-ballism (n ¼ 1), and hypokinetic rigid syndrome (n ¼ 1). The etiology of movement disorders included cerebral palsy (n ¼ 18), heredodegenerative diseases (n ¼ 1, striatal necrosis), neurometabolic deficits (n ¼ 2, Lesh Nyhan disease and tyrosine hydroxylase deficit), and undefined causes (n ¼ 4). All participants were treated with oral drugs, according to the type of movement disorder: trihexyphenidyl (n ¼ 21), L-DOPA (n ¼ 2), and tetrabenazine (n ¼ 2). The second group included 43 patients (24 boys, 19 girls) aged 4-18.3 years at T0 (mean age, 10.02 years; SD 4.51) with various types of movement disorders: dystonia (n ¼ 27), chorea (n ¼ 4), chorea-ballism (n ¼ 4), hypokinetic rigid syndrome (n ¼ 3), myoclonus (n ¼ 3), and myoclonus-dystonia (n ¼ 2). In the two cases of myoclonus-dystonia, dystonia was treated and scored as the prevalent movement disorder. In this group, we identified these etiologies: dyskinetic cerebral palsy (n ¼ 27, two of which were affected by neurosensorial deafness resulting from kernicterus), myoclonus-dystonia (n ¼ 2, one genetically confirmed DYT11e), L-DOPAeresponsive dystonia (n ¼ 1, DYT1-DYT5 negative), benign hereditary chorea (n ¼ 1, TITF1 positive), juvenile parkinsonism (n ¼ 2), brain arteriovenous malformation (n ¼ 2), and neurometabolic deficit (n ¼ 1, beta galactosidase deficiency, GM1). The cause of movement disorder remained undefined in seven children. The patients were treated with trihexyphenidyl (n ¼ 31), L-DOPA (n ¼ 6), tetrabenazine (n ¼ 4), piracetam (n ¼ 1), and pimozide (n ¼ 1) on the basis of the prevalent movement disorder. The drugs were given up to the minimal effective amount by gradual increase in the first 3 months, and then the pharmacological doses were optimized in the following 3 months (range of drug dosage: trihexyphenidyl 0.5 mg/kg/ daye1 mg/kg/day, piracetam 50 mg/kg/day, L-DOPA 2-8 mg/kg/day, tetrabenazine 0.25-1 mg/kg/day, pimozide 0.2 mg/kg/day).
Data analysis Univariate repeated measures analysis of variance (ANOVA) with a Greenhouse-Geisser correction by SPSS 20 was performed to analyze the scale responsiveness for the three indices (e.g., Index I, Index II, Global Index) in each group (0-3 years; 4-18 years) with time (T0, T1, and T2). To identify the source of significant differences among means, post-hoc analysis was performed using the Bonferroni test. The significant level for post-hoc comparisons was set at 0.05. A regression analysis for estimating the relationship between the changes after 1 year of treatment as the dependent variable (D: score at T2 T0) and the age, as the independent variable, was performed for each index of the two scales. Moreover, to better understand the MD-CRS capability to reveal changes related to different etiologies of movement disorders, we
R. Battini et al. / Pediatric Neurology 53 (2015) 73e77
75
TABLE 1. Bonferroni Post-hoc Test Results
MD-CRS 0-3
Index I T1 versus T0 T2 versus T0 T2 versus T1 Index II T1 versus T0 T2 versus T0 T2 versus T1 Global Index T1 versus T0 T2 versus T0 T2 versus T1
MD-CRS 4-18
D Mean (SE)
Confidence Interval
P-value
D Mean (SE)
Confidence Interval
P-value
0.08 (0.01) 0.11 (0.02) 0.03 (0.01)
0.04-0.11 0.06-0.16 0.01-0.06
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Movement Disorder-Childhood Rating Scale: A Sensitive Tool to Evaluate Movement Disorders Roberta Battini MD, PhD a, *, Ilaria Olivieri MD a, b, Roberta Di Pietro PT a, Manuela Casarano MD, PhD a, Giuseppina Sgandurra MD, PhD a, Domenico M. Romeo MD c, Giovanni Cioni MD a, b a
Department of Developmental Neuroscience, Istituto Di Ricovero e Cura a Carattere Scientifico Fondazione Stella Maris, Pisa, Italy Department of Clinical and Experimental Medicine, University of Pisa, Italy c Department of Paediatric Neurology, Catholic University, Rome, Italy b
abstract BACKGROUND: The Movement Disorder-Childhood Rating Scale represents a new tool for assessment of movement disorders during developmental age. In this study, we evaluated a cohort of 68 patients affected by various types of movement disorders and treated with specific drugs over one year to verify the usefulness of the Movement Disorder-Childhood Rating Scale. METHOD: The participants were divided into two groups according to their ages (0-3 years; 4-18 years) and were evaluated using Movement Disorder-Childhood Rating Scale 0-3 or 4-18 at baseline (i.e., before starting pharmacological treatment [T0], after 6 months [T1], and after 12 months [T2] of treatment. Univariate repeated measures analysis of variance with a Greenhouse-Geisser correction by SPSS 20 was performed to analyze the scale responsiveness for the three indices (e.g., Index I, Index II, Global Index) in each group with time (T0, T1, and T2). In addition, the Bonferroni test was performed to identify the source of significant differences among means. RESULTS: Significant differences were found between time points (T1 versus T0, T2 versus T0, and T2 versus T1) in both scales for all indexes with the exception for T2 versus T1 for Index II in both scales and for T2 versus T1 for the Global Index in the older age group. There was no significant correlation between observed changes in the scores and the age of the children, either for Movement Disorder-Childhood Rating Scale 0-3 or 4-18. CONCLUSION: Our results suggest that Movement Disorder-Childhood Rating Scale is a suitable tool to detect changes independently from age and could be used as outcome measure for clinical trials. Keywords: pediatric movement disorder, MD-CRS, movement disorders treatment, movement disorders assessment tool
Pediatr Neurol 2015; 53: 73-77 Ó 2015 Elsevier Inc. All rights reserved.
Introduction
Movement disorders are a clinically, pathologically, and genetically heterogeneous group of neurological conditions, considered as common cause of disability in childhood.1-4 Consent: Written informed consent was obtained from the patients. A copy of the written consent is available for review by the Editor of this journal. Competing interests: All authors declare that they have no competing interests.
Article History: Received November 23, 2014; Accepted in final form February 17, 2015 * Communications should be addressed to: Dr. Battini; Department of Developmental Neuroscience; IRCCS Stella Maris; Viale del Tirreno 331; 56128 Calambrone; Pisa, Italy. E-mail address: [email protected] 0887-8994/$ e see front matter Ó 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2015.02.014
Interest in pediatric movement disorders has recently increased because of the advances in diagnosis and treatment that have occurred in the past few years. Clinical presentation, outcome, and management of many of these neurological disorders in children differ substantially from adults, so there has been the need to develop rating scales specifically designed for children affected by dyskinetic cerebral palsy5 and by movement disorders resulting from various neurological causes.6,7 The Movement Disorder-Childhood Rating Scale (MD-CRS) is a scale created in 2008-2009 at Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Stella Maris to evaluate the influence of various movement disorders on daily living activities, motor function, and the effect on the
74
R. Battini et al. / Pediatric Neurology 53 (2015) 73e77
development of children and adolescents; it is divided in two forms, one for age 4-18 years7 and another for the first 3 years of life6 (see Appendix 1 and 2 in supplementary material). The scale responsiveness of the MD-CRS has been evaluated in the two preliminary pilot studies on dystonic patients, aged 4-18 years and aged 0-3 years, before and after 3 and 6 months of a specific drug treatment.6,7 Other authors have assessed changes following L-DOPA treatment in a patient affected by nonprogressive chorea8 and have evaluated the clinical response during specific treatment in a study using EPI-743 in 10 patients aged 1-13 years affected by Leigh syndrome and other mitochondrial diseases.9 More recently, our group reported our experience of MDCRS assessment in patients affected by dyskinetic cerebral palsy treated with anticholinergic drug for one year,10 confirming the MD-CRS as a sensitive tool to detect changes and as a possible outcome measure during natural history data collection or during clinical trials in children with movement disorders. In this article, we discuss the results of a study aimed to: (1) evaluate the responsiveness of the MD-CRS scale during 1 year of follow-up in a wider cohort of patients affected by various movement disorders, before and after specific pharmacological treatment and (2) establish whether the changes on the scales were related to the age at testing and/or to different etiology of movement disorders. Methods The study was performed on 68 children and adolescents aged 0-18 years with various types of movement disorders of different etiology at the time of starting treatment with oral drugs specific for movement disorders and followed for 1 year. The subjects affected by movement disorders consecutively admitted between 2011 and 2013 to the Department of Developmental Neuroscience, IRCCS Stella Maris, Pisa, Italy, and to the Department of Paediatric Neurology, Catholic University, Rome, Italy, were included and enrolled in the study. We excluded patients who had not completed the 1-year follow-up within 2013 and those who did not take therapy regularly or treated with intrathecal baclofen pump or deep brain stimulation to ensure the same type of treatment for all the subjects and to avoid for example surgical biases (different steady-state or possible surgical complications). All the enrolled patients were assessed by child neurologists to classify the movement disorders and underwent to a comprehensive diagnostic protocol in an attempt to identify the movement disorders’ etiologies.6 The patients were divided into two groups according to the age (0-3 and 4-18 years) and were evaluated using MD-CRS 0-3 or 4-18, respectively, before starting pharmacological treatment (T0), after 6 months (T1), and after 12 months (T2) of therapy. We defined the followup timing at 6 months because this could be the necessary time for steady-state achievement, in particular for the youngest patients when the incremental dosage is lower. If patients were affected by more than one movement disorder (i.e., myoclonus-dystonia), we decided to score and treat the prevalent one, as described in MD-CRS. The changes in Index I (general assessment), Index II (movement disorder severity), and the Global Index were calculated to quantify the responsiveness of each section of the scale. Each index could range from 0 to 1 and was divided into five classes, according to severity of movement disorder. Class 1 included a 0-0.2 index (healthy), class 2 a 0.2-0.4 index (mildly affected), class 3 a 0.4-0.6 index (moderately affected), class 4 a 0.6-0.8 index (severely affected), and Class 5 a 0.8-1 index
(profoundly affected). In each patient, a class for part I (class I) and a class for part II (class II) was obtained. On the basis of the Global Index, a Global Class was obtained in each patient, according to the ranges previously described.6,7 All assessments were recorded on video of an average duration of 25 minutes; the videotapes collected in all patients were independently rated by three clinicians with significant experience in the field of movement disorders; if different score were obtained, the results were discussed to achieve a consensus on the score. Five percent of the scores (about 10 patients) were evaluated again to achieve agreement; overall, the interrater reliability was very high (MD-CRS 0-3: 0.95-0.98; MD-CRS 4-18: 0.96-0.99) in line with the data already published.6,7 The study was approved by the Ethical Committee of IRCCS Stella Maris and informed written consent for treatment was obtained from the parents of each patient, with particular attention to drugs used for off-label treatment either for age or for type of disease.
Participants The subjects were divided in two groups according to the age related to the two versions of the scale. The first group included 25 children (21 boys, 4 girls) aged 0.6-3.1 years at T0 (mean age, 1.97 years; standard deviation [SD] 0.76) with various types of movement disorders: dystonia (n ¼ 21), chorea (n ¼ 2), chorea-ballism (n ¼ 1), and hypokinetic rigid syndrome (n ¼ 1). The etiology of movement disorders included cerebral palsy (n ¼ 18), heredodegenerative diseases (n ¼ 1, striatal necrosis), neurometabolic deficits (n ¼ 2, Lesh Nyhan disease and tyrosine hydroxylase deficit), and undefined causes (n ¼ 4). All participants were treated with oral drugs, according to the type of movement disorder: trihexyphenidyl (n ¼ 21), L-DOPA (n ¼ 2), and tetrabenazine (n ¼ 2). The second group included 43 patients (24 boys, 19 girls) aged 4-18.3 years at T0 (mean age, 10.02 years; SD 4.51) with various types of movement disorders: dystonia (n ¼ 27), chorea (n ¼ 4), chorea-ballism (n ¼ 4), hypokinetic rigid syndrome (n ¼ 3), myoclonus (n ¼ 3), and myoclonus-dystonia (n ¼ 2). In the two cases of myoclonus-dystonia, dystonia was treated and scored as the prevalent movement disorder. In this group, we identified these etiologies: dyskinetic cerebral palsy (n ¼ 27, two of which were affected by neurosensorial deafness resulting from kernicterus), myoclonus-dystonia (n ¼ 2, one genetically confirmed DYT11e), L-DOPAeresponsive dystonia (n ¼ 1, DYT1-DYT5 negative), benign hereditary chorea (n ¼ 1, TITF1 positive), juvenile parkinsonism (n ¼ 2), brain arteriovenous malformation (n ¼ 2), and neurometabolic deficit (n ¼ 1, beta galactosidase deficiency, GM1). The cause of movement disorder remained undefined in seven children. The patients were treated with trihexyphenidyl (n ¼ 31), L-DOPA (n ¼ 6), tetrabenazine (n ¼ 4), piracetam (n ¼ 1), and pimozide (n ¼ 1) on the basis of the prevalent movement disorder. The drugs were given up to the minimal effective amount by gradual increase in the first 3 months, and then the pharmacological doses were optimized in the following 3 months (range of drug dosage: trihexyphenidyl 0.5 mg/kg/ daye1 mg/kg/day, piracetam 50 mg/kg/day, L-DOPA 2-8 mg/kg/day, tetrabenazine 0.25-1 mg/kg/day, pimozide 0.2 mg/kg/day).
Data analysis Univariate repeated measures analysis of variance (ANOVA) with a Greenhouse-Geisser correction by SPSS 20 was performed to analyze the scale responsiveness for the three indices (e.g., Index I, Index II, Global Index) in each group (0-3 years; 4-18 years) with time (T0, T1, and T2). To identify the source of significant differences among means, post-hoc analysis was performed using the Bonferroni test. The significant level for post-hoc comparisons was set at 0.05. A regression analysis for estimating the relationship between the changes after 1 year of treatment as the dependent variable (D: score at T2 T0) and the age, as the independent variable, was performed for each index of the two scales. Moreover, to better understand the MD-CRS capability to reveal changes related to different etiologies of movement disorders, we
R. Battini et al. / Pediatric Neurology 53 (2015) 73e77
75
TABLE 1. Bonferroni Post-hoc Test Results
MD-CRS 0-3
Index I T1 versus T0 T2 versus T0 T2 versus T1 Index II T1 versus T0 T2 versus T0 T2 versus T1 Global Index T1 versus T0 T2 versus T0 T2 versus T1
MD-CRS 4-18
D Mean (SE)
Confidence Interval
P-value
D Mean (SE)
Confidence Interval
P-value
0.08 (0.01) 0.11 (0.02) 0.03 (0.01)
0.04-0.11 0.06-0.16 0.01-0.06
