A Standardized Workflow for Multimodal Assessment of Right-to-Left Shunt-Related Ischemic Brain Injury

Right-to-left shunt (RLS) has been associated with cryptogenic stroke, migraine, and other neurological conditions in which ischemic brain injury may be clinically relevant. In routine practice, however, assessment is often fragmented. Shunt presence may be documented, but shunt burden, provoked versus non-provoked patterns, anatomical complexity, and MRI-defined brain injury are not always integrated into a reproducible workflow. Here, we describe a standardized protocol for multimodal assessment of RLS-related ischemic brain injury in a clinically selected cohort. The workflow includes patient screening, exclusion of major vascular and systemic factors that could independently contribute to brain parenchymal injury, contrast-enhanced transcranial Doppler ultrasound (c-TCD) confirmation and shunt grading, brain magnetic resonance imaging (MRI) classification, transthoracic and/or transesophageal echocardiographic anatomical assessment, structured data extraction, and dataset cleaning. To improve reproducibility, the protocol also standardizes key coding steps, including shunt-grade harmonization, classification of RLS as simple or complex, and interpretation of D-dimer values reported below the assay threshold. Using this workflow, a harmonized analytic cohort of 60 RLS-positive patients was established. MRI identified 23 MRI-negative and 37 MRI-positive patients. Representative analyses showed that MRI-positive findings were more frequent in patients with greater shunt burden and more complex anatomical phenotypes. This protocol provides an operational model for incorporating c-TCD, MRI, echocardiography, and structured clinical parameters into the evaluation of MRI-defined ischemic brain injury in RLS-positive patients. It should be interpreted as a workflow for standardized multimodal phenotyping rather than as a standalone physiologic assessment of all clinically significant or hypoxemia-related RLS.