Factors Influencing Disease Progression in Autosomal Dominant Cerebellar Ataxia and Spastic Paraplegia

Perrine Charles
Arch Neurol. 2012-04-01; 69(4): 500
DOI: 10.1001/ARCHNEUROL.2011.2713

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1. Arch Neurol. 2012 Apr;69(4):500-8. doi: 10.1001/archneurol.2011.2713.

Factors influencing disease progression in autosomal dominant cerebellar ataxia
and spastic paraplegia.

Tezenas du Montcel S(1), Charles P, Goizet C, Marelli C, Ribai P, Vincitorio C,
Anheim M, Guyant-Maréchal L, Le Bayon A, Vandenberghe N, Tchikviladzé M, Devos D,
Le Ber I, N’Guyen K, Cazeneuve C, Tallaksen C, Brice A, Durr A.

Author information:
(1)Department of Biostatistics and Medical Informatics, and Pitié-Salpêtrière
Charles-Foix Clinical Research Unit, Hôpital Pitié-Salpêtrière, 47 boulevard de
l’Hôpital, Paris, France.

OBJECTIVES: To evaluate disease progression and determine validity of clinical
tools for therapeutic trials.
DESIGN: Prospective cohort study (36 months).
SETTING: Referral center.
PATIENTS: One hundred sixty-two patients with autosomal dominant cerebellar
ataxia and 64 with hereditary spastic paraplegia.
MAIN OUTCOME MEASURES: The quantitative Composite Cerebellar Functional Severity
Score with the writing test (CCFSw) and Scale for the Assessment and Rating of
Ataxia (SARA) score.
RESULTS: Disease worsened in patients with SCA1, SCA2, and SCA3 mutations (mean
[SE] increase in CCFSw, +0.014 [0.005] to +0.025 [0.004] per year), improved in
patients with SPG4 mutations (mean [SE] increase in CCFSw, -0.012 [0.003] per
year; P = .02), and remained stable in patients with SCA6, SCA7, or other SCA
mutations (mean [SE] increase in CCFSw, -0.015 [0.011] to +0.009 [0.013] per
year) or hereditary spastic paraplegia with other SPG mutations (mean [SE]
increase in CCFSw, -0.005 [0.005] per year). Progression was faster in patients
with SCA2 mutations and normal alleles with 22 or fewer repeats (P = .02) and in
patients with SCA3 mutations with parkinsonism and/or dystonia at baseline (P =
.003). Whereas CCFSw distinguished between patients with ataxia and spasticity,
SARA scores increased in both groups. A 2-arm trial with SARA score as the
outcome measure would require 57 patients with SCA2 mutations, 70 with SCA1
mutations, and 75 with SCA3 mutations per group to detect a 50% reduction in
disease progression (power, 80%; α = .05).
CONCLUSIONS: Disease progressed faster in SCA s with polyglutamine expansions in
SCA1, 2, and 3 than the other groups. Both outcome measures are suitable for
therapeutic trials; SARA requires fewer patients to attain the same power, but
CCFSw needs less stratification. We demonstrate that the choice of clinical
outcome measure is critical for reliable evaluation of progression in
neurodegenerative diseases.

DOI: 10.1001/archneurol.2011.2713
PMID: 22491195 [Indexed for MEDLINE]

Auteurs Bordeaux Neurocampus