Contribution of new and chronic cortical lesions to disability accrual in multiple sclerosis
Authors: Beck Erin S , Mullins W Andrew , dos Santos Silva Jonadab , Filippini Stefano , Parvathaneni Prasanna , Maranzano Josefina , Morrison Mark , Suto Daniel J , Donnay Corinne , Dieckhaus Henry , Luciano Nicholas J , Sharma Kanika , Gaitán María Ines , Liu Jiaen , de Zwart Jacco A , van Gelderen Peter , Cortese Irene , Narayanan Sridar , Duyn Jeff H , Nair Govind , Sati Pascal , Reich Daniel S 
Published: April 2024

Abstract
Cortical lesions are common in multiple sclerosis and are associated with disability and progressive disease. We asked whether cortical lesions continue to form in people with stable white matter lesions and whether the association of cortical lesions with worsening disability relates to pre-existing or new cortical lesions.
Fifty adults with multiple sclerosis and no new white matter lesions in the year prior to enrolment (33 relapsing-remitting and 17 progressive) and a comparison group of nine adults who had formed at least one new white matter lesion in the year prior to enrolment (active relapsing-remitting) were evaluated annually with 7 tesla (T) brain MRI and 3T brain and spine MRI for 2 years, with clinical assessments for 3 years. Cortical lesions and paramagnetic rim lesions were identified on 7T images.
Seven total cortical lesions formed in 3/30 individuals in the stable relapsing-remitting group (median 0, range 0–5), four total cortical lesions formed in 4/17 individuals in the progressive group (median 0, range 0–1), and 16 cortical lesions formed in 5/9 individuals in the active relapsing-remitting group (median 1, range 0–10, stable relapsing-remitting versus progressive versus active relapsing-remitting P = 0.006). New cortical lesions were not associated with greater change in any individual disability measure or in a composite measure of disability worsening (worsening Expanded Disability Status Scale or 9-hole peg test or 25-foot timed walk). Individuals with at least three paramagnetic rim lesions had a greater increase in cortical lesion volume over time (median 16 µl, range −61 to 215 versus median 1 µl, range −24 to 184, P = 0.007), but change in lesion volume was not associated with disability change. Baseline cortical lesion volume was higher in people with worsening disability (median 1010 µl, range 13–9888 versus median 267 µl, range 0–3539, P = 0.001, adjusted for age and sex) and in individuals with relapsing-remitting multiple sclerosis who subsequently transitioned to secondary progressive multiple sclerosis (median 2183 µl, range 270–9888 versus median 321 µl, range 0–6392 in those who remained relapsing-remitting, P = 0.01, adjusted for age and sex). Baseline white matter lesion volume was not associated with worsening disability or transition from relapsing-remitting to secondary progressive multiple sclerosis.
Cortical lesion formation is rare in people with stable white matter lesions, even in those with worsening disability. Cortical but not white matter lesion burden predicts disability worsening, suggesting that disability progression is related to long-term effects of cortical lesions that form early in the disease, rather than to ongoing cortical lesion formation.