(C-012) Defining the prodromal phase in amyotrophic lateral sclerosis: a nationwide registry-based study

Background: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease whose early symptoms can be vague and nonspecific, leading to a long diagnostic delay. Understanding its prodrome, the period after the pathology has begun, but before typical symptoms appear, is crucial for early diagnosis and intervention, but the specific characteristics and duration of this phase remain unclear. To address this, we conducted an agnostic search for the earliest ALS signs by analyzing changes in drug prescription patterns.

Objectives: The aim was to better define the prodromal phase of ALS and its duration, potentially leading to earlier detection and intervention strategies.

Methods: We conducted a nested case-control study using nationwide Norwegian registries. During the follow-up period 2005-2019, incident ALS cases were identified, and each case was individually matched to 100 controls by sex, age, and education level using incidence density sampling. Information on drug prescriptions was gathered from the Norwegian Prescription Database (NorPD). We calculated prescription rates for up to ten years before diagnosis, performed lag-time analyses, and used machine learning to predict ALS using drug prescriptions in different time intervals prior to diagnosis.

Results: We identified 2,084 incident ALS patients and 208,400 matched controls. We observed changes in the overall prescription patterns for individuals who developed ALS two to three years before their disease was diagnosed, with consistent results across the different analytic approaches. Furthermore, when examining the prescription patterns for specific groups of drugs, we observed that 25 of 42 therapeutical drug classes were prescribed more frequently to ALS patients than matched controls. Muscle relaxants and drugs for the treatment of bone diseases were prescribed significantly more frequently six and five years before ALS was diagnosed, respectively.

Conclusions: We observed changes in prescription patterns among ALS patients as early as six years before the disease was diagnosed, indicating that the prodromal phase of ALS is longer than previously recognized. These findings highlight the potential for identifying individuals who develop ALS earlier in the disease course, potentially allowing for earlier intervention and ultimately improved outcomes.