The Optic Nerve as a New Diagnostic Frontier in Multiple Sclerosis: How the 2024 McDonald Criteria Leverage Multimodal Evaluation for Earlier Diagnosis

The revised 2024 McDonald criteria recognize the optic nerve as a fifth topographical location for dissemination in space (DIS), raising critical questions regarding its diagnostic utility and technical requirements. To analyze this new inclusion, we provide a focused review and illustrate its clinical significance through a case series of three patients where optic nerve assessment was critical for diagnosis. We analyze the operationalization of key diagnostic tools, including optical coherence tomography (OCT) (defining retinal nerve fiber and ganglion cell layer thinning thresholds and inter-eye asymmetry, assessed outside acute neuritis), visual evoked potentials (VEPs) (P100 latency criteria), and 3T orbital magnetic resonance imaging (MRI) (using fat-suppressed T2/short-tau inversion recovery (STIR) and post-gadolinium sequences). Furthermore, we specify how dissemination in time (DIT) was met (presence of CSF-specific oligoclonal bands or new T2/gadolinium-enhancing lesions) and how key mimics (e.g., myelin oligodendrocyte glycoprotein antibody disease (MOGAD), neuromyelitis optica spectrum disorder (NMOSD), ischemic/hereditary neuropathies) were excluded via antibody testing and clinical/laboratory findings. The analysis suggests that the 2024 multiple sclerosis (MS) criteria, by recognizing the optic nerve, may enhance diagnostic sensitivity. In our cohort, multimodal optic nerve assessment was essential to meet DIS criteria, successfully expediting the MS diagnosis and treatment initiation. This multimodal approach also highlights the optic nerve's potential as a source for quantitative biomarkers and a target for future neuroprotective strategies. We conclude that including the optic nerve as a DIS site represents a major diagnostic advance. The presented cases underscore the practical application of the 2024 criteria, stressing the importance of comprehensive evaluation, but also highlighting the critical need for careful exclusion of mimics, vigilance to avoid overdiagnosis, and the necessity of standardized acquisition protocols and robust normative databases for generalizing this approach.