Patients were classified as having limb, bulbar or diaphragmatic onset ALS. For the purposes of analysis, those with diaphragmatic onset were classified with those with limb onset because of the common spinal basis of lower motor neuron degeneration. ALS milestones for investigation as potential staging criteria were selected on the basis of being easily clinically available by being routinely collected at any clinical visit, straightforward to define in terms of presence or absence of involvement, and useful for phenotypic classification (Wijesekera et al., 2009 (link)). Milestones were defined as symptom onset (functional involvement by weakness, wasting, spasticity, dysarthria or dysphagia of one CNS region defined as bulbar, upper limb, lower limb or diaphragmatic), diagnosis, functional involvement of a second region, functional involvement of a third region, needing gastrostomy and non-invasive ventilation. As wasting was almost always associated with weakness, and for patients with ALS spasticity manifests as weakness, we did not differentiate between those patients whose onset was not weakness, but rather spasticity or wasting without weakness. Timing of involvement was based on the date of onset of symptoms and dates of development of functionally significant symptoms in a second and third region, which were gathered from the clinical history. Diagnosis was defined as a confirmed diagnosis of ALS made either by the referring neurologist or at the tertiary centre, as recorded in the case records. The need for gastrostomy was defined as the time gastrostomy or nasogastric feeding was provided or refused. The need for non-invasive ventilation was defined as the time non-invasive ventilation was provided, trialled or refused.
Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration, a similar method to that used in a previous study of timings of medical interventions (Bromberg et al., 2010 (link)). Thus the time to each milestone was a value between 0 and 1, with 0 being symptom onset and 1 being death. Date of death was ascertained by clinic records, death certificates and contact with the patient's registered general practitioner. The highest milestone recorded at last follow-up was used. Riluzole use was also recorded and defined as any use longer than 2 weeks.
Milestone timings were standardized as proportions of time elapsed through the disease course using information from patients who had died by dividing time to a milestone by disease duration, a similar method to that used in a previous study of timings of medical interventions (Bromberg et al., 2010 (link)). Thus the time to each milestone was a value between 0 and 1, with 0 being symptom onset and 1 being death. Date of death was ascertained by clinic records, death certificates and contact with the patient's registered general practitioner. The highest milestone recorded at last follow-up was used. Riluzole use was also recorded and defined as any use longer than 2 weeks.