Identification and outcomes of clinical phenotypes in amyotrophic lateral sclerosis/motor neuron disease: Australian National Motor Neuron Disease observational cohort

Abstract

Objective: To capture the clinical patterns, timing of key milestones and survival of patients presenting with amyotrophic lateral sclerosis/motor neuron disease (ALS/MND) within Australia.

Methods: Data were prospectively collected and were timed to normal clinical assessments. An initial registration clinical report form (CRF) and subsequent ongoing assessment CRFs were submitted with a completion CRF at the time of death.

Design: Prospective observational cohort study.

Participants: 1834 patients with a diagnosis of ALS/MND were registered and followed in ALS/MND clinics between 2005 and 2015.

Results: 5 major clinical phenotypes were determined and included ALS bulbar onset, ALS cervical onset and ALS lumbar onset, flail arm and leg and primary lateral sclerosis (PLS). Of the 1834 registered patients, 1677 (90%) could be allocated a clinical phenotype. ALS bulbar onset had a significantly lower length of survival when compared with all other clinical phenotypes (p<0.004). There were delays in the median time to diagnosis of up to 12 months for the ALS phenotypes, 18 months for the flail limb phenotypes and 19 months for PLS. Riluzole treatment was started in 78-85% of cases. The median delays in initiating riluzole therapy, from symptom onset, varied from 10 to 12 months in the ALS phenotypes and 15-18 months in the flail limb phenotypes. Percutaneous endoscopic gastrostomy was implemented in 8-36% of ALS phenotypes and 2-9% of the flail phenotypes. Non-invasive ventilation was started in 16-22% of ALS phenotypes and 21-29% of flail phenotypes.

Conclusions: The establishment of a cohort registry for ALS/MND is able to determine clinical phenotypes, survival and monitor time to key milestones in disease progression. It is intended to expand the cohort to a more population-based registry using opt-out methodology and facilitate data linkage to other national registries.

Keywords: EPIDEMIOLOGY.

Figure 1

The clinical phenotypes are detailed, amyotrophic lateral sclerosis, flail and primary lateral sclerosis (PLS). Clinical phenotypes are allocated by identifying the region of symptom onset combined with the segmental distribution of upper and lower motor neuron signs. Patients with combined upper and lower motor neuron signs in one segment with at least one other segment involved with either upper motor neuron (UMN) and/or lower motor neuron (LMN) signs are classified into a clinical phenotype. Flail arm have the initial onset of LMN signs in the arms and absent arm reflexes. They have UMN and/or LMN signs in the legs and variable bulbar involvement and evolving neck weakness. Flail leg begin with LMN signs in the legs and areflexia, which extend to the arms with very late bulbar involvement. PLS is defined by having only UMN signs in all three segments; the onset can be in any region. Definitions for UMN and LMN signs for each region are listed. In order to maintain consistency, a region required the presence of at least one of the predefined clinical signs listed in the panel in order to be designated as having UMN, LMN or combined UMN/LMN signs.

Figure 2

Kaplan-Meier curves of patients censored at the time of death according to clinical phenotype. Survival according to the phenotypes with amyotrophic lateral sclerosis bulbar, onset having significantly different curves to flail arm and leg (p<0.003 and <0.004).

Figure 3

All cases with a reported date of death, median (StdDev) survival in lunar months according to clinical phenotype.