Diagnostic Delay in Amyotrophic Lateral Sclerosis: A Systematic Review and Meta-Analysis Comparing Time From Symptom...

Diagnostic delay is a recognized challenge in amyotrophic lateral sclerosis (ALS), depriving patients of timely access to disease-modifying therapy and multidisciplinary care. Although several individual cohorts have reported diagnostic delay separately for bulbar-onset and limb-onset ALS, few studies have directly compared the two, and their estimates have not been pooled. We aimed to compare time from symptom onset to diagnosis in bulbar-onset versus limb-onset ALS. We searched PubMed and Cochrane CENTRAL (Cochrane Central Register of Controlled Trials) from inception through April 2026 for studies reporting diagnostic delay separately for the two onset types. Where upper- and lower-limb onset were reported separately, these were combined into a single limb-onset group using standard formulae; medians with interquartile ranges were converted to means and standard deviations using the method of Wan et al. A random-effects meta-analysis (DerSimonian-Laird) pooled studies reporting a usable measure of dispersion by onset group, with the remaining studies summarized narratively. The outcome was the mean difference (MD) in diagnostic delay in months, where a negative value indicates faster diagnosis in bulbar onset; heterogeneity was quantified with I² and risk of bias with the Newcastle-Ottawa Scale. In total, 13 studies (898 bulbar-onset and 2,438 limb-onset patients from eight countries) met the inclusion criteria; nine contributed to the meta-analysis, as four reported no usable measure of dispersion and were summarized narratively. Bulbar-onset patients were diagnosed significantly faster than limb-onset patients (MD = -4.42 months; 95% confidence interval -5.73 to -3.11; p < 0.001), with moderate heterogeneity (I² = 56%). The direction of effect was consistent across all studies, and the pooled estimate was stable on leave-one-out analysis. The four non-pooled studies were each directionally consistent. Bulbar-onset ALS is diagnosed approximately 4 months faster than limb-onset ALS, likely because distinctive bulbar symptoms prompt earlier specialist referral whereas limb weakness is attributed to more common musculoskeletal or orthopedic conditions. Strategies raising awareness of limb-onset ALS among primary care and orthopedic physicians are warranted.