Recent advances in the diagnosis and prognosis of amyotrophic lateral sclerosis

Abstract

The diagnosis of amyotrophic lateral sclerosis can be challenging due to its heterogeneity in clinical presentation and overlap with other neurological disorders. Diagnosis early in the disease course can improve outcomes as timely interventions can slow disease progression. An evolving awareness of disease genotypes and phenotypes and new diagnostic criteria, such as the recent Gold Coast criteria, could expedite diagnosis. Improved prognosis, such as that achieved with the survival model from the European Network for the Cure of ALS, could inform the patient and their family about disease course and improve end-of-life planning. Novel staging and scoring systems can help monitor disease progression and might potentially serve as clinical trial outcomes. Lastly, new tools, such as fluid biomarkers, imaging modalities, and neuromuscular electrophysiological measurements, might increase diagnostic and prognostic accuracy.

Figure 1.. ALS phenotypic heterogeneity in initial presentation and staging.

(A) Schematic of involvement of LMN (yellow), UMN (blue), and both LMN and UMN (green) dysfunction at initial presentation in spinal and bulbar onset, flail arm and leg, and PLS phenotypes. Spinal onset ALS involves variable UMN and/or LMN dysfunction in a combination of limbs Bulbar onset ALS involves UMN and/or LMN dysfunction in bulbar muscles (facial, tongue, pharyngeal). Flail arm ALS involves LMN dysfunction in the arms, although mild UMN dysfunction can occur in the legs. Flail leg ALS frequently involves asymmetric LMN dysfunction in the legs. PLS mainly involves UMN dysfunction in the arms and legs or bulbar region, although restricted LMN dysfunction can develop in the later disease stages or become more widespread if it transitions to ALS, often within 4.5 years of symptom onset. (B) Distribution of ALS phenotypes in the Australian National Motor Neuron Disease Registry (n=1,677); each human figure represents one percentage point. (C) Distribution of ALS phenotypes in the Italian Piemonte and Valle d’Aosta Registry (n=1,332);^, each human figure represents one percentage point; median survival in years is presented under each phenotype. Note that the two registries use slightly different classification systems of ALS phenotypic presentation. (D) King’s staging with four stages indicated (1, 2A/B, 3, 4A/B; blue); time to progress to stages and median survival at each stage (in months) are also annotated. ALS-MiToS staging with six stages indicated (0, 1, 2, 3, 4, 5; orange); staging based on four functional domains from the ALSFRS-R: (i) movement (walking/self-care; ALSFRS-R question 6 or 8); (ii) swallowing (ALSFRS-R question 3); (iii) communicating (ALSFRS-R questions 1 and 4), and (iv) breathing (ALSFRS-R question 10 or 12). Intensifying color indicates progression along stages for both King’s and ALS-MiToS. LMN, lower motor neuron; PLMN, pure LMN; PLS, primary lateral sclerosis; PUMN, pure UMN; UMN, upper motor neuron; y, year. Created, in part, with BioRender.com.