Neutrophil-to-lymphocyte ratio in amyotrophic lateral sclerosis: a systematic review and meta-analysis

Abstract Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with limited diagnostic and prognostic biomarkers. The neutrophil-to-lymphocyte ratio (NLR), a marker of systemic inflammation, has been proposed as a potential indicator. This systematic review and meta-analysis assesses the diagnostic and prognostic value of NLR in ALS. We searched PubMed, Scopus, Embase, and Web of Science through June 2025 for peer-reviewed studies evaluating NLR in adults with ALS diagnosed by established criteria. Eligible studies reported validated measurements of NLR and diagnostic or prognostic outcomes. Two reviewers independently extracted data and assessed quality. Random-effects meta-analyses were performed, with heterogeneity, publication bias, evidence certainty, and sources of heterogeneity evaluated using meta-regression. Sixteen studies from 12 countries including 357,044 participants met inclusion criteria, comprising 8,710 ALS patients (mean age 60.3 years; 59.1% male) and 348,334 controls (mean age 57.8 years; 47.6% male). Meta-analysis of 11 studies showed a pooled mean NLR of 2.74 in ALS patients (95% CI 2.42, 3.10; I2 = 95.4%), while three control studies yielded a pooled mean NLR of 1.94 (95% CI 1.55, 2.43; I2 = 94.7%). Comparison of three studies demonstrated a 35% higher NLR in ALS patients than controls (95% CI 1.03, 1.76; I2 = 88.3%), with low certainty according to GRADE due to observational design and substantial heterogeneity. Elevated NLR was consistently associated with worse clinical outcomes, including faster disease progression, lower ALSFRS-r scores, reduced forced vital capacity, shorter survival, and increased mortality. Pooled univariate analyses from four studies showed that higher NLR predicted mortality (HR = 1.16; 95% CI 1.04, 1.29; I2 = 93.8%). Multivariable-adjusted analyses from six studies confirmed NLR as an independent predictor of poorer survival (HR = 1.13; 95% CI 1.06, 1.21; I2 = 86.5%), with heterogeneity modestly reduced after adjustment for age and sample size. Certainty of evidence for prognostic outcomes was rated low to moderate. Associations between higher NLR and age at onset, sex, and classical ALS phenotype were inconsistent. NLR correlated with inflammatory markers and gut microbiota features, supporting a potential mechanistic link between systemic inflammation and ALS disease progression. Elevated NLR is associated with ALS diagnosis and poorer prognosis, including faster disease progression and reduced survival. Despite heterogeneity and potential bias, NLR appears to be a readily accessible biomarker for disease monitoring and risk stratification in ALS, warranting validation in large, longitudinal studies.