Monitoring progression in Friedreich ataxia (FRDA): the use of clinical scales

Abstract

Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder associated with ataxia, dysarthria, pyramidal tract signs, sensory loss, cardiomyopathy and diabetes. There is no cure for FRDA so far. Studies of the natural history of the disease and future therapeutic trials require development of appropriate outcome markers. Since any therapeutic benefit is expected to modulate deterioration over time rather than to reverse disability, potential outcome measures must be sensitive instruments carefully analysed for their significance. Clinical scales may represent an appropriate measuring tool.Over the last few years the construction, evaluation and validation of sensitive clinical scales for the assessment of disease severity and progression in ataxia have had considerable impact on our understanding of the disease. Currently, there are three different scales that are most frequently applied: The International Cooperative Ataxia Rating Scale (ICARS), the Friedreich Ataxia Rating Scale (FARS) and the Scale for the Assessment and Rating of Ataxia (SARA). All scales have been validated and compared with regard to their testing properties. Friedreich ataxia (FRDA) is a progressive neurodegenerative disorder resulting from mutations within the first intron of the FRDA gene on chromosome 9 leading to impaired frataxin levels and impaired mitochondrial function. To date, there is no cure for FRDA. The study of the natural history of the disease and the execution of future therapeutic trials call for the development of appropriate outcome markers. Therapies may lead to a symptomatic effect resulting in improvement of symptoms and/or may interfere with the disease pathogenesis leading to a slowing-down of disease progression. Potential outcome measures must be sensitive instruments carefully analysed for their significance with respect to either effect. Otherwise, the lack of appropriate assessment tools may undermine any scientific evidence for therapeutic effectiveness. Clinical scales may represent an appropriate and cheap tool since they do not require elaborate infrastructure. Quality characteristics of clinical scalesA scale should be easy to learn and perform to facilitate integration into clinical routine. In addition, it should be rather compact to decrease fatigue in both the proband and the examiner. Furthermore, it should be robust and not influenced by external factors or fluctuations over the course of a day or from day to day. Basically, scales must correspond to certain quality aspects: A measuring tool must fulfil standards of acceptability, reliability and validity. A scale is acceptable if scores span the entire range without major floor (more than 20% of values drop under a certain threshold) or ceiling effects (more than 20% of scores correspond to the high-end range). To correctly display a wide range of clinical severity, a scale must also display adequate linearity. This is analysed by regression analysis applying a linear model. Reliability refers to the influence of random errors o...

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