MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation and application of MRI diagnostic criteria contribute to misdiagnosis. Some diseases, now recognized as conditions distinct from multiple sclerosis, may satisfy the MRI criteria for multiple sclerosis (e.g. neuromyelitis optica spectrum disorders, Susac syndrome), thus making the diagnosis of multiple sclerosis more challenging, especially if biomarker testing (such as serum anti-AQP4 antibodies) is not informative. Improvements in MRI technology contribute and promise to better define the typical features of multiple sclerosis lesions (e.g. juxtacortical and periventricular location, cortical involvement). Greater understanding of some key aspects of multiple sclerosis pathobiology has allowed the identification of characteristics more specific to multiple sclerosis (e.g. central vein sign, subpial demyelination and lesional rims), which are not included in the current multiple sclerosis diagnostic criteria. In this review, we provide the clinicians and researchers with a practical guide to enhance the proper recognition of multiple sclerosis lesions, including a thorough definition and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses. We also discuss the possible place of emerging qualitative features of lesions which may become important in the near future.

Recent evidence has shown the existence of a CNS ‘waste clearance’ system, defined as the glymphatic system. Glymphatic abnormalities have been described in several neurodegenerative conditions, including Alzheimer’s and Parkinson’s disease. Glymphatic function has not been thoroughly explored in multiple sclerosis, where neurodegenerative processes are intermingled with inflammatory processes.We aimed to investigate glymphatic system function in multiple sclerosis and to evaluate its association with clinical disability, disease course, demyelination and neurodegeneration, quantified using different MRI techniques.In this retrospective study, we enrolled 71 multiple sclerosis patients (49 relapsing-remitting and 22 progressive multiple sclerosis) and 32 age- and sex-matched healthy control subjects. All subjects underwent neurological and MRI assessment including high-resolution T1, T2 and double inversion recovery sequences, diffusion and susceptibility weighted imaging. We calculated the diffusion along perivascular space index, a proxy for glymphatic function, cortical and deep grey matter volume, white and cortical grey matter lesion volume and normal-appearing white matter microstructural damage.Multiple sclerosis patients showed an overall lower diffusion along perivascular space index versus healthy controls (estimated mean difference: −0.09, P = 0.01). Both relapsing-remitting and progressive multiple sclerosis patients had lower diffusion along perivascular space index versus healthy controls (estimated mean difference: −0.06, P = 0.04 for relapsing-remitting and −0.19, P = 0.001 for progressive multiple sclerosis patients). Progressive multiple sclerosis patients showed lower diffusion along perivascular space index versus relapsing-remitting multiple sclerosis patients (estimated mean difference: −0.09, P = 0.03). In multiple sclerosis patients, lower diffusion along perivascular space index was associated with more severe clinical disability (r = −0.45, P = 0.001) and longer disease duration (r = −0.37, P = 0.002). Interestingly, we detected a negative association between diffusion along perivascular space index and disease duration in the first 4.13 years of the disease course (r = −0.38, P = 0.04) without any association thereafter (up to 34 years of disease duration). Lower diffusion along perivascular space index was associated with higher white (r = −0.36, P = 0.003) and cortical (r = −0.41, P = 0.001) lesion volume, more severe cortical (r = 0.30, P = 0.007) and deep (r = 0.42, P = 0.001) grey matter atrophy, reduced fractional anisotropy (r = 0.42, P = 0.001) and increased mean diffusivity (r = −0.45, P = 0.001) in the normal-appearing white matter.Our results suggest that the glymphatic system is impaired in multiple sclerosis, especially in progressive stages. Impaired glymphatic function was associated with measures of both demyelination and neurodegeneration and reflects a more severe clinical disability. These findings suggest that glymphatic impairment may be a pathological mechanism underpinning multiple sclerosis. The dynamic interplay with other pathological substrates of the disease deserves further investigation.

Objectives: To assess the value of conventional and magnetization transfer (MT) MRI measures of white matter (WM) and gray matter (GM) damage, and their 12-month change, in predicting long-term disability and cognitive impairment in multiple sclerosis (MS). Methods: Conventional and MT MRI brain scans were obtained at baseline and at 12 months in 73 patients, who were followed prospectively with clinical visits and rating of the Expanded Disability Status Scale score and the MS severity score (MSSS) for a median period of 13.3 years. At 13-year follow-up, a neuropsychological assessment was also performed when possible. T2-hyperintense and T1-hypointense lesion volumes, GM fraction (GMF), WM fraction, thalamic fraction, average lesion MT ratio (MTR), average GM MTR, average normal-appearing WM MTR, and thalamic MTR were measured. Random forest and multivariable analyses were performed to identify the predictors of neurologic deterioration and cognitive impairment at 13 years. Results: At 13-year follow-up, 66% of patients showed significant worsening of disability and 37% had worsened cognitively. The multivariable model, in which Expanded Disability Status Scale deterioration at final follow-up was the dependent variable, identified baseline GMF (odds ratio [OR] = 0.79, p = 0.01) as the only predictor of worsening of disability (C-index = 0.69). Baseline disease duration (OR = 1.50, p = 0.08) and average GM MTR (OR = 0.87, p = 0.03) were independent variables associated with cognitive deterioration (C-index = 0.97). Baseline MSSS (β = 0.50, p < 0.0001) and baseline GMF (β = −0.32, p = 0.0005) predicted MSSS at follow-up (r² = 0.45). Conclusions: GM damage is one of the key factors associated with long-term accumulation of disability and cognitive impairment in MS.