Diagnostic pitfalls and complex cases in MS

Accurate diagnosis of multiple sclerosis (MS) remains a significant clinical challenge despite major advances in imaging, fluid biomarkers, and diagnostic criteria. Over the past decades, the diagnostic framework has shifted from a primarily clinical assessment to one increasingly grounded in biological and paraclinical evidence. The introduction of the 2024 McDonald criteria represents a notable evolution, incorporating novel biomarkers such as the central vein sign, paramagnetic rim lesions, and the kappa free light chain index, and expanding anatomical regions for dissemination in space. The new criteria also represent a paradigm shift away from dissemination in time and offer new options to confirm the diagnosis. These innovations aim to enhance diagnostic precision and allow earlier recognition of both relapsing and progressive MS. However, substantial pitfalls persist, especially in patients whose presentations diverge from classical MS patterns. In this review, we discuss a series of complex and illustrative cases that underscore the breadth of diagnostic uncertainty, including hereditary small-vessel disease mimicking demyelination, multifocal white matter lesions later identified as primary central nervous system lymphoma, fulminant demyelinating episodes, solitary progressive lesions consistent with solitary sclerosis, and progressive phenotypes newly classifiable under the 2024 McDonald criteria. Across these scenarios, atypical features (such as strong family history, tumor-like infiltration, or isolated lesions) emphasize the importance of maintaining a broad differential diagnosis and recognizing the many disorders capable of imitating MS on clinical, radiological, or pathological grounds. Collectively, these cases highlight the need for structured, multidisciplinary diagnostic strategy that combines clinical expertise with advanced imaging, cerebrospinal fluid biomarkers, and, when necessary, extended investigations including genetic testing or biopsy. While the 2024 McDonald criteria constitute a major advance, careful interpretation remains essential to avoid misdiagnosis. Understanding these pitfalls is crucial for improving diagnostic accuracy and ensuring timely initiation of appropriate therapy.