The progression rate of spinocerebellar ataxia type 2 changes with stage of disease

BACKGROUND: Spinocerebellar ataxia type 2 (SCA2) affects several neurological structures, giving rise to multiple symptoms. However, only the natural history of ataxia is well known, as measured during the study duration. We aimed to describe the progression rate of ataxia, by the Scale for the Assessment and Rating of Ataxia (SARA), as well as the progression rate of the overall neurological picture, by the Neurological Examination Score for Spinocerebellar Ataxias (NESSCA), and not only during the study duration but also in a disease duration model. Comparisons between these models might allow us to explore whether progression is linear during the disease duration in SCA2; and to look for potential modifiers. RESULTS: Eighty-eight evaluations were prospectively done on 49 symptomatic subjects; on average (SD), study duration and disease duration models covered 13 (2.16) months and 14 (6.66) years of individuals' life, respectively. SARA progressed 1.75 (CI 95%: 0.92-2.57) versus 0.79 (95% CI 0.45 to 1.14) points/year in the study duration and disease duration models. NESSCA progressed 1.45 (CI 95%: 0.74-2.16) versus 0.41 (95% CI 0.24 to 0.59) points/year in the same models. In order to explain these discrepancies, the progression rates of the study duration model were plotted against disease duration. Then an acceleration was detected after 10 years of disease duration: SARA scores progressed 0.35 before and 2.45 points/year after this deadline (p = 0.013). Age at onset, mutation severity, and presence of amyotrophy, parkinsonism, dystonic manifestations and cognitive decline at baseline did not influence the rate of disease progression. CONCLUSIONS: NESSCA and SARA progression rates were not constant during disease duration in SCA2: early phases of disease were associated with slower progressions. Modelling of future clinical trials on SCA2 should take this phenomenon into account, since disease duration might impact on inclusion criteria, sample size, and study duration. Our database is available online and accessible to future studies aimed to compare the present data with other cohorts

NESSCA Validation and Responsiveness of Several Rating Scales in Spinocerebellar Ataxia Type 2

Spinocerebellar ataxia type 2 (SCA2), caused by a CAG expansion (CAGexp) at ATXN2, has a complex clinical picture. While validated ataxia scales are available, comprehensive instruments to measure all SCA2 neurological manifestations are required. This study aims to validate the Neurological Examination Score for the assessment of Spinocerebellar Ataxias (NESSCA) to be used in SCA2 and to compare its responsiveness to those obtained with other instruments. NESSCA, SARA, SCAFI, and CCFS scales were applied in symptomatic SCA2 patients. Correlations were done with age at onset, disease duration, CAGexp, and between scales. Responsiveness was estimated by comparing deltas of stable to worse patients after 12 months, according to Patient Global Impression of change, and the area under the curve (AUC) of the Receiver Operating Characteristics curve of scores range. Eighty-eight evaluations (49 patients) were obtained. NESSCA had an even distribution and correlated with disease duration (r = 0.55), SARA (r = 0.63), and CAGexp (rho = 0.32): both explained 44% of NESSCA variance. Deltas (95% CI) after 1 year in stable and worse patients were only significantly different for SARA. NESSCA, SARA, SCAFI, and CCFS AUC were 0.63, 0.81, 0.49, and 0.48, respectively. NESSCA is valid to be used in SCA2. However, the only instrument that presented good responsiveness to change in 1 year was SARA. We suggest that NESSCA can be used as a secondary outcome in future trials in SCA2 due to the burden of neurological disabilities related to disease progression.CNPq-Conselho Nacional de Desenvolvimento Científico e TecnológicoFIPE-HCPA-Fundo de Incentivo a Pesquisa do Hospital de Clinicas de Porto AlegreINAGEMP-Instituto Nacional de Genetica Medica PopulacionalFAPERGSCNPqHosp Clin Porto Alegre, Serv Neurol, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Programa Posgrad Ciencias Med, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Fac Med, Porto Alegre, RS, BrazilUniv Fed São Paulo, Disciplina Neurol Clin, Setor Neurol Geral & Ataxias, UNIFESP,Escola Paulista Med, São Paulo, BrazilFundação Oswaldo Cruz, Lab Epidemiol Malformacoes Congenitas, Rio De Janeiro, BrazilUniv Fed Estado Rio de Janeiro, Dept Genet & Biol Mol, Rio De Janeiro, BrazilHosp Clin Porto Alegre, Serv Genet Med, Porto Alegre, RS, BrazilHosp Clin Porto Alegre, Lab Identificacao Genet, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Dept Bioquim, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Dept Matemat & Estat, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Programa Posgrad Epidemiol, Porto Alegre, RS, BrazilUniv Fed Rio Grande do Sul, Dept Med Interna, Porto Alegre, RS, BrazilInst Nacl Genet Med Populac INAGEMP, Porto Alegre, RS, BrazilHosp Clin Porto Alegre, Med Genet Serv, Rua Ramiro Barcelos 2350, BR-90035903 Porto Alegre, RS, BrazilUniv Fed São Paulo, Disciplina Neurol Clin, Setor Neurol Geral & Ataxias, UNIFESP,Escola Paulista Med, São Paulo, BrazilCNPq: 78057/2012-1FIPE-HCPA: GPPG HCPA 12-0357FIPE-HCPA: GPPG HCPA 12-0396Web of Scienc