Diagnostic Yield of Comprehensive Etiologic Evaluation in Young Adults with Ischemic Stroke: Toward a Phenotype-Driven Approach

Background/Objectives: Young-onset ischemic stroke shows substantial etiologic heterogeneity. However, the value and diagnostic yield of advanced cardiac and autoimmune evaluations in young adults remain uncertain. Methods: Patients aged 25–55 years admitted with acute ischemic stroke to King Fahd University Hospital in Saudi Arabia between January 2020 and December 2025 were included. Evaluation followed a multidisciplinary young-stroke pathway, incorporating neurovascular imaging, cardiac assessment, and targeted autoimmune and rheumatologic investigations. A Clinically Meaningful Diagnostic Yield (CMDY) was defined as a diagnostic finding that resulted in etiologic reclassification, management modification, or changes to secondary prevention strategy. Results: A total of 480 patients were included (median age, 40 years; 67.7% men). CMDY was observed in 200 (41.7%) patients. Among 79 patients initially classified as having embolic stroke of an undetermined source, 35 (44.3%) were assigned a determined etiologic mechanism following evaluation and follow-up. Patients with undetermined stroke etiology decreased from 16.5% after first-pass evaluation to 9.2% after diagnostic completion. Patent foramen ovale/atrial septal defect-associated stroke mechanisms were identified in 61 patients (12.7%), autoimmune/inflammatory stroke mechanisms in 26 patients (5.4%), and atrial fibrillation-related cardioembolic stroke in 18 patients (3.8%). Clinically relevant mechanisms were identified in 169 patients (35.2%) whose primary etiologic classification remained unchanged. Independent predictors of CMDY were hypertension, prior stroke or transient ischemic attack, multi-territory infarction, and cortical infarction. Conclusions: Etiologic evaluation yielded clinically meaningful findings in over two-fifths of young adults with ischemic stroke and influenced etiologic assessment, treatment, and secondary prevention. Diagnostic yield was greatest among patients with prior cerebrovascular events and cortical or multi-territory infarctions, supporting a selective, phenotype-driven approach that warrants prospective multicenter validation.