Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations

Pérez-Lloret, Santiago; Warrenburg, Bart van de; Rossi, Malco; Rodríguez‐Blázquez, Carmen; Zesiewicz, Theresa A.; Saute, Jonas Alex Morales; Dürr, Alexandra; Nishizawa, Masatoyo; Martinez‐Martín, Pablo; Stebbins, Glenn T.; Schrag, Anette; Škorvánek, Matej

doi:10.1002/mds.28313

Cited by 58 publications

(52 citation statements)

References 88 publications

(304 reference statements)

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“…Second, the novel CI-CS primary endpoint has not been previously used or yet validated. It was implemented, however, due to the methodological limitations of applying pre-existing ataxia scales in heterogeneous diseases, in which cases, the scales may be too broad and therefore not sensitive to capture small but meaningful functional changes [7,18]. The validated NPC Clinical Severity Scale is only validated to measure disease progression after a minimum of 1 year; thus, it is not sensitive enough to capture or measure change after 6-weeks [19].…”

Section: Discussionmentioning

confidence: 99%

Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

et al. 2021

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Objective To investigate the safety and efficacy of N-acetyl-l-leucine (NALL) on symptoms, functioning, and quality of life in pediatric (≥ 6 years) and adult Niemann–Pick disease type C (NPC) patients. Methods In this multi-national, open-label, rater-blinded Phase II study, patients were assessed during a baseline period, a 6-week treatment period (orally administered NALL 4 g/day in patients ≥ 13 years, weight-tiered doses for patients 6–12 years), and a 6-week post-treatment washout period. The primary Clinical Impression of Change in Severity (CI-CS) endpoint (based on a 7-point Likert scale) was assessed by blinded, centralized raters who compared randomized video pairs of each patient performing a pre-defined primary anchor test (8-Meter Walk Test or 9-Hole Peg Test) during each study periods. Secondary outcomes included cerebellar functional rating scales, clinical global impression, and quality of life assessments. Results 33 subjects aged 7–64 years with a confirmed diagnosis of NPC were enrolled. 32 patients were included in the primary modified intention-to-treat analysis. NALL met the CI-CS primary endpoint (mean difference 0.86, SD = 2.52, 90% CI 0.25, 1.75, p = 0.029), as well as secondary endpoints. No treatment-related serious adverse events occurred. Conclusions NALL demonstrated a statistically significant and clinical meaningfully improvement in symptoms, functioning, and quality of life in 6 weeks, the clinical effect of which was lost after the 6-week washout period. NALL was safe and well-tolerated, informing a favorable benefit-risk profile for the treatment of NPC. Clinicaltrials.gov identifier NCT03759639.

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Section: Discussionmentioning

confidence: 99%

Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

et al. 2021

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“…Higher scores indicate greater motor disease severity for both scales. BARS, which is based on the Modified ICARS and correlated to both SARA and ICARS, was used as the assessment tool for participants with ataxia because of its brevity and because its scoring criteria for the FNT emphasize segmentation of movement [21]. Participants were equipped with nine-axis IMUs (Opal, APDM Wearable Technologies) on both wrists and seated upright with their feet firmly on the floor in front of a 12.9 in.…”

Section: Data Collectionmentioning

confidence: 99%

Decomposition of Reaching Movements Enables Detection and Measurement of Ataxia

et al. 2021

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Technologies that enable frequent, objective, and precise measurement of ataxia severity would benefit clinical trials by lowering participation barriers and improving the ability to measure disease state and change. We hypothesized that analyzing characteristics of sub-second movement profiles obtained during a reaching task would be useful for objectively quantifying motor characteristics of ataxia. Participants with ataxia (N=88), participants with parkinsonism (N=44), and healthy controls (N=34) performed a computer tablet version of the finger-to-nose test while wearing inertial sensors on their wrists. Data features designed to capture signs of ataxia were extracted from participants’ decomposed wrist velocity time-series. A machine learning regression model was trained to estimate overall ataxia severity, as measured by the Brief Ataxia Rating Scale (BARS). Classification models were trained to distinguish between ataxia participants and controls and between ataxia and parkinsonism phenotypes. Movement decomposition revealed expected and novel characteristics of the ataxia phenotype. The distance, speed, duration, morphology, and temporal relationships of decomposed movements exhibited strong relationships with disease severity. The regression model estimated BARS with a root mean square error of 3.6 points, r2 = 0.69, and moderate-to-excellent reliability. Classification models distinguished between ataxia participants and controls and ataxia and parkinsonism phenotypes with areas under the receiver-operating curve of 0.96 and 0.89, respectively. Movement decomposition captures core features of ataxia and may be useful for objective, precise, and frequent assessment of ataxia in home and clinic environments.

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“…Other scales include the Modified ICARS (MICARS), the Brief Ataxia Rating Scale (BARS), and the Neurological Examination Score for Spinocerebellar Ataxia (NESSCA). 58 None of these scales are meant to address non‐ataxic symptoms, for which additional scales have been developed. These additional scales include the Inventory of Non‐Ataxia Signs, which rates several neurological signs including spasticity, tremor, and dystonia, and the Cerebellar Cognitive Affective Syndrome Scale (CCAS), which is a dedicated cognitive scale to identify cognitive deficits in the context of cerebellar decline.…”

Section: Efforts Toward Clinical Trial Readinessmentioning

confidence: 99%

Spinocerebellar ataxia clinical trials: opportunities and challenges

Brooker

Edamakanti

Akasha

et al. 2021

Ann Clin Transl Neurol

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The spinocerebellar ataxias (SCAs) are a group of dominantly inherited diseases that share the defining feature of progressive cerebellar ataxia. The disease process, however, is not confined to the cerebellum; other areas of the brain, in particular, the brainstem, are also affected, resulting in a high burden of morbidity and mortality. Currently, there are no disease-modifying treatments for the SCAs, but preclinical research has led to the development of therapeutic agents ripe for testing in patients. Unfortunately, due to the rarity of these diseases and their slow and variable progression, there are substantial hurdles to overcome in conducting clinical trials. While the epidemiological features of the SCAs are immutable, the feasibility of conducting clinical trials is being addressed through a combination of strategies. These include improvements in clinical outcome measures, the identification of imaging and fluid biomarkers, and innovations in clinical trial design. In this review, we highlight current challenges in initiating clinical trials for the SCAs and also discuss pathways for researchers and clinicians to mitigate these challenges and harness opportunities for clinical trial development.

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Assessment of Ataxia Rating Scales and Cerebellar Functional Tests: Critique and Recommendations

Cited by 58 publications

References 88 publications

Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

Efficacy and safety of N-acetyl-l-leucine in Niemann–Pick disease type C

Decomposition of Reaching Movements Enables Detection and Measurement of Ataxia

Spinocerebellar ataxia clinical trials: opportunities and challenges

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