J Neurol DOI 10.1007/s00415-014-7353-4
ORIGINAL COMMUNICATION
Quantitative analysis of upper-limb ataxia in patients with spinocerebellar degeneration Naohisa Ueda • Yasuhito Hakii • Shigeru Koyano • Yuichi Higashiyama • Hideto Joki • Yasuhisa Baba • Yume Suzuki • Yoshiyuki Kuroiwa • Fumiaki Tanaka
Received: 23 January 2014 / Revised: 9 April 2014 / Accepted: 11 April 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Spinocerebellar degeneration (SCD) is a progressive neurodegenerative disorder in which cerebellar ataxia causes motor disability. There are no widely applicable methods for objective evaluation of ataxia in SCD. An objective system to evaluate ataxia is necessary for use in clinical trials of newly developed medication and rehabilitation. The aim of this study was to develop a simple method to quantify the degree of upper-limb ataxia. Fortynine patients with SCD participated in this study. Patients were instructed to trace an Archimedean spiral template, and the gap between the template spiral and the drawn spiral (gap area; GA) was measured using Image J software. Ataxia was rated using the Scale for the Assessment and Rating of Ataxia (SARA) and cerebellar volume was evaluated in 37 patients using an axial cross-section of magnetic resonance images that were obtained within 6 months of clinical evaluation. Regression analysis was performed to assess the relation between GA and patient age, disease duration, SARA score, and cerebellar volume. N. Ueda S. Koyano Y. Higashiyama H. Joki Y. Suzuki F. Tanaka (&) Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan e-mail: [email protected] Y. Hakii Department of Neurology, Saiseikai Yokohama City Nanbu Hospital, 3-2-10 Konandai, Konan-ku, Yokohama, Kanagawa 234-8503, Japan Y. Baba Y. Kuroiwa (&) Department of Neurology and Stroke Center, School of Medicine, University Hospital Mizonokuchi, Teikyo University, 3-8-3 Mizonokuchi, Takatsu-ku, Kawasaki, Kanagawa 213-8507, Japan e-mail: [email protected]
GA was significantly related to total SARA score (r = 0.660, p \ 0.001), the posture and gait (r = 0.551, p \ 0.001), speech (r = 0.527, p \ 0.001), hand movements (r = 0.553, p \ 0.001), and heel-shin slide (r = 0.367, p = 0.036) SARA subscores, and cerebellar volume (r = 0.577, p \ 0.001) but was not related to patient age (r = 0.176, p = 0.227) or disease duration (r = 0.236, p = 0.103). GA is a simple, useful method to objectively quantify the degree of cerebellar ataxia, especially upper-limb ataxia, and can be widely adopted in various settings, including clinical trials. Keywords Cerebellar ataxia Objective quantification Spiral drawing SARA Cerebellar volume
Introduction Patients with spinocerebellar degeneration (SCD) have a variety of symptoms including impaired ocular movement, dysarthria, limb ataxia, and truncal ataxia, and ataxia is a principal factor of motor disturbance in SCD. SCD is a progressive neurodegenerative disorder and some reports suggest that rehabilitation may improve motor performance [1, 2], but no effective medications have been developed so far. Reliable tools to evaluate ataxia in SCD are required to validate the efficacy of rehabilitation and disease-modifying therapies that will be developed in the near future. Several scales have been used to evaluate motor function in SCD patients, such as the International Cooperative Ataxia Rating Scale [3], the Scale for the Assessment and Rating of Ataxia (SARA) [4], and the Friedreich’s Ataxia Rating Scale [5], and all consist of various motor tests to evaluate posture, gait, speech, and upper-limb performance. However, these scales all rely on subjective assessment by
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observers. The Spinocerebellar Ataxia Functional Index [6] was developed to objectively evaluate ataxia using a ninehole peg test and objective quantification of gait and speech, and the Composite Cerebellar Functional Severity Score [7] was developed to numerically rate the ataxia using a nine-hole peg test and a hand click test; however, both are represented by a Z score calculated among the participants and neither is generally recognized. Other procedures that have been proposed to quantify cerebellar ataxia include video analysis. Bastian and colleagues analyzed the movement of multiple joints by videotaping markers placed on the joints, and reported that this was useful for detecting decomposition and dysmetria in patients with limb ataxia [8]. Menegoni and colleagues [9] used the optoelectronic system to analyze upper-limb motion in patients with cerebellar ataxia and reported that movement precision, smoothness, and velocity were related to ataxia. However, these analyses require complicated and specialized apparatus and are limited for more general clinical use. The aim of this study was to develop an objective evaluation tool to quantify the degree of upperlimb ataxia in SCD patients that uses a simple method so that it can be widely adopted.
Methods Patients We studied 49 patients with SCD, aged 32–86 years (mean age 63.5 ± 11.0 years, 31 males and 18 females; Table 1). Patients were diagnosed with autosomal-dominant cerebellar ataxia (ADCA, n = 24), sporadic cortical cerebellar atrophy (n = 10), or multiple system atrophy-cerebellar type (n = 15) according to clinical findings and magnetic resonance imaging (MRI) findings that excluded other etiologies. The ADCA group consisted of three patients with spinocerebellar ataxia (SCA) type 2 (SCA2), four patients with SCA3, ten patients with SCA6, three patients with SCA31, one patient with dentatorubral-pallidoluysian atrophy, and three patients with unknown ADCA. The diagnosis of ADCA was based on a family history compatible with dominant transmission and the results of DNA
Table 1 Clinical characteristics of the study population N (male/female)
49 (31/18)
Age, mean ± SD (years)
63.5 ± 11.0
Subtype (ADCA/CCA/MSA-C)
24/10/15
Disease duration, mean ± SD (years)
7.38 ± 6.34
ADCA autosomal-dominant cerebellar ataxia, CCA sporadic cortical cerebellar atrophy, MSA-C multiple system atrophy-cerebellar type, SD standard deviation
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analysis. All patients were right-handed. Exclusion criteria included history of stroke, other neuromuscular disease, dementia, and the existence of severe motor impairments that prevented the patient from holding a pen and drawing figures. All patients provided written informed consent. The study was conducted according to the Declaration of Helsinki and its later amendments and was approved by the Ethics Committee of Yokohama City University Hospital. Spiral collection and analysis Each patient traced a drawing of a spiral with their right hand. An Archimedean spiral in the clockwise direction with three loops was printed on A4 size paper and used as the template (Fig. 1a). The spiral maximum radius was 6.0 cm with an interloop distance of 2.0 cm. Patients were instructed to hold a pen and trace the spiral template as precisely as possible at a self-paced speed. The spiral was drawn from the inside to the outside and the forearm was not allowed to rest on the desk during drawing. When a drawn spiral had an end point that differed to the end point of the template spiral, a line was made between the drawn and the template end points. Spiral images were captured using a scanner system (Fig. 1b). The gap between the template spiral and the drawn spiral (gap area; GA) was quantified using Image J software (Version 1.46, NIH, USA) and used to represent the motor performance deficit due to ataxia. Clinical assessments The degree of ataxia was rated before the spiral drawings using SARA [4], the most widely accepted subjective scale for SCD. One author (NU) performed all SARA tests to avoid interrater differences. The total SARA score was subdivided into four functional subscores: posture and gait (items 1–3), speech (item 4), hand movements (items 5–7) and heel-shin slide (item 8). Neuroimaging assessments Thirty-seven patients underwent brain MRI on a 1.5-T scanner. MRI scans were conducted within 6 months of the spiral drawing test (either before or after). Axial T1weighted images (repetition time, 450 ms, excitation time, 17 ms) at the middle cerebellar peduncle level were used to evaluate the cerebellar area, which was used as a substitute for volumetry of the cerebellum, according to the procedure by Kamitani and colleagues [10] (Fig. 2). Because cranial size varied across patients, the ratio of cerebellar area to posterior fossa area was calculated as the cerebellar
J Neurol
Fig. 1 The circular spiral template (a) and an example of a spiral drawing made by a patient (b)
using Pearson’s correlation coefficient. The minimum level of significance was set at p \ 0.05.
Results
Fig. 2 Measurement of cerebellar area (a) and posterior fossa area (b) on an axial T1-weighted magnetic resonance image at the middle cerebellar peduncle level using Image J software
area ratio. The cerebellar and posterior fossa areas were calculated manually using Image J software.
There was no significant correlation between patient age and GA evaluated using a liner regression model (r = 0.176, p = 0.227), although there was a slight tendency for GA to increase with patient age. There was no significant correlation between disease duration and GA (r = 0.236, p = 0.103). There was a significant positive correlation between total SARA score and GA (r = 0.660, p \ 0.001; Fig. 3a). Each subscore of SARA also showed a significant positive correlation with GA (posture and gait, r = 0.551, p \ 0.001; speech, r = 0.527, p \ 0.001; hand movements, r = 0.553, p \ 0.001; heel-shin slide, r = 0.367, p = 0.036; Fig. 3b–e). There was a significant negative correlation between cerebellar area ratio and GA (r = 0.577, p \ 0.001; Fig. 3f), whereby cerebellar volume decreased as GA increased.
Statistical analysis
Discussion
The relation between GA and patient age, disease duration, total SARA score and each of the four SARA subscores was assessed using Spearman’s correlation coefficient. The relation between GA and cerebellar area ratio was assessed
In this study, we developed and tested a method to objectively quantify cerebellar ataxia using simple apparatus. The method required only a pen, A4-sized paper, a scanner, a computer, and free Image J software. Our results
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Fig. 3 The relation between the gap between the template spiral and the drawn spiral (gap area; GA) and the total Scale for the Assessment and Rating of Ataxia (SARA) score (a r = 0.660, p \ 0.001), the posture and gait (b r = 0.551, p \ 0.001), speech (c r = 0.527,
p \ 0.001), hand movements (d r = 0.553, p \ 0.001), and heel-shin slide (e r = 0.367, p = 0.036) SARA subscores, and the cerebellar area ratio (f r = 0.577, p \ 0.001)
showed that GA, which was the gap between the template and the drawn spirals, was not related to patient age or disease duration but was related to total SARA score. These results suggest that higher values of GA did not reflect simple disease progression or deterioration, but specifically reflected cerebellar ataxia. As GA was calculated from hand drawings, it was most strongly related to the hand movements subscore of SARA; however, it was also significantly related to the other SARA subscores (posture and gait, speech, and heel-shin slide). We therefore propose that this measure represents the overall degree of cerebellar ataxia, and particularly the degree of upperlimb ataxia. Cerebellar ataxia in the upper limb is mainly composed of decomposition of movement, dysmetria and terminal oscillation, and at present it is not clear which aspects are reflected by GA. Cerebellar volume, represented by cerebellar area ratio, was negatively correlated with GA. There are several reports of the relation between cerebellar volume and ataxia [11–25]. In degenerative SCD (SCA1, SCA2, SCA3, SCA6, SCA17, Friedreich’s ataxia, autosomal-dominant ataxia type III, episodic ataxia type 2, multiple system atrophy, and sporadic cortical cerebellar atrophy), the progress of cerebellar volume reduction evaluated using a volumetric MRI method parallels the decline in motor performance [12–24]. The same relation exists between
cerebellar volume and motor disturbance in patients with cerebellar atrophy due to metabolic etiology (alcoholic cerebellar atrophy [11] and adult Niemann-Pick type C [25] ). The methods used to evaluate cerebellar ataxia in most previous studies, including the above-mentioned reports, were semi-quantitative scales that depended on subjective estimation by observers, for example the International Cooperative Ataxia Rating Scale, the SARA score, the cerebellar ataxia score [26], and the brief ataxia rating scale [27]. Objective scores have been used in only a few papers [6–9]. The Spinocerebellar Ataxia Functional Index, the Composite Cerebellar Functional Severity Score, and videotaping methods have been developed to objectively evaluate the motor performance of cerebellar patients, but these scores only partly correlated with the degree of ataxia evaluated by established scales, such as SARA [6, 7]. In addition, all these procedures require specialized apparatus and complicated analysis methods, making them difficult to use in a clinical environment. Additional objective methods have been developed to evaluate cerebellar ataxia: Sullivan and colleagues [11] devised quantitative gait and balance tests that were correlated with cerebellar white matter volume in patients with alcoholism, and Brandauer and colleagues [17] developed a scale using grasping performance that was
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associated with cerebellar volume reduction in SCA6, autosomal-dominant ataxia type III, and sporadic cortical cerebellar atrophy patients. However, these methods are also not easy to use in clinical practice. In this study, we validated GA, an objective and numerical outcome based on a simple spiral drawing, as a measure of cerebellar ataxia. GA was significantly related to the severity of ataxia and cerebellar volume in patients with SCD. The principles of our methodology can easily be developed into a more sophisticated system that uses a tablet computer to reduce the analysis time. We emphasize that GA is a simple and valuable measure of cerebellar ataxia, and that it might be useful in largescale studies, such as clinical trials of newly developed medication and rehabilitation. Acknowledgments This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labor and Welfare, Japan. Conflicts of interest None of the authors declare a conflict of interest.
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References 15. 1. Ilg W, Schatton C, Schicks J, Giese MA, Scho¨ls L, Synofzik M (2012) Video game-based coordinative training improves ataxia in children with degenerative ataxia. Neurology 79:2056–2060 2. Miyai I, Ito M, Hattori N, Mihara M, Hatakeyama M, Yagura H, Sobue G, Nishizawa M (2012) Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair 26:515–522 3. Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B (1997) International COOPERATIVE Ataxia Scale for pharmacological assessment of the cerebellar syndrome. J Neurol Sci 145:205–211 4. Schmitz-Hu¨bsch T, Tezenas du Montcel S, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Scho¨ls L, Szymanski S, van de Warrenburg BPC, Du¨rr A, Klockgether T (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720 5. Subramony SH, May W, Lynch D, Gomez C, Fischbeck K, Hallett M, Taylor P, Wilson R, Ashizawa T (2005) Measuring Friedreich ataxia. Interrater reliability of a neurologic rating scale. Neurology 64:1261–1262 6. Schmitz-Hu¨bsch T, Giunti P, Stephenson DA, Globas C, Baliko L, Sacca` F, Mariotti C, Rakowicz M, Szymanski S, Infante J, van de Warrenburg BPC, Timmann D, Fancellu R, Rola R, Depondt C, Scho¨ls L, Zdzienicka E, Kang JS, Do¨hlinger S, Kremer B, Melegh B, Filla A, Klockgether T (2008) SCA functional index. A useful compound performance measure for spinocerebellar ataxia. Neurology 71:486–492 7. du Montcel ST, Charles P, Ribai P, Goizet C, Le Bayon A, Labauge P, Guyant-Mare´chal L, Forlani S, Jauffret C, Vandenberghe N, N’guyen K, Le Ber I, Devos D, Vincitorio CM, Manto MU, Tison F, Hannequin D, Ruberg M, Brice A, Durr A (2008)
16.
17.
18.
19.
20.
21.
22.
Composite cerebellar functional severity score: validation of a quantitative cerebellar impairment. Brain 131:1352–1361 Bastian AJ, Martin TA, Keating JG, Thach WT (1996) Cerebellar ataxia. Abnormal control of interaction torques across multiple joints. J Neurophysiol 76:492–509 Menegoni F, Milano E, Trotti C, Galli M, Bigoni M, Baudo S, Mauro A (2009) Quantitative evaluation of functional limitation of upper limb movements in subjects affected by ataxia. Eur J Neurol 16:232–239 Kamitani T, Kuroiwa Y, Wang L, Li M, Ikegami T, Matsubara S (2003) Event-related potentials during visual S1-S2 paradigm in multiple system atrophy: relation to morphologic changes on brain MRO measurement. Parkinsonism Relat Disord 10:93–100 Sullivan EV, Deshmukh A, Desmond JE, Lim KO, Pfefferbaum A (2000) Cerebellar volume decline in normal aging, alcoholism, and Korsakoff’s syndrome: relation to ataxia. Neuropsychology 14:341–352 Brenneis C, Bo¨sch SM, Schocke M, Wenning GK, Poewe W (2003) Atrophy pattern in SCA2 determined by voxel-based morphometry. NeuroReport 14:1799–1802 Guerrini L, Lolli F, Ginestroni A, Belli G, Nave RD, Tessa C, Foresti S, Cosottini M, Piacentini S, Salvi F, Plasmati R, Grandis DD, Siciliano G, Filla A, Mascalchi M (2004) Brainstem neurodegeneration correlates with clinical dysfunction in SCA1 but not in SCA2. A quantitative volumetric, diffusion and proton spectroscopy MR study. Brain 127:1785–1790 Richter S, Dimitrova A, Maschke M, Gizewski E, Beck A, Aurich V, Timmann D (2005) Degree of cerebellar ataxia correlates with three-dimensional MRI-based cerebellar volume in pure cerebellar degeneration. Eur Neurol 54:23–27 Brenneis C, Boesch SM, Egger KE, Seppi K, Scherfler C, Schocke M, Wenning GK, Poewe W (2006) Cortical atrophy in the cerebellar variant of multiple atrophy: a voxel-based morphometry study. Mov Disord 21:159–165 Nave RD, Ginestroni A, Gianneli M, Tessa C, Salvatore E, Salvi F, Dotti MT, Michele GD, Piacentini S, Piacentini S (2007) Brain structural damage in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 79:82–85 Brandauer B, Hermsdo¨rfer J, Beck A, Aurich V, Gizewski ER, Marquardt C, Timmann D (2008) Impairments of prehension kinematics and grasping forces in patients with cerebellar degeneration and the relationship to cerebellar atrophy. Clinical Neurophysiol 119:2528–2537 Ginestroni A, Nave RD, Tessa C, Gianneli M, Grandis DD, Plasmati R, Salvi F, Piacentini S, Piacentini S (2008) Brain structural damage in spinocerebellar ataxia type 1. A VBM study. J Neurol 25:1153–1158 Nave RD, Ginestroni A, Tessa C, Cosottini M, Gianneli M, Salvatore E, Sartucci F, Michele GD, Dotti MT, Piacentini S, Mascalchi M (2008) Brain structural damage in spinocerebellar ataxia type 2. A voxel-based morphometry study. Mov Disord 23:899–903 Nave RD, Ginestroni A, Tessa C, Salvatore E, Grandis DD, Plasmati R, Salvi F, Michele GD, Dotti MT, Piacentini S, Mascalchi M (2008) Brain white matter damage in SCA1 and SCA2. An in vivo study using voxel-based morphometry, histogram analysis of mean diffusivity and tract-based spatial statistics. Neuroimage 43:10–19 Reetz K, Lencer R, Hagenah JM, Gaser C, Tadic V, Walter U, Wolters A, Steinlechner S, Zu¨hlke C, Brockmann K, Klein C, Rolfs A, Binkofski F (2010) Structural changes associated with progression of motor deficits in spinocerebellar ataxia 17. Cerebellum 9:210–217 Schulz JB, Borkert J, Wolf S, Schmitz-Hu¨bsch T, Rakowicz M, Mariotti C, Schoels L, Timmann D, van de Warrenburg B, Du¨rr A, Pandolfo M, Kang JS, Mandly AG, Na¨gele T, Grisoli M,
123
J Neurol Boguslawska R, Bauer P, Klockgether T, Hauser TK (2010) Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia 1, 3 and 6. Neuroimage 49:158–168 23. Camargos ST, Marques-Jr W, dos Santos AC (2011) Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients. Arq Neuropsiquiatr 69:292–296 24. Eichler L, Ballenberg B, Hahn HK, Ko¨ster O, Scho¨ls L, Lukas C (2011) Quantitative assessment of brain stem and cerebellar atrophy in spinocerebellar ataxia types 3 and 6: impact on clinical status. AJNR 32:890–897
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25. Walterfang M, Abel LA, Desmond P, Fahey MC, Bowman EA, Velakoulis D (2013) Cerebellar volume correlates with saccadic gain and ataxia in adult Niemann-Pick type C. Mol Genet Metab 108:85–89 26. Klockgether T, Schroth G, Diener HC, Dichgans J (1990) Idiopathic cerebellar ataxia of late onset: natural history and MRI morphology. J Neurol Neurosurg Psychiatry 53:297–305 27. Schmahmann JD, Gardner R, MacMore J, Vangel MG (2009) Development of a brief ataxia rating scale (BARS) based on a modified form of the ICARS. Mov Disord 24:1820–1828
ORIGINAL COMMUNICATION
Quantitative analysis of upper-limb ataxia in patients with spinocerebellar degeneration Naohisa Ueda • Yasuhito Hakii • Shigeru Koyano • Yuichi Higashiyama • Hideto Joki • Yasuhisa Baba • Yume Suzuki • Yoshiyuki Kuroiwa • Fumiaki Tanaka
Received: 23 January 2014 / Revised: 9 April 2014 / Accepted: 11 April 2014 Ó Springer-Verlag Berlin Heidelberg 2014
Abstract Spinocerebellar degeneration (SCD) is a progressive neurodegenerative disorder in which cerebellar ataxia causes motor disability. There are no widely applicable methods for objective evaluation of ataxia in SCD. An objective system to evaluate ataxia is necessary for use in clinical trials of newly developed medication and rehabilitation. The aim of this study was to develop a simple method to quantify the degree of upper-limb ataxia. Fortynine patients with SCD participated in this study. Patients were instructed to trace an Archimedean spiral template, and the gap between the template spiral and the drawn spiral (gap area; GA) was measured using Image J software. Ataxia was rated using the Scale for the Assessment and Rating of Ataxia (SARA) and cerebellar volume was evaluated in 37 patients using an axial cross-section of magnetic resonance images that were obtained within 6 months of clinical evaluation. Regression analysis was performed to assess the relation between GA and patient age, disease duration, SARA score, and cerebellar volume. N. Ueda S. Koyano Y. Higashiyama H. Joki Y. Suzuki F. Tanaka (&) Department of Neurology and Stroke Medicine, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, Kanagawa 236-0004, Japan e-mail: [email protected] Y. Hakii Department of Neurology, Saiseikai Yokohama City Nanbu Hospital, 3-2-10 Konandai, Konan-ku, Yokohama, Kanagawa 234-8503, Japan Y. Baba Y. Kuroiwa (&) Department of Neurology and Stroke Center, School of Medicine, University Hospital Mizonokuchi, Teikyo University, 3-8-3 Mizonokuchi, Takatsu-ku, Kawasaki, Kanagawa 213-8507, Japan e-mail: [email protected]
GA was significantly related to total SARA score (r = 0.660, p \ 0.001), the posture and gait (r = 0.551, p \ 0.001), speech (r = 0.527, p \ 0.001), hand movements (r = 0.553, p \ 0.001), and heel-shin slide (r = 0.367, p = 0.036) SARA subscores, and cerebellar volume (r = 0.577, p \ 0.001) but was not related to patient age (r = 0.176, p = 0.227) or disease duration (r = 0.236, p = 0.103). GA is a simple, useful method to objectively quantify the degree of cerebellar ataxia, especially upper-limb ataxia, and can be widely adopted in various settings, including clinical trials. Keywords Cerebellar ataxia Objective quantification Spiral drawing SARA Cerebellar volume
Introduction Patients with spinocerebellar degeneration (SCD) have a variety of symptoms including impaired ocular movement, dysarthria, limb ataxia, and truncal ataxia, and ataxia is a principal factor of motor disturbance in SCD. SCD is a progressive neurodegenerative disorder and some reports suggest that rehabilitation may improve motor performance [1, 2], but no effective medications have been developed so far. Reliable tools to evaluate ataxia in SCD are required to validate the efficacy of rehabilitation and disease-modifying therapies that will be developed in the near future. Several scales have been used to evaluate motor function in SCD patients, such as the International Cooperative Ataxia Rating Scale [3], the Scale for the Assessment and Rating of Ataxia (SARA) [4], and the Friedreich’s Ataxia Rating Scale [5], and all consist of various motor tests to evaluate posture, gait, speech, and upper-limb performance. However, these scales all rely on subjective assessment by
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observers. The Spinocerebellar Ataxia Functional Index [6] was developed to objectively evaluate ataxia using a ninehole peg test and objective quantification of gait and speech, and the Composite Cerebellar Functional Severity Score [7] was developed to numerically rate the ataxia using a nine-hole peg test and a hand click test; however, both are represented by a Z score calculated among the participants and neither is generally recognized. Other procedures that have been proposed to quantify cerebellar ataxia include video analysis. Bastian and colleagues analyzed the movement of multiple joints by videotaping markers placed on the joints, and reported that this was useful for detecting decomposition and dysmetria in patients with limb ataxia [8]. Menegoni and colleagues [9] used the optoelectronic system to analyze upper-limb motion in patients with cerebellar ataxia and reported that movement precision, smoothness, and velocity were related to ataxia. However, these analyses require complicated and specialized apparatus and are limited for more general clinical use. The aim of this study was to develop an objective evaluation tool to quantify the degree of upperlimb ataxia in SCD patients that uses a simple method so that it can be widely adopted.
Methods Patients We studied 49 patients with SCD, aged 32–86 years (mean age 63.5 ± 11.0 years, 31 males and 18 females; Table 1). Patients were diagnosed with autosomal-dominant cerebellar ataxia (ADCA, n = 24), sporadic cortical cerebellar atrophy (n = 10), or multiple system atrophy-cerebellar type (n = 15) according to clinical findings and magnetic resonance imaging (MRI) findings that excluded other etiologies. The ADCA group consisted of three patients with spinocerebellar ataxia (SCA) type 2 (SCA2), four patients with SCA3, ten patients with SCA6, three patients with SCA31, one patient with dentatorubral-pallidoluysian atrophy, and three patients with unknown ADCA. The diagnosis of ADCA was based on a family history compatible with dominant transmission and the results of DNA
Table 1 Clinical characteristics of the study population N (male/female)
49 (31/18)
Age, mean ± SD (years)
63.5 ± 11.0
Subtype (ADCA/CCA/MSA-C)
24/10/15
Disease duration, mean ± SD (years)
7.38 ± 6.34
ADCA autosomal-dominant cerebellar ataxia, CCA sporadic cortical cerebellar atrophy, MSA-C multiple system atrophy-cerebellar type, SD standard deviation
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analysis. All patients were right-handed. Exclusion criteria included history of stroke, other neuromuscular disease, dementia, and the existence of severe motor impairments that prevented the patient from holding a pen and drawing figures. All patients provided written informed consent. The study was conducted according to the Declaration of Helsinki and its later amendments and was approved by the Ethics Committee of Yokohama City University Hospital. Spiral collection and analysis Each patient traced a drawing of a spiral with their right hand. An Archimedean spiral in the clockwise direction with three loops was printed on A4 size paper and used as the template (Fig. 1a). The spiral maximum radius was 6.0 cm with an interloop distance of 2.0 cm. Patients were instructed to hold a pen and trace the spiral template as precisely as possible at a self-paced speed. The spiral was drawn from the inside to the outside and the forearm was not allowed to rest on the desk during drawing. When a drawn spiral had an end point that differed to the end point of the template spiral, a line was made between the drawn and the template end points. Spiral images were captured using a scanner system (Fig. 1b). The gap between the template spiral and the drawn spiral (gap area; GA) was quantified using Image J software (Version 1.46, NIH, USA) and used to represent the motor performance deficit due to ataxia. Clinical assessments The degree of ataxia was rated before the spiral drawings using SARA [4], the most widely accepted subjective scale for SCD. One author (NU) performed all SARA tests to avoid interrater differences. The total SARA score was subdivided into four functional subscores: posture and gait (items 1–3), speech (item 4), hand movements (items 5–7) and heel-shin slide (item 8). Neuroimaging assessments Thirty-seven patients underwent brain MRI on a 1.5-T scanner. MRI scans were conducted within 6 months of the spiral drawing test (either before or after). Axial T1weighted images (repetition time, 450 ms, excitation time, 17 ms) at the middle cerebellar peduncle level were used to evaluate the cerebellar area, which was used as a substitute for volumetry of the cerebellum, according to the procedure by Kamitani and colleagues [10] (Fig. 2). Because cranial size varied across patients, the ratio of cerebellar area to posterior fossa area was calculated as the cerebellar
J Neurol
Fig. 1 The circular spiral template (a) and an example of a spiral drawing made by a patient (b)
using Pearson’s correlation coefficient. The minimum level of significance was set at p \ 0.05.
Results
Fig. 2 Measurement of cerebellar area (a) and posterior fossa area (b) on an axial T1-weighted magnetic resonance image at the middle cerebellar peduncle level using Image J software
area ratio. The cerebellar and posterior fossa areas were calculated manually using Image J software.
There was no significant correlation between patient age and GA evaluated using a liner regression model (r = 0.176, p = 0.227), although there was a slight tendency for GA to increase with patient age. There was no significant correlation between disease duration and GA (r = 0.236, p = 0.103). There was a significant positive correlation between total SARA score and GA (r = 0.660, p \ 0.001; Fig. 3a). Each subscore of SARA also showed a significant positive correlation with GA (posture and gait, r = 0.551, p \ 0.001; speech, r = 0.527, p \ 0.001; hand movements, r = 0.553, p \ 0.001; heel-shin slide, r = 0.367, p = 0.036; Fig. 3b–e). There was a significant negative correlation between cerebellar area ratio and GA (r = 0.577, p \ 0.001; Fig. 3f), whereby cerebellar volume decreased as GA increased.
Statistical analysis
Discussion
The relation between GA and patient age, disease duration, total SARA score and each of the four SARA subscores was assessed using Spearman’s correlation coefficient. The relation between GA and cerebellar area ratio was assessed
In this study, we developed and tested a method to objectively quantify cerebellar ataxia using simple apparatus. The method required only a pen, A4-sized paper, a scanner, a computer, and free Image J software. Our results
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Fig. 3 The relation between the gap between the template spiral and the drawn spiral (gap area; GA) and the total Scale for the Assessment and Rating of Ataxia (SARA) score (a r = 0.660, p \ 0.001), the posture and gait (b r = 0.551, p \ 0.001), speech (c r = 0.527,
p \ 0.001), hand movements (d r = 0.553, p \ 0.001), and heel-shin slide (e r = 0.367, p = 0.036) SARA subscores, and the cerebellar area ratio (f r = 0.577, p \ 0.001)
showed that GA, which was the gap between the template and the drawn spirals, was not related to patient age or disease duration but was related to total SARA score. These results suggest that higher values of GA did not reflect simple disease progression or deterioration, but specifically reflected cerebellar ataxia. As GA was calculated from hand drawings, it was most strongly related to the hand movements subscore of SARA; however, it was also significantly related to the other SARA subscores (posture and gait, speech, and heel-shin slide). We therefore propose that this measure represents the overall degree of cerebellar ataxia, and particularly the degree of upperlimb ataxia. Cerebellar ataxia in the upper limb is mainly composed of decomposition of movement, dysmetria and terminal oscillation, and at present it is not clear which aspects are reflected by GA. Cerebellar volume, represented by cerebellar area ratio, was negatively correlated with GA. There are several reports of the relation between cerebellar volume and ataxia [11–25]. In degenerative SCD (SCA1, SCA2, SCA3, SCA6, SCA17, Friedreich’s ataxia, autosomal-dominant ataxia type III, episodic ataxia type 2, multiple system atrophy, and sporadic cortical cerebellar atrophy), the progress of cerebellar volume reduction evaluated using a volumetric MRI method parallels the decline in motor performance [12–24]. The same relation exists between
cerebellar volume and motor disturbance in patients with cerebellar atrophy due to metabolic etiology (alcoholic cerebellar atrophy [11] and adult Niemann-Pick type C [25] ). The methods used to evaluate cerebellar ataxia in most previous studies, including the above-mentioned reports, were semi-quantitative scales that depended on subjective estimation by observers, for example the International Cooperative Ataxia Rating Scale, the SARA score, the cerebellar ataxia score [26], and the brief ataxia rating scale [27]. Objective scores have been used in only a few papers [6–9]. The Spinocerebellar Ataxia Functional Index, the Composite Cerebellar Functional Severity Score, and videotaping methods have been developed to objectively evaluate the motor performance of cerebellar patients, but these scores only partly correlated with the degree of ataxia evaluated by established scales, such as SARA [6, 7]. In addition, all these procedures require specialized apparatus and complicated analysis methods, making them difficult to use in a clinical environment. Additional objective methods have been developed to evaluate cerebellar ataxia: Sullivan and colleagues [11] devised quantitative gait and balance tests that were correlated with cerebellar white matter volume in patients with alcoholism, and Brandauer and colleagues [17] developed a scale using grasping performance that was
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associated with cerebellar volume reduction in SCA6, autosomal-dominant ataxia type III, and sporadic cortical cerebellar atrophy patients. However, these methods are also not easy to use in clinical practice. In this study, we validated GA, an objective and numerical outcome based on a simple spiral drawing, as a measure of cerebellar ataxia. GA was significantly related to the severity of ataxia and cerebellar volume in patients with SCD. The principles of our methodology can easily be developed into a more sophisticated system that uses a tablet computer to reduce the analysis time. We emphasize that GA is a simple and valuable measure of cerebellar ataxia, and that it might be useful in largescale studies, such as clinical trials of newly developed medication and rehabilitation. Acknowledgments This study was supported by Grants-in-Aid for Scientific Research from the Ministry of Health, Labor and Welfare, Japan. Conflicts of interest None of the authors declare a conflict of interest.
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References 15. 1. Ilg W, Schatton C, Schicks J, Giese MA, Scho¨ls L, Synofzik M (2012) Video game-based coordinative training improves ataxia in children with degenerative ataxia. Neurology 79:2056–2060 2. Miyai I, Ito M, Hattori N, Mihara M, Hatakeyama M, Yagura H, Sobue G, Nishizawa M (2012) Cerebellar ataxia rehabilitation trial in degenerative cerebellar diseases. Neurorehabil Neural Repair 26:515–522 3. Trouillas P, Takayanagi T, Hallett M, Currier RD, Subramony SH, Wessel K, Bryer A, Diener HC, Massaquoi S, Gomez CM, Coutinho P, Ben Hamida M, Campanella G, Filla A, Schut L, Timann D, Honnorat J, Nighoghossian N, Manyam B (1997) International COOPERATIVE Ataxia Scale for pharmacological assessment of the cerebellar syndrome. J Neurol Sci 145:205–211 4. Schmitz-Hu¨bsch T, Tezenas du Montcel S, Baliko L, Berciano J, Boesch S, Depondt C, Giunti P, Globas C, Infante J, Kang JS, Kremer B, Mariotti C, Melegh B, Pandolfo M, Rakowicz M, Ribai P, Rola R, Scho¨ls L, Szymanski S, van de Warrenburg BPC, Du¨rr A, Klockgether T (2006) Scale for the assessment and rating of ataxia: development of a new clinical scale. Neurology 66:1717–1720 5. Subramony SH, May W, Lynch D, Gomez C, Fischbeck K, Hallett M, Taylor P, Wilson R, Ashizawa T (2005) Measuring Friedreich ataxia. Interrater reliability of a neurologic rating scale. Neurology 64:1261–1262 6. Schmitz-Hu¨bsch T, Giunti P, Stephenson DA, Globas C, Baliko L, Sacca` F, Mariotti C, Rakowicz M, Szymanski S, Infante J, van de Warrenburg BPC, Timmann D, Fancellu R, Rola R, Depondt C, Scho¨ls L, Zdzienicka E, Kang JS, Do¨hlinger S, Kremer B, Melegh B, Filla A, Klockgether T (2008) SCA functional index. A useful compound performance measure for spinocerebellar ataxia. Neurology 71:486–492 7. du Montcel ST, Charles P, Ribai P, Goizet C, Le Bayon A, Labauge P, Guyant-Mare´chal L, Forlani S, Jauffret C, Vandenberghe N, N’guyen K, Le Ber I, Devos D, Vincitorio CM, Manto MU, Tison F, Hannequin D, Ruberg M, Brice A, Durr A (2008)
16.
17.
18.
19.
20.
21.
22.
Composite cerebellar functional severity score: validation of a quantitative cerebellar impairment. Brain 131:1352–1361 Bastian AJ, Martin TA, Keating JG, Thach WT (1996) Cerebellar ataxia. Abnormal control of interaction torques across multiple joints. J Neurophysiol 76:492–509 Menegoni F, Milano E, Trotti C, Galli M, Bigoni M, Baudo S, Mauro A (2009) Quantitative evaluation of functional limitation of upper limb movements in subjects affected by ataxia. Eur J Neurol 16:232–239 Kamitani T, Kuroiwa Y, Wang L, Li M, Ikegami T, Matsubara S (2003) Event-related potentials during visual S1-S2 paradigm in multiple system atrophy: relation to morphologic changes on brain MRO measurement. Parkinsonism Relat Disord 10:93–100 Sullivan EV, Deshmukh A, Desmond JE, Lim KO, Pfefferbaum A (2000) Cerebellar volume decline in normal aging, alcoholism, and Korsakoff’s syndrome: relation to ataxia. Neuropsychology 14:341–352 Brenneis C, Bo¨sch SM, Schocke M, Wenning GK, Poewe W (2003) Atrophy pattern in SCA2 determined by voxel-based morphometry. NeuroReport 14:1799–1802 Guerrini L, Lolli F, Ginestroni A, Belli G, Nave RD, Tessa C, Foresti S, Cosottini M, Piacentini S, Salvi F, Plasmati R, Grandis DD, Siciliano G, Filla A, Mascalchi M (2004) Brainstem neurodegeneration correlates with clinical dysfunction in SCA1 but not in SCA2. A quantitative volumetric, diffusion and proton spectroscopy MR study. Brain 127:1785–1790 Richter S, Dimitrova A, Maschke M, Gizewski E, Beck A, Aurich V, Timmann D (2005) Degree of cerebellar ataxia correlates with three-dimensional MRI-based cerebellar volume in pure cerebellar degeneration. Eur Neurol 54:23–27 Brenneis C, Boesch SM, Egger KE, Seppi K, Scherfler C, Schocke M, Wenning GK, Poewe W (2006) Cortical atrophy in the cerebellar variant of multiple atrophy: a voxel-based morphometry study. Mov Disord 21:159–165 Nave RD, Ginestroni A, Gianneli M, Tessa C, Salvatore E, Salvi F, Dotti MT, Michele GD, Piacentini S, Piacentini S (2007) Brain structural damage in Friedreich’s ataxia. J Neurol Neurosurg Psychiatry 79:82–85 Brandauer B, Hermsdo¨rfer J, Beck A, Aurich V, Gizewski ER, Marquardt C, Timmann D (2008) Impairments of prehension kinematics and grasping forces in patients with cerebellar degeneration and the relationship to cerebellar atrophy. Clinical Neurophysiol 119:2528–2537 Ginestroni A, Nave RD, Tessa C, Gianneli M, Grandis DD, Plasmati R, Salvi F, Piacentini S, Piacentini S (2008) Brain structural damage in spinocerebellar ataxia type 1. A VBM study. J Neurol 25:1153–1158 Nave RD, Ginestroni A, Tessa C, Cosottini M, Gianneli M, Salvatore E, Sartucci F, Michele GD, Dotti MT, Piacentini S, Mascalchi M (2008) Brain structural damage in spinocerebellar ataxia type 2. A voxel-based morphometry study. Mov Disord 23:899–903 Nave RD, Ginestroni A, Tessa C, Salvatore E, Grandis DD, Plasmati R, Salvi F, Michele GD, Dotti MT, Piacentini S, Mascalchi M (2008) Brain white matter damage in SCA1 and SCA2. An in vivo study using voxel-based morphometry, histogram analysis of mean diffusivity and tract-based spatial statistics. Neuroimage 43:10–19 Reetz K, Lencer R, Hagenah JM, Gaser C, Tadic V, Walter U, Wolters A, Steinlechner S, Zu¨hlke C, Brockmann K, Klein C, Rolfs A, Binkofski F (2010) Structural changes associated with progression of motor deficits in spinocerebellar ataxia 17. Cerebellum 9:210–217 Schulz JB, Borkert J, Wolf S, Schmitz-Hu¨bsch T, Rakowicz M, Mariotti C, Schoels L, Timmann D, van de Warrenburg B, Du¨rr A, Pandolfo M, Kang JS, Mandly AG, Na¨gele T, Grisoli M,
123
J Neurol Boguslawska R, Bauer P, Klockgether T, Hauser TK (2010) Visualization, quantification and correlation of brain atrophy with clinical symptoms in spinocerebellar ataxia 1, 3 and 6. Neuroimage 49:158–168 23. Camargos ST, Marques-Jr W, dos Santos AC (2011) Brain stem and cerebellum volumetric analysis of Machado Joseph disease patients. Arq Neuropsiquiatr 69:292–296 24. Eichler L, Ballenberg B, Hahn HK, Ko¨ster O, Scho¨ls L, Lukas C (2011) Quantitative assessment of brain stem and cerebellar atrophy in spinocerebellar ataxia types 3 and 6: impact on clinical status. AJNR 32:890–897
123
25. Walterfang M, Abel LA, Desmond P, Fahey MC, Bowman EA, Velakoulis D (2013) Cerebellar volume correlates with saccadic gain and ataxia in adult Niemann-Pick type C. Mol Genet Metab 108:85–89 26. Klockgether T, Schroth G, Diener HC, Dichgans J (1990) Idiopathic cerebellar ataxia of late onset: natural history and MRI morphology. J Neurol Neurosurg Psychiatry 53:297–305 27. Schmahmann JD, Gardner R, MacMore J, Vangel MG (2009) Development of a brief ataxia rating scale (BARS) based on a modified form of the ICARS. Mov Disord 24:1820–1828
