Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients

Abstract

ObjectiveThe Scale for the Assessment and Rating of Ataxia (SARA) is the most widely applied clinical outcome assessment (COA) for genetic ataxias, but presents metrological and regulatory challenges. To facilitate trial planning, we characterize its responsiveness (including subitem‐level relations to ataxia severity and patient‐focused outcomes) across a large number of ataxias, and provide first natural history data for several of them.MethodsSubitem‐level correlation and distribution‐based analysis of 1,637 SARA assessments in 884 patients with autosomal recessive/early onset ataxia (370 with 2–8 longitudinal assessments) were complemented by linear mixed effects modeling to estimate progression and sample sizes.ResultsAlthough SARA subitem responsiveness varied between ataxia severities, gait/stance showed a robust granular linear scaling across the broadest range (SARA < 25). Responsiveness was diminished by incomplete subscale use at intermediate or upper levels, nontransitions (“static periods”), and fluctuating decreases/increases. All subitems except nose‐finger showed moderate‐to‐strong correlations to activities of daily living, indicating that metric properties—not content validity—limit SARA responsiveness. SARA captured mild‐to‐moderate progression in many genotypes (eg, SYNE1‐ataxia: 0.55 points/yr, ataxia with oculomotor apraxia type 2: 1.14 points/yr, POLG‐ataxia: 1.56 points/yr), but no change in others (autosomal recessive spastic ataxia of Charlevoix‐Saguenay, COQ8A‐ataxia). Whereas sensitivity to change was optimal in mild ataxia (SARA < 10), it substantially deteriorated in advanced ataxia (SARA > 25; 2.7‐fold sample size). Use of a novel rank‐optimized SARA without subitems finger‐chase and nose‐finger reduces sample sizes by 20 to 25%.InterpretationThis study comprehensively characterizes COA properties and annualized changes of the SARA across and within a large number of ataxias. It suggests specific approaches for optimizing its responsiveness that might facilitate regulatory qualification and trial design. ANN NEUROL 2023

Modeling disease progression in spinocerebellar ataxias

“…6,7 Previous investigations have pointed to a number of metric weaknesses in SARA using conventional statistical methods in ataxia cohorts that were smaller and more heterogeneous than the combined cohort investigated here. 16,17 Our results underscore the usefulness of SARA to assess overall progression across disease stages. Since diseases stages are defined by walking ability, it is not surprising that the SARA items related to gait and stance, as well as the SARA sum score, to which these two items strongly contribute with 14 of 40 maximal score points, were identified as important predictors.…”

Multifeature quantitative motor assessment of upper limb ataxia including drawing and reaching

“…However, the actual number of patients who were no longer able to walk independently was unexpectedly low, probably because of bias toward less advanced ataxia patients being able to present to clinic, and/or the exclusion of patients with functionally relevant non‐cerebellar impairment, which is common in most advanced genetic ataxias. 2 Further, this study aimed to validate the quantitative motor assessment of upper limb movements generically across many degenerative ataxias, including both relatively common and ultra‐rare genetic ataxias, for which separate validation will never be possible. Although phenotypical assessments of the motor domain may well be transferable across ataxias, additional validation studies in genetically stratified cohorts are thus still warranted before implementation as trial outcome.…”

“…With molecular treatments on the horizon for the first genetic ataxias, sensitive outcome measures are now urgently needed to conduct sufficiently powered interventional trials. 1 While the sensitivity of clinical outcome assessments for the severity and progression of ataxia is limited, 2 , 3 , 4 digital‐motor assessments have been shown to provide more objective, reliable, and longitudinally responsive outcome measures, particularly for the impairment of gait and stance. 5 , 6 , 7 , 8 …”

“… 17 In addition to functional relevance, digital‐motor assessment in the upper limb domain might also meet two pragmatic needs for clinical ataxia trials: First, it may outperform the relatively poor sensitivity of current clinician‐reported outcomes (ClinROs)—such as the Scale for the Assessment and Rating of Ataxia (SARA)—and even clinical performance outcomes (PerfOs) such as the Nine‐Hole Peg Test (9HPT) in this domain. 2 , 3 , 5 , 18 , 19 Second, specifically upper limb digital‐motor assessments may be applicable across all disease stages, including both the advanced stage—when loss of free ambulation hampers clinical or digital motor assessment of gait and stance—and particularly also the most trial‐relevant mild stage before clinician‐reported assessments become responsive to appendicular ataxia. 2 , 20 …”

“… 2 , 3 , 5 , 18 , 19 Second, specifically upper limb digital‐motor assessments may be applicable across all disease stages, including both the advanced stage—when loss of free ambulation hampers clinical or digital motor assessment of gait and stance—and particularly also the most trial‐relevant mild stage before clinician‐reported assessments become responsive to appendicular ataxia. 2 , 20 …”