Clinical patterns of dystonia and choreoathetosis in participants with dyskinetic cerebral palsy

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1 DEVELOPMENTAL MEDICINE & CHILD NEUROLOGY ORIGINAL ARTICLE Clinical patterns of dystonia and choreoathetosis in participants with dyskinetic cerebral palsy ELEGAST MONBALIU 1 PAUL DE COCK 2 ELS ORTIBUS 3 LIEVE HEYRMAN 1 KATRIJN KLINGELS 1 HILDE FEYS 1 1 Department of Rehabilitation Sciences, KU Leuven, Leuven; 2 Department of Public Health and Primary Care, KU Leuven, Leuven; 3 Department of Development and Regeneration, KU Leuven, Leuven, Belgium. Correspondence to Elegast Monbaliu at Department of Rehabilitation Sciences, KU Leuven, Tervuursevest 11, 31 Leuven, Belgium. Elegast.Monbaliu@faber.kuleuven.be This article is commented on by Himmelmann on page 112 of this issue. PUBLICATION DATA Accepted for publication 14th June 15. Published online 15th July 15. ABBREVIATIONS CFCS Communication Function Classification System DIS Dyskinesia Impairment Scale MACS Manual Ability Classification System SCPE Surveillance of Cerebral Palsy in Europe AIM The aim of the study was to map clinical patterns of dystonia and choreoathetosis and to assess the relation between functional classifications and basal ganglia and thalamus lesions in participants with dyskinetic cerebral palsy (CP). METHODS In this cross-sectional study, 55 participants with dyskinetic CP (mean age 14y 6mo, SD 4y 1mo; range 6 22y) were assessed with the Dyskinesia Impairment Scale and classified with the Gross Motor Function Classification System (GMFCS), Manual Ability Classification System (MACS), and Communication Function Classification System (CFCS). RESULTS Dystonia and choreoathetosis are simultaneously present. levels of dystonia (7.2%) were significantly higher than levels of choreoathetosis (26.7%) and both were significantly higher during activity than at rest (both p<.1). High correlations were found between dystonia levels and GMFCS level (Spearman s rank correlation coefficient, r S =.7; 95% confidence interval [CI].53.81; p<.1) and MACS (r S =.65; 95% CI.47.81; p<.1), and fair correlation with CFCS (r s =.36; 95% CI=.11.57; p<.5). No significant correlation was found between choreoathetosis levels and motor classifications. Finally, higher choreoathetosis levels were found in participants with pure thalamus and basal ganglia lesions (p=.3) than mixed lesions, but not for dystonia (p=.41). INTERPRETATION Dystonia and choreoathetosis increase during activity. However, dystonia predominates and seems to have a larger impact on functional abilities. Our findings further suggest that choreoathetosis seems to be more linked to pure thalamus and basal ganglia lesions than dystonia. Dyskinetic cerebral palsy (CP) is the second largest CP group and one of the most disabling CP types. 1 3 In dyskinetic CP, dystonia and choreoathetosis are mostly simultaneously present. 4,5 Both can be described in the context in which they occur in movements and postures, at rest and during action, or associated with specific tasks and in terms of amplitude and duration. 4 In dyskinetic CP, dystonia and choreoathetosis are known to be generally present over the limbs, trunk, neck, eye, and mouth. 4 Although the presence of these phenomena is generally described in dyskinetic CP, little is known about their movement and posture characteristics. No previous study has mapped the occurrence and severity of dystonia and choreoathetosis and their distribution over different body regions, during action and at rest. Reasons for this may be found in the pathological complexity and the difficulty of measuring dystonia and choreoathetosis in dyskinetic CP. 6 8 However, in view of targeted treatment, a good understanding of clinical patterns is crucial. Further, the Gross Motor Function Classification System (GMFCS), 9 the Manual Ability Classification System (MACS), 1 and the Communication Function Classification System (CFCS) 11 have been widely used to classify functionality in participants with CP. 12 However, in dyskinetic CP it remains unclear whether or not the severity of dystonia and choreoathetosis differs according to functional severity. Equally, a diverse clinical presentation of dystonia and choreoathetosis may be seen, depending on the affected brain structures. According to the Surveillance of Cerebral Palsy in Europe (SCPE), 5 the basal ganglia and thalamus are typically affected in dyskinetic CP, but lesions in cortical/subcortical and white matter regions have also been reported However, these reports merely provide a description of the brain abnormalities. So far, no study has systematically assessed the relationship between the clinical characteristics of dystonia and choreoathetosis and the underlying brain lesion, such as in the basal ganglia and thalamus. 138 DOI: /dmcn Mac Keith Press

2 The aims of this study were therefore (1) to assess the occurrence and severity of dystonia and choreoathetosis over 12 body regions during action and at rest in dyskinetic CP, (2) to investigate whether or not these clinical characteristics differ according to the severity levels based on the GMFCS, MACS, and CFCS, and (3) to determine the relation between these clinical features and thalamus and basal ganglia lesions. We hypothesized that the prevalence and severity of dystonia and choreoathetosis are higher during voluntary activities than at rest, higher in the arms than in the legs, and more pronounced in the distal parts. Secondly, a high correspondence was expected between presence of dystonia and choreoathetosis and functionality scales. Finally, we hypothesized a strong relationship between occurrence of dystonia and choreoathetosis and lesions in basal ganglia and thalamus. METHOD Participants All children and adolescents from five Flemish special education schools for children with motor disabilities were screened in January 12 for inclusion in this cross-sectional study. Inclusion criteria were dyskinetic CP, ability to understand the test instructions, and ages 5 to 22 years. Exclusion criteria were orthopaedic and/or neurosurgical interventions in the previous year and spine fusion. Ethics approval was obtained from the institutional ethics committee and written informed consent was given from parents and participants. Assessment The Dyskinesia Impairment Scale (DIS) 7 was included to assess the clinical characteristics of dystonia and choreoathetosis. The DIS is a reliable and valid video-based ordinal scale and is subdivided into dystonia and choreoathetosis subscales. 7,8 Both subscales grade the duration and amplitude of dystonia/choreoathetosis during action and at rest in 12 body regions, including the central body regions (eyes, mouth, neck, and trunk) and limbs (proximal/distal; right/left). Total raw grades were converted into percentages. The GMFCS, 9 MACS, 1 and CFCS 11 were used to grade the severity from level I (most able) to level V (least able) for gross motor function, manual abilities, and communication. Finally, magnetic resonance imaging (MRI) was used to classify brain lesions. According to the recommendation of SCPE, 5 brain lesions originating from cortical lesions. Consequently, brain lesions were described as periventricular white matter, lesions in the thalamus, basal ganglia, cortical lesions, and maldevelopments and other lesions. Each neuroanatomical structure was graded when no lesion was noticeable on MRI and 1 when a lesion was identified. Procedure All participants were assessed and videotaped at their special education school and graded by EM between February What this paper adds First study to analyse dystonia and choreoathetosis separately in dyskinetic cerebral palsy (CP). Dystonia and choreoathetosis are simultaneously present in dyskinetic CP. Dystonia and choreoathetosis increase with activity. Dystonia is more severe and influences function more than choreoathetosis. More choreoathetosis is observed in participants with pure thalamus and basal ganglia lesions. and June 12. MRI protocols were available in 42 participants. All images were reviewed by a neuropaediatrician (EO). Findings were compared with the radiology report and discussed in case of inconsistency. The neuropaediatrician and neuroradiologist were blind to clinical assessments and the clinical assessors were blind to MRI results. Statistical analysis Shapiro Wilk tests indicated that most variables were not normally distributed. Wilcoxon signed-ranks tests were used for comparisons between total DIS percentages and arm and leg region levels of dystonia and choreoathetosis. In addition, comparisons were made between the levels during action and rest and between duration and amplitude for the total level, arm and leg levels, and proximal and distal parts of the limbs. The relationships between the abovementioned parameters were explored using Spearman s rank correlation coefficient (r S ). A correlation coefficient above.75 was considered an excellent relationship; between.5 and.75 moderate to good; between.5 and.25 fair; and between. and.25 indicated no relationship. 16 To investigate the relationship between dystonia and choreoathetosis with the functional classifications (GMFCS, MACS, and CFCS), Spearman s rank correlation coefficients were used. The comparison between brain lesions in basal ganglia and thalamus, and dystonia and choreoathetosis percentages was assessed using one-tailed Mann Whitney U tests. Statistical analysis was conducted with Statistica 11. (StatSoft Inc., Tulsa, OK, USA). The level of significance was set at p<.1. RESULTS Participants Eighty-six participants had a diagnosis of dyskinetic CP. Sixty-three participants fulfilled the criteria, of whom eight refused to participate in the study. Fifty-five participants (3 males and 25 females) aged between 6 years and 22 years (mean age 14y 6mo, SD 4y 1mo) provided informed consent and were included in this study. According to the GMFCS, 1 participants were classified in level I, five in level II, six in level III, seven in level IV, and 27 in level V. Five participants were classified in MACS level I, eight in level II, seven in level III, 11 in level IV, and 24 in level V. For the CFCS, six participants were categorized in level I, in level II, 18 in level III, eight in level IV, and three in level V. Individual characteristics are provided in Table SI and Figure S1 (online supporting information). Clinical Patterns of Dystonia and Choreoathetosis Elegast Monbaliu et al. 139

3 Table I: and interquartile range of the outcome measures on the Dyskinesia Impairment Scale, statistical comparison, and correlation coefficients Measure Dystonia Choreoathetosis Wilcoxon r S (95% CI) p value Total body level 7.2 (52.1.9) 26.7 ( ) <.1.39 (.14.59).2 Total arm level 83.3 ( ) 28.1 ( ) <.1.43 (.19.62).2 Total leg level 78.1 ( ) 16.7 ( ) <.1.19 (.8 to.43).7 Activity Rest Dystonia. ( ) 57.3 ( ) <.1.87 (.79.92) <.1 Choreoathetosis 38.1 ( ) 18.8 ( ) <.1.75 (.61.85).6 Duration Amplitude Dystonia Total level 77.1 ( ) 67.4 ( ).86 (.77.92) <.1 Action 84.1 ( ) 77.3 ( ).76 (.62.85) <.1 Rest 64.6 ( ) 5. ( ).92 (.87.95) <.1 Choreoathetosis Total level 27.5 ( ) 23.6 ( ).95 (.92.97) <.1 Action 38.8 (19..) 33.3 ( ).96 (.93.98) <.1 Rest.8 ( ) 18.8 ( ).92 (.87.95) <.1 CI, confidence interval; r S, Spearman s rho correlation coefficient (to test strength of the relationship between groups); Wilcoxon, Wilcoxon signed-rank test to test significant difference between groups. % Dystonia Choreoathetosis. EYES MOUTH NECK TRUNK ARMright_prox ARMright_dis ARMleft_prox ARMleft_dis LEGright_prox LEGright_dis LEGleft_prox LEGleft_dis Figure 1: The median percentages (%) of the Dyskinesia Impairment Scale for the body regions. dis, distal; prox, proximal. Clinical characteristics of dystonia and choreoathetosis Dystonia versus choreoathetosis The total median DIS percentage level was 49.7% (interquartile range [IQR] %) and ranged between 11.1% and 73.6%. percentage level for dystonia was 7.2% (IQR %; range %) and for choreoathetosis 26.7% (IQR %; range. 71.%) (Table I). Dystonia and choreoathetosis were simultaneously present in all participants, except for one patient with only dystonia (see Figure S1). Statistical comparison between dystonia and choreoathetosis for total body, arm, and leg levels revealed significantly higher levels of dystonia than choreoathetosis (p<.1; see Table I). Correlation coefficients (see Table I) between dystonia and choreoathetosis were fair for the total level (r S =.39) and the total arm level (r S =.43), but no significant correlation was found for the leg region (r S =.19). Action versus rest Significantly higher values (p<.1) were found during action than rest, for both the dystonia and the choreoathetosis subscales (see Table I). Correlation coefficients between action and rest were.87 and.75 for dystonia and choreoathetosis respectively. Duration versus amplitude Correlation coefficients between duration and amplitude levels were.86 for dystonia and.95 for choreoathetosis (see Table I). 1 Developmental Medicine & Child Neurology 16, 58:

4 Body regions For all regions (Fig. 1), median levels of dystonia exceeded 5.%, except for the trunk. For the central body regions, the median percentages were highest for the mouth (75.%), neck (66.7%), and eyes (5.%). The arms showed higher median percentage dystonia levels (range %) than the legs (range %). For choreoathetosis, the median percentages were highest for the mouth (37.5%), neck (25.%), eye (25.%), and arm regions (range of median levels %). Choreoathetosis levels for the leg region (range of median levels %) and the trunk region (8.3%) were lower. Descriptive statistics of the body regions are provided in Table SII (online supporting information). Statistical comparisons (Table II) showed significantly higher levels (p<.1) in the arms than the legs for choreoathetosis but not for dystonia. Both for the arms and for the legs, comparison of the proximal with the distal parts showed significantly higher dystonia levels (p<.1) in the distal parts. Additionally, correlation coefficients were significant for all parameters, with values for coefficients varying from moderate to excellent (Table II). Relation between dystonia and choreoathetosis and functional classification systems Good correlations were found between GMFCS level and total dystonia level (r S =.7; 95% CI.53.81; p<.1) and between GMFCS level and dystonia level in the legs (r S =.65; 95% CI.47.78; p<.1). The MACS level also showed good correlations with total dystonia level (r S =.68; 95% CI.47.81; p<.1) and arm region level (r S =.74; 95% CI.59.84; p<.1). Fair correlations were found between CFCS level and total dystonia level (r S =.36; 95% CI.11.57; p=.2) and dystonia mouth region level (r S =.36; 95% CI.11.57; p=.2). No significant correlations were found between GMFCS level and total choreoathetosis level (r S =.17; 95% CI=.1 to.42; p=.18) or choreoathetosis level in the legs (r S =.4; 95% CI=.23 to.3; p=.86) or between MACS level and total choreoathetosis level (r S =.21; 95% CI.6 to.45; p=.9) or choreoathetosis arm levels (r S =.22; 95% CI.5.46; p=.8). Similarly, no significant associations were found between CFCS level (r S =.26; 95% CI.49 to.1; p=.6) and total choreoathetosis and mouth region levels (r S =.11; 95% CI.36 to.16; p=.3). Box plots (Fig. 2) are a means of visualizing the dystonia and choreoathetosis total percentage levels according to the different functional levels of the GMFCS, MACS, and CFCS. Relation between dystonia and choreoathetosis and thalamus and basal ganglia lesions MRI findings were available for 42 participants. Findings were normal in five participants. Ten participants showed pure lesions in the thalamus and basal ganglia. These participants were classified as the pure basal ganglia and thalamus lesion group. Twenty-seven participants showed mixed lesions. To determine the relationship of dystonia and choreoathetosis with basal ganglia and thalamus lesions, a comparison was made between the pure thalamus and basal ganglia lesion group (n=1) and the mixed lesion group (n=27). The median percentage level for dystonia was 66.9% (IQR %) in the pure basal ganglia and thalamus group, and 75.% (IQR %) in the mixed lesion group. For choreoathetosis, these values were 35.2% (IQR %) and 17.3% (IQR %) respectively. Mann Whitney U tests revealed significant higher choreoathetosis levels (p=.3) in participants in the pure thalamus and basal ganglia lesions group than in the mixed lesion group. No significant difference was found for dystonia levels (p=.41). DISCUSSION The first aim of this study was to analyse the occurrence and severity of dystonia and choreoathetosis in dyskinetic CP. The results revealed a simultaneous occurrence of dystonia and choreoathetosis in the vast majority of the Table II: and interquartile range of the outcome measures on the Dyskinesia Impairment Scale (n=55), statistical comparison and correlation coefficients Measure Arms Legs Wilcoxon r S (95% CI) p value Dystonia 83.3 ( ) 78.1 ( ).2.66 (.48.79) <.1 Choreoathetosis 28.1 ( ) 16.7 ( ) <.1.69 (.52.81) <.1 Arms proximal Arms distal Dystonia 83.3 ( ) 93.8 ( ) <.1.63 (.44.77) <.1 Choreoathetosis 31.3 ( ) 28.1 ( ) (.64.86) <.1 Legs proximal Legs distal Dystonia 68.8 ( ) 83.3 ( ) <.1.53 (.31.69) <.1 Choreoathetosis 18.8 ( ).8 (. 43.8) (.43.76) <.1 CI, confidence interval; r S, Spearman s rho correlation coefficient; Wilcoxon, Wilcoxon signed-rank test to analyse significant difference between groups. Clinical Patterns of Dystonia and Choreoathetosis Elegast Monbaliu et al. 141

5 Dystonia % score Choreoathetosis % score Dystonia % score GMFCS Choreoathetosis % score GMFCS MACS MACS Dystonia % score Choreoathetosis % score CFCS CFCS Figure 2: and interquartile range of the dystonia and choreoathetosis levels for the five levels of the Gross Motor Function Classification System (GMFCS), the Manual Ability Classification System (MACS), and the Communication Function Classification System (CFCS). participants. This confirms the clinical description that in dyskinetic CP the combination of chorea, athetosis, and dystonia is more common than any of the three alone. 4 Nevertheless, correlation coefficients between choreoathetosis and dystonia were only fair. This emphasizes the independent occurrence of both clinical phenomena in dyskinetic CP and supports the subdivision of dyskinesia into dystonia and choreoathetosis in the classification of CP as proposed by the SCPE. 17 Interestingly, our results revealed that the severity of dystonia was significantly higher than that of choreoathetosis, with median percentage levels of 7.2% and 26.7% respectively. This is the first study to describe this finding. Secondly, dystonia and choreoathetosis were found to be higher during activity than at rest, which corresponds with the clinical description by the Taskforce on Childhood Movement Disorders. 4 A good correlation was also found between action and rest. This result may be relevant when assessing 142 Developmental Medicine & Child Neurology 16, 58:

6 participants with cognitive impairments and/or limited functional abilities, who are less able to perform voluntary asked activities. 18 Further, the duration of dystonia and choreoathetosis was graded significantly higher than the amplitude. The results also revealed an excellent correlation between duration and amplitude levels, which raises the question if both duration and amplitude need to be graded. However, future intervention studies may indicate which characteristic, duration or amplitude, will be most responsive to treatment. To date, several intervention studies have assessed the influence of medical treatment on dystonia, but so far its effect on duration and amplitude remains unexplored. With respect to the occurrence and severity of dystonia and choreoathetosis across body regions, dystonia was more prominent in the distal than the proximal part of the limbs, whereas choreoathetosis was more equally distributed. This may be explained by the presence of chorea and athetosis in the distal and proximal parts of the limbs because athetosis typically involves the distal extremities while chorea is more seen in the proximal parts. 4,17 One could query whether or not chorea and athetosis should be further differentiated as separate clinical characteristics. However, these hyperkinetic movements have many clinical features in common, such as duration and suppressibility, 4 and are more difficult to discriminate than dystonia in the context of a clinical scale observation. Nevertheless, it may be a future challenge to implement kinematic movement analysis or electromyography in the distinction between chorea and athetosis. For the neck and mouth regions, a high occurrence of dystonia and choreoathetosis was found, a finding which is clinically well known and may explain the prominent communication problems in dyskinetic CP. 23 The eye region also showed a clear presence of dystonia and choreoathetosis. Dyskinetic eye movements such as difficulties with pursuit, fixation, and voluntary saccades may have a major impact on mobility, communication, reading, writing, learning, and daily living skills in this patient group. 24 However, current knowledge on dyskinesia patterns in the eye region is still limited. Interestingly, in the trunk region, choreoathetosis was low and dystonia prevalence even lower. This may reflect the presence of underlying axial hypotonia in dyskinetic CP. The second aim of this study was to investigate whether or not the presence of dystonia and choreoathetosis would differ according to the level of gross motor function (GMFCS), manual ability (MACS), and communication (CFCS). Correlation coefficients showed that dystonia increased significantly with increasing levels of functional severity, in particular for the GMFCS and the MACS, which accords with clinical expectations. Correlation with the CFCS was only fair. However, communication measured by the CFCS is more than speech alone, in particular in dyskinetic CP. Newly developed classification scales, such as the Viking Speech Scale 25 and the Eating and Drinking Classification Scale, 26 might reveal stronger associations. Strikingly, no associations were found with choreoathetosis, suggesting that dystonia has a more negative impact on gross motor function and manual ability, and even on communication, than choreoathetosis. It can be hypothesized that the sustained muscle contractions typical of dystonia restrict functional abilities to a much larger extent than the hyperkinetic hallmarks of choreoathetosis. This is a unique result, as no previous studies have investigated this relationship. Obviously, further research to confirm these findings is needed. Finally, it was hypothesized that dystonia and choreoathetosis would be strongly associated with thalamus and basal ganglia lesions Our study revealed basal ganglia and thalamus lesions in 7% of the participants. However, there were also participants without basal ganglia and thalamus involvement, and many participants also had mixed lesions. Participants with pure thalamus and basal ganglia lesions showed significantly more severe choreoathetosis, whereas no association was found with dystonia. To date, it remains unclear how basal ganglia abnormalities could produce dystonia, 27 and it may be hypothesized that other brain regions, such as the cerebellum, are also part of the pathophysiological system. However, caution in interpretation of these findings is needed because of the small sample size. Moreover, data were based on available MRI findings. More advanced imaging techniques will undoubtedly contribute in further elucidating the pathophysiology of underlying choreoathetosis and dystonia in dyskinetic CP. 27 This study also warrants some critical reflections. First, the age range of 5 to 22 years is large, and no distinction was made between different age groups. Consequently, the development of dystonia and choreoathetosis characteristics with increasing age remains unclear. Therefore, future longitudinal studies are indicated to enhance insights in the natural history of dystonia and choreoathetosis in dyskinetic CP. Secondly, despite the reasonably large cohort for this study population, there were few participants in each level of the GMFCS, MACS, and CFCS. Finally, in a considerable number of participants, findings on MRI were normal or brain lesions were mixed. In addition, no detailed grading system was used to differentiate between the different basal ganglia structures, because of the poor quality of MRI in several cases. These limitations restrict straightforward conclusions on the structure function relationship. Therefore, future research with a larger sample size with recent and more advanced imaging methods is recommended, taking into account the complementary role of lesions in other brain regions and neurological pathways. However, this study was the first to map the clinical patterns of dystonia and choreoathetosis in participants with dyskinetic CP. In total, 55 participants with predominant dyskinetic CP across all levels of the GMFCS, MACS, and CFCS were sampled, with a representative distribution similar to that of previous population studies. 3,12,28 The differential results between dystonia and choreoathetosis, Clinical Patterns of Dystonia and Choreoathetosis Elegast Monbaliu et al. 143

7 and also in relation to the functional classifications and underlying brain lesions, advanced our understanding of both clinical phenomena. CONCLUSION This study demonstrated a simultaneous presence of dystonia and choreoathetosis in dyskinetic CP, but with a clear predominance of dystonia in the vast majority of the participants. Additionally, dystonia and choreoathetosis were more pronounced during action than rest. Higher levels of dystonia were associated with a more severe motor function classification level, suggesting that dystonia has a larger impact than choreoathetosis on functional abilities. Finally, this study found that pure thalamus and basal ganglia lesions were associated with the severity of choreoathetosis but not with dystonia. These new findings on the dyskinetic characteristics may serve as a sound basis for further research and contribute to a better-targeted treatment. ACKNOWLEDGEMENTS This work was supported by a grant from the Marguerite-Marie Delacroix Foundation. The authors have stated that they had no interests that could be perceived as posing a conflict or bias. SUPPORTING INFORMATION The following additional material may be found online: Figure S1: Individual total percentage scores on the Dyskinesia Impairment Scale and proportion of dystonia versus choreoathetosis Table SI: Patient characteristics Table SII:, interquartile range, and score range of the dystonia and choreoathetosis body regions scores on the Dyskinesia Impairment Scale REFERENCES 1. Cans C, Guillem P, Baille F, et al. Surveillance of cerebral palsy in Europe: a collaboration of cerebral palsy surveys and registers. Dev Med Child Neurol ; 42: Bax M, Tydeman C, Flodmark O. Clinical and MRI correlates of cerebral palsy: the European Cerebral Palsy Study. JAMA 6; 296: Himmelmann K, McManus V, Hagberg G, Uvebrant P, Kr ageloh-mann I, Cans C, on behalf of the SCPE collaboration. 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