Rating disease progression of Friedreich's ataxia by the International Cooperative Ataxia Rating Scale: analysis of a 603-patient database

Abstract

The aim of this cross-sectional study was to analyse disease progression in Friedreich's ataxia as measured by the International Cooperative Ataxia Rating Scale. Single ratings from 603 patients with Friedreich's ataxia were analysed as a function of disease duration, age of onset and GAA repeat lengths. The relative contribution of items and subscales to the total score was studied as a function of disease progression. In addition, the scaling properties were assessed using standard statistical measures. Average total scale progression per year depends on the age of disease onset, the time since diagnosis and the GAA repeat length. The age of onset inversely correlates with increased GAA repeat length. For patients with an age of onset ≤14 years associated with a longer repeat length, the average yearly rate of decline was 2.5 ± 0.18 points in the total International Cooperative Ataxia Rating Scale for the first 20 years of disease duration, whereas patients with a later onset progress more slowly (1.8 ± 0.27 points/year). Ceiling effects in posture, gait and lower limb scale items lead to a reduced sensitivity of the scale in the severely affected population with a total score of >60 points. Psychometric scaling analysis shows generally favourable properties for the total scale, but the subscale grouping could be improved. This cross-sectional study provides a detailed characterization of the International Cooperative Ataxia Rating Scale. The analysis further provides rates of change separated for patients with early and late disease onset, which is driven by the GAA repeat length. Differences in the subscale dynamics merit consideration in the design of future clinical trials applying this scale as a neurological assessment instrument in Friedreich's ataxia.

Figure 1

Scatter plot of ICARS rating versus age at assessment (A) and disease duration (B). Mean values are indicated as dashed lines. There are 603 patients represented in A whereas disease duration data were available for only 529 patients in B.

Figure 2

(A) Total ICARS is plotted against disease duration (up to 20 years: black circles and straight line fit; >20 years: grey diamonds) separated for subgroup of patients <14 years of age at the time of diagnosis (left, n = 327) or >14 years (right, n = 202). (B) The mean ICARS is shown over disease duration grouped into 5-year intervals, coloured by data source.

Figure 3

Age of onset (on the left y-axis) is plotted against GAA triplet repeat length of the shorter allele (filled grey circles) for 389 patients with Friedreich’s ataxia for which both age of onset and repeat length were available. Patients were grouped in ranges of 200 repeats starting from 0–200 up to >800, and the ICARS annual rate of change (right y-axis) in these groups is plotted as black squares connected by a line. The vertical dashed line indicates the median repeat length of 700, and the horizontal dashed line indicates an age of disease onset of 14 years (see subgroup analysis in Tables 1 and 2).

Figure 4

Heat map representing the individual item scores from lowest score (green) to maximum score (red) for each of the 19 ICARS scale items. The actual test represented by individual ICARS item numbers can be looked up in Supplementary Table 1 or in Trouillas 1997. x-axis: data are displayed as 20 bins of 5.0 points across the total ICARS range. y-axis: proportion of patients within each bin reaching minimum (green), maximum (red) or intermediate item scores (green-red color spectrum). KF = kinetic functions; OD = oculomotor disorders; PG = posture and gait disturbances; SD = speech disorders.

Figure 5

The mean ICARS item as a function of total ICARS is plotted in groups corresponding to the four ICARS subscales. The actual test represented by individual ICARS item numbers can be looked up in Supplementary Table 1 or in Trouillas 1997. x-axis: data are displayed as 20 bins across the total 100 point ICARS range. y-axis: mean item value per bin. KF = kinetic functions; OD = oculomotor disorders; PG = posture and gait disturbances; SD = speech disorders.