Introduction ALS functional rating scale (revised) (ALSFRS-R) is the most widely used functional rating system in patients with amyotrophic lateral sclerosis (ALS). However, heterogeneity in ALSFRS-R progression renders analysis challenging. We have explored the characteristics of total ALSFRS-R, and ALSFRS-R subscores in longitudinal and survival models, to determine whether subscore analysis enhances the precision of the instrument.
Methods All cases with ALSFRS-R scores on the Irish ALS register were included. ALSFRS-R subscores were defined for bulbar, motor and respiratory domains. Longitudinal models were used to visualise fitted total ALSFRS-R and ALSFRS-R subscore progression. In addition, the prognostic value of convenience and computed ALSFRS-R slope and subscore slopes were compared.
Results 407 incident cases were identified with a complete ALSFRS-R measure. 233 (57%) patients were male, and 125 (31%) had bulbar-onset disease. ALSFRS-R bulbar and motor subscore slopes provided a better fit in prognostic models when combined over the total ALSFRS-R slope. Longitudinal analysis revealed that the ALSFRS-R motor subscore deteriorated earlier in spinal-onset disease over bulbar-onset disease, while in bulbar-onset disease the ALSFRS-R bulbar subscore deteriorated earlier and faster than in spinal-onset disease.
Discussion Our analysis builds on previous knowledge of ALSFRS-R subscores. Decline in ALSFRS-R motor subscores in patients with spinal-onset disease, and decline in ALSFRS-R bulbar subscores in patients with bulbar-onset disease, may predate reported disease onset dates. Respiratory subscores were not prognostically informative after adjustment for bulbar and motor subscores. These results provide robust evidence that the ALSFRS-R should not be reported as a single combined score, but rather as domain specific subscores.
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Contributors JR designed the study, analysed the data and wrote the manuscript. TB assisted with study design, collected data and edited the manuscript. AV collected data, managed the register database and edited the manuscript. MH collected data, managed the register database and edited the manuscript. OH set up and led the Irish ALS register, collected data, contributed to the study design and analysis and edited the manuscript.
Funding The research leading to these results has received funding from the Health Research Board Interdisciplinary Capacity Enhancement Programme, the European Community's Seventh Framework Programme (FP7/2007-2013) under the Health Cooperation programme and the project EUROMOTOR (number 259867), from the European Joint Progamme in Neurodegeneration (SOPHIA and ALS-CarE), from the Irish Institute of Clinical Neuroscience (IICN: 12549. 201616) and the Charities Research Motor Neuron and Irish Motor Neuron Disease Association. The funding sources played no role in the preparation of this manuscript.
Competing interests JR was funded by the Health Research Board Clinical Fellowship Programme (HPF-2014-527). TB was funded on a Clinical Research Fellowship from the Irish Institute of Clinical Neuroscience. OH is funded by the Health Research Board Clinician Scientist Programme. OH has received speaking honoraria from Novarits, Biogen Idec, Sanofi Aventis and Merck-Serono. She has been a member of advisory panels for Biogen Idec, Allergen, Ono Pharmaceuticals, Novartis, Cytokinetics and Sanofi Aventis. She serves as Editor-in-Chief of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia.
Ethics approval The Irish ALS Register complies with Irish Data protection legislation (1988 and 2003), and has been approved by the Beaumont Hospital Ethics Committee (02/28 and 05/49).
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement Data sharing requests are made in writing through Professor Hardiman (email@example.com) and require a formal data sharing agreement with approval from the University Technology Transfer Department. Data sharing agreements must include details on how the data will be stored, who will have access to the data and intended use of the data, and agreements as to the allocation of intellectual property.