Brain Advance Access originally published online on March 31, 2008
Brain 2008 131(5):1352-1361; doi:10.1093/brain/awn059
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Composite cerebellar functional severity score: validation of a quantitative score of cerebellar impairment
1AP-HP, Department of Biostatistics and Medical Informatics and Pitié-Salpêtrière Charles-Foix Clinical Research Unit, 2University Pierre et Marie Curie, EA 3974, Modelling in Clinical Research, 3AP-HP, Pitié-Salpêtrière Hospital, Department of Genetics and Cytogenetics, 4INSERM, UMR_S679 Neurologie & Thérapeutique Expérimentale, 5Federative Institute for Neuroscience Research (IFR70), Pitié-Salpêtrière Hospital, 6AP-HP, Pitié-Salpêtrière Hospital, Federation of Neurology, F-75013 Paris, 7Bordeaux CHU Hospitals, Pellegrin Hospital, Department of Medical Genetics and Federation of Clinical Neurosciences, Bordeaux, 8Nîmes Hospitals, Carémeau Hospital, Service of Neurology, Nîmes, 9Rouen Hospitals, Charles Nicolle Hospital, Clinical Genetics Unit, Rouen, 10Lyon Hospitals, Pierre Wertheimer Neurological Hospital, Service of Neurology C, Lyon, 11Marseille Hospitals, La Timone Hospital, Department of Genetics, Marseille, 12Lille CHU Hospitals, Roger Salengro Hospital, Service of Neurology, Lille, France, 13FNRS, ULB Erasme, Service of Neurology, Brussels, Belgium and 14UPMC Univ Paris 06, UMR_S679, F-75005, Paris, France
Correspondence to: Alexandra Dürr, MD, PhD, INSERM UMR_S679 and Department of Genetics and Cytogenetics, Hôpital Pitié-Salpêtrière, 47-83 boulevard de l'Hopital, 75651 Paris Cedex 13- France E-mail: durr{at}ccr.jussieu.fr
Reliable and easy to perform functional scales are a prerequisite for future therapeutic trials in cerebellar ataxias. In order to assess the specificity of quantitative functional tests of cerebellar dysfunction, we investigated 123 controls, 141 patients with an autosomal dominant cerebellar ataxia (ADCA) and 53 patients with autosomal dominant spastic paraplegia (ADSP). We evaluated four different functional tests (nine-hole pegboard, click, tapping and writing tests), in correlation with the scale for the assessment and rating of cerebellar ataxia (SARA), the scale of functional disability on daily activities (part IV of the Huntington disease rating scale), depression (the Public Health Questionnaire PHQ-9) and the EQ-5D visual analogue scale for self-evaluation of health status. There was a significant correlation between each functional test and a lower limb score. The performance of controls on the functional tests was significantly correlated with age. Subsequent analyses were therefore adjusted for this factor. The performances of ADCA patients on the different tests were significantly worse than that of controls and ADSP patients; there was no difference between ADSP patients and controls. Linear regression analysis showed that only two independent tests, the nine-hole pegboard and the click test on the dominant side (P < 0.0001), accounted for the severity of the cerebellar syndrome as reflected by the SARA scores, and could be represented by a composite cerebellar functional severity (CCFS) score calculated as follows:
The CCFS score was significantly higher in ADCA patients compared to controls (1.12 ± 0.18 versus 0.85 ± 0.05, Pc < 0.0001) and ADSP patients (1.12 ± 0.18 versus 0.90 ± 0.08, Pc < 0.0001) and was correlated with disease duration (P < 0.0001) but independent of self-evaluated depressive mood in ADCA. Among genetically homogeneous subgroups of ADCA patients (Spinocerebellar ataxia 1, 2, 3), SCA3 patients had significantly lower (better) CCFS scores than SCA2 (Pc < 0.04) and the same tendency was observed in SCA1. Their CCFS scores remained significantly worse than those of ADSP patients with identified SPG4 mutations (P < 0.0001). The pegboard and click tests are easy to perform and accurately reflect the severity of the disease. The CCFS is a simple and validated method for assessing cerebellar ataxia over a wide range of severity, and will be particularly useful for discriminating paucisymptomatic carriers from affected patients and for evaluating disease progression in future therapeutic trials.
Key Words: cerebellar ataxia; spastic paraplegia; Composite Cerebellar Functional Severity (CCFS) score; natural history
Abbreviations: ADCA, autosomal dominant cerebellar ataxia; ADSP, autosomal dominant spastic paraplegia; CCFS, composite cerebellar functional severity; ICARS, International Cooperative Ataxia Rating Scale; MSFC, multiple sclerosis functional composite; PASAT, paced auditory serial addition test; SARA, Scale for the Assessment and Rating of Ataxia; VAS, visual analogue scale.
Received October 26, 2007. Revised February 20, 2008. Accepted February 25, 2008.