Mov Disord. Dec;20(12) International Cooperative Ataxia Rating Scale (ICARS): appropriate for studies of Friedreich’s ataxia? Cano SJ(1). The International Cooperative Ataxia Rating Scale (ICARS) is an outcome measure that was created in by the Committee of the World Federation of. INTERNATIONAL CO-OPERATIVE ATAXIA RATING SCALE. I: POSTURE AND GAIT DISTURBANCE. SCORE: 1. WALKING. CAPACITIES observed during a 10 .

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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 atazia of onset inversely correlates with increased GAA repeat length. 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 atwxia 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. The molecular basis reflects intronic GAA triplet repeat expansions in the gene encoding the mitochondrial protein frataxin, resulting in mitochondrial respiratory chain dysfunction and elevated oxidative stress icarw in Santos et al. This point scale with generally high inter-rater reliability comprises 19 individual items combined into four subscales addressing posture and gait disturbances, kinetic functions, speech disorders and oculomotor qtaxia Trouillas et al.

For example, improvements in fine motor skills, swallowing, speech and upper limb ataxia have been specifically reported in open-label and placebo-controlled intervention studies Hausse et al.

Therefore, it is of interest to better understand the sensitivity and relative contribution of change for icags ICARS item and aggregate subscales taaxia patients with different ages and disease histories.

One general problem in planning and interpretation of clinical outcomes in rare diseases is the limited availability of reliable natural history data to adequately power prospective clinical trials.

In ataxai, a suitable rating scale should be sensitive enough to allow assessments of change within a patient population with varying age and disease history and to detect changes over a feasible treatment period Delatycki, Faster rates were shown to be associated with earlier age of onset Ribai et al.

GAA triplet repeat lengths were reported for the sorter allele of the disease-specific expansion. Psychometric analysis followed the general methodology on assessment of summated rating scales Spector,which was already applied by Cano et al.

Specifically, we calculated floor and ceiling effects on the item and subscale level. To test for internal consistency, correlations of items within subscales and also between icarw were ocars using standard least squares linear regression. The GAA repeat length was available for of patients. The mean and median repeat lengths from these patients were andrespectively. In contrast, an initial increase during the first 20 years of disease was followed by a relative stabilization thereafter Fig.

For a more quantitative analysis and to further assess the influence of age of onset on ICARS rating, we performed a linear regression of the ICARS during the first 20 ataxoa of disease progression with increasing cut-offs for age of onset, thereby including successively more patients.

Figure 2 and Table 1 show the results for two groups of patients with a chosen cut-off of 14 years.

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Likewise, we did not detect any obvious difference in the rate of change according to the geographical region from which patients were recruited Europe: Melbourne dataset; Table 1 and Fig. Also, despite the fact that for MICONOS disease duration was derived from age ataixa diagnosis and thus might underestimate disease duration, the rate was comparable with the other centres. No correlation was seen after 20 years of disease progression Fig.

Mean values are indicated as dashed lines. There are patients represented in A whereas disease duration data were available for only patients in B. The calculated annual ICARS rate during the first 20 years of the disease for early-onset patients can be broken down to contributions by the individual ICARS subscale posture and gait disturbances: Table 2 summarizes the age of onset for different intervals of repeat lengths.


The vertical dashed line indicates the median repeat length ofand the horizontal dashed line indicates an age of disease onset of 14 years see subgroup analysis in Tables 1 and 2. Our data show that with shorter repeats, the disease progression or severity is indeed milder, consistent with the fact that detectable onset of symptoms occurs later.

However, individual scale items were prone to ataxiw floor and ceiling effects. Higher floor and ceiling effects for items in the oculomotor disorders subscale may partly be explained by the comparatively small weight given its three items a maximum of 1, 2 and 3 item points.

To visualize the dynamic range of each of the 19 scale items in relation to disease severity, we produced a heat map with the minimum item score indicated in green, the maximum item score indicated in red and the dynamic range ataaxia between as green—red colour spectrum Fig.

The scale items with a dynamic range across all ataxiq severity stages were scale items 10— These items appeared to have minimal floor and ceiling effects at the ends of the ICARS scale spectrum.

Heat map representing the individual item scores from lowest score green to maximum score red for each of the 19 ICARS scale items. This graphical presentation also showed the heterogeneity in ratings for individual items with disease progression.

A case in point is item 9, where patients with a total ICARS between 45 and 65 points can present with either minimum or maximum scores i.

We next analysed the relative contribution of individual scale items to the total score in dependence of disease progression Fig. The plot reveals the extent to which individual scale items contributed as the total ICARS score increases. Speech and oculomotor disorders subscale items followed a more linear progression across the entire disease severity spectrum.

The results presented so far add to the understanding of the relative contribution of individual ICARS subscales and items to the total ICARS rating in relation to disease progression and severity.

To test the validity of the ICARS, the correlation coefficients R were calculated for item-own-remainder and item-other correlations on the subscale level and for item-total scale correlations.

In addition, correlations between all subscales and also between all individual items were analysed. The item-own-remainder subscale correlations ranged from 0. The average item-own-remainder correlation coefficient was 0. The highest item-own-remainder subscale correlation of 0. These findings are consistent with the aforementioned floor and ceiling effects, for which the same three items matched better with the respective other subscale.

The lowest item-own-subscale correlation 0. The correlation coefficient between subscales ranged from 0.

On the other hand, cross-sectional data, when based on a large number of patients, provide a valid alternative to establish the severity of disease and rates of predicted disease progression offering the advantage of covering a wide range of disease states. However, we acknowledge that the use of disease duration to calculate disease progression rate in cross-sectional data presents a limitation of this study mainly because of uncertainties in accurately defining the onset of the disease.

Additional limitations of this approach could result from rater-dependent assessment differences and because only a single data point per patient is collected. In this study, we have attempted to overcome these limitations by including a large patient cohort and by ensuring proper experience to maximize standardizations in using the ICARS.

More than half of the predicted rate of decline is attributed to the posture and gait disturbances subscale, and patients have typically reached an ICARS of 60 points after 20 years. Thereafter, the posture and gait disturbances subscale and lower limb items of the kinetic functions subscale have reached a ceiling, and only fine motor skills, speech and ocular items contributed to further decline.

A different pattern was observed in patients with a late onset i. Similar findings of different rates of predicted disease progression depending on age of onset were made previously in a smaller retrospective study Ribai et al. By calculating the predicted rate of decline as a function of GAA repeat length, we also show that early disease onset translates to a faster progression of symptoms as captured by the ICARS rating.


The authors found no relationship between ICARS score and the severity of cardiac involvement or exercise performance, and the ICARS was found not to be a predictor for the severity of cardiac involvement. However, a detailed understanding of the dynamic range of each of the ICARS subscales and items might provide the basis for meaningful interpretations of study data.

This is supported by recent studies of idebenone in paediatric patients, where idebenone clearly demonstrated positive effects on the kinetic functions and speech disorders subscales while the posture and gait disturbances subscale continued to worsen irrespective of idebenone intervention Di Prospero et al.

ICARS Archives – Friedreich’s Ataxia News

In future atqxia, prospectively defined analyses on the level of ICARS subscales and items could help in deciphering potential therapeutic effects meaningful to patients. In this respect, the descriptive analysis of the dynamic ranges including floor and ceiling effects of the ICARS subscales and items, as described in this study, will be an important consideration in defining patient inclusion criteria.

Our findings are numerically similar to those previously reported on atxaia much smaller database Cano et al. Although total ICARS fulfils basic criteria for summated rating scales Spector,the grouping of items in subscales in the current version of the scale appears more problematic.

Such modifications are supported in our study by the data on the item—subscale correlations, the relative sensitivity to ceiling effects and the dynamic range of the items constituting the respective posture and gait disturbances and kinetic functions subscales.

In this way, a modified kinetic functions subscale would lack significant ceiling effects in any item and would be sensitive across a wide range of disease severities. A potential drawback of such rearrangement would be the fact that the posture and gait disturbances subscale would become disproportionally heavy compared with the remaining subscales.

However, in light of the emerging picture that interpretation of potential therapeutic interventions might also be based on subscale data, as indicated earlier in the text, such adaptations of the subscale structure of the ICARS appear warranted for this disease. However, there kcars still only limited data available to establish reference values for disease progression.

The study further provides iicars rate of changes of the ICARS separated for patients with early and late disease onset as well as for patients with different disease duration i. We also show the influence of GAA triplet repeat length both on age of onset and predicted rate of progression or disease severity.

All other authors declare no conflict of interest. Supplementary material is available at Brain online. The authors thank Mika Leinonen 4Pharma, Sweden, statistical advisor for discussion and support in the interpretation of the data.

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BrainVolumeIssue 1, 1 JanuaryPages —, https: R and SE from linear regression model using least squares. View large Download slide. Expanding view of phenotype and oxidative stress in Friedreich’s ataxia patients with and without idebenone.

Neurological effects of high-dose idebenone in patients with Friedreich’s ataxia: How is disease progress in Friedreich’s ataxia best measured? A study of four rating scales. A phase 3, double-blind, placebo-controlled trial of idebenone in Friedreich ataxia. Assessment of neurological efficacy of idebenone in pediatric patients with Friedreich’s ataxia: Neurological, cardiological, and oculomotor progression in patients with Friedreich ataxia during long-term follow-up.

Summated rating scale construction: Quantitative applications in the social sciences. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. The heart in Friedreich ataxia: For Permissions, please email: Email alerts New issue alert.

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