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. 2025 Apr 8;104(7):e210274.
doi: 10.1212/WNL.0000000000210274. Epub 2025 Mar 4.

Investigating Whether Dissemination in Time Is Essential to Diagnose Relapsing Multiple Sclerosis

Wallace J Brownlee  1   2 , Michael A Foster  1 , Giuseppe Pontillo  1   3 , Indran Davagnanam  4 , Sara Collorone  1 , Ferran Prados  1   5   6 , Baris Kanber  1   5 , Frederik Barkhof  1   2   3   5 , Alan J Thompson  1 , Ahmed T Toosy  1 , Olga Ciccarelli  1
Affiliations

Investigating Whether Dissemination in Time Is Essential to Diagnose Relapsing Multiple Sclerosis

Wallace J Brownlee et al. Neurology. .

Abstract

Background and objectives: The diagnosis of multiple sclerosis (MS) requires evidence of both dissemination in space (DIS) and time (DIT); oligoclonal bands (OCBs) in the CSF can substitute for DIT on MRI. We investigated whether DIT (or positive CSF) is necessary to make a diagnosis of MS in patients who fulfil a high number of DIS criteria.

Methods: We prospectively recruited patients with a first demyelinating event evaluated with brain and spinal cord MRI within 3 months of onset. The patients were followed up clinically and with MRI. We retrospectively applied DIS criteria requiring lesions in ≥2/4, ≥3/4, or 4/4 regions typically affected in MS (periventricular, cortical/juxtacortical, infratentorial, spinal cord) and ≥2/5, ≥3/5, ≥4/5, and 5/5 regions (including the optic nerve) to baseline assessments. We investigated the performance of each set of DIS criteria for a diagnosis of MS using the 2017 McDonald criteria, requiring both DIS (lesions in ≥2/4 regions) plus DIT on MRI (gadolinium-enhancing and nonenhancing lesions, new T2 lesions at follow-up) or CSF-specific OCBs, as the gold standard.

Results: We included 244 patients (mean age 32.5 years, 154 [63%] female); 187 (77%) patients were diagnosed with MS using the 2017 McDonald criteria over a mean follow-up of 11.2 years. DIS alone, requiring lesions in ≥2/4, ≥3/4, or 4/4 regions, exhibited reducing sensitivity (84%, 58%, and 26%, respectively) and increasing specificity (91%, 98%, 100%) for an MS diagnosis. In 112 (46%) patients with optic nerve assessment with orbital MRI or visual evoked potentials, DIS in ≥2/5, ≥3/5, ≥4/5, or 5/5 regions also resulted in reducing sensitivity (96%, 83%, 61%, 30%) and increasing specificity (44%, 83%, 100%, 100%) for MS diagnosis. We propose a diagnostic algorithm for MS in patients with a first demyelinating event based on the number of DIS regions fulfilled.

Discussion: In patients with a first demyelinating event, DIS in ≥4 regions typically affected in MS is highly specific, indicating an extremely low risk of false-positive results, and misdiagnosis. Using DIS in ≥4 regions would reduce the need for follow-up MRI or CSF examination in all patients with suspected MS, streamlining the diagnostic process. Limitations include an over-representation of patients with optic neuritis at onset, a low rate of CSF examination, and lack of optical coherence tomography data.

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Conflict of interest statement

W.J. Brownlee has received speaker honoraria and/or acted as a consultant for Biogen, Janssen, Merck, Novartis, Roche, Sanofi, Sandoz, and Viatris. M.A. Foster is supported by a grant from the MRC (MR/S026088/1) and has received speaker honoraria from Merck. G. Pontillo has received research grants from ECTRIMS (2022), MAGNIMS (2020), and ESNR (2021). I. Davagnanam has no relevant disclosures. S. Collorone is supported by the Rosetrees Trust (A1332 and MS632) and has received speaker honoraria from Merck. F. Prados is partially funded by the NIHR UCLH Biomedical Research Centre initiative, is guest editor of Neuroimage, and is a member of the editorial board of Discover Imaging. B. Kanber is supported by the NIHR Biomedical Research Centre at UCL and UCLH. F. Barkhhof acts as a member of the steering committee or Data Safety Monitoring Board for Biogen, Merck, ATRI/ACTC, and Prothena; is a consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, and Combinostics; has research agreements with Merck, Biogen, GE Healthcare, and Roche; and is cofounder and shareholder of Queen Square Analytics Ltd. A.J. Thompson receives an honorarium from SAGE Publishers as editor-in-chief of Multiple Sclerosis Journal; has received support from UCL/UCLH NIHR Biomedical Research Centre; and acted as co-chair at UCL-Eisai Steering Committee drug discovery collaboration (fees paid to the institution). A.T. Toosy has received speaker honoraria from Merck, Biomedia, Sereno Symposia International Foundation, Bayer, and At the Limits, and meeting expenses from Merck, Biogen Idec, and Novartis; was the UK PI for 2 clinical trials sponsored by MEDDAY pharmaceutical company (MD1003 in optic neuropathy [MS-ON: NCT02220244] and progressive MS [MS-SPI2: NCT02936037]); has been supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837), and RoseTrees Trust (A1332 and PGL21/10079); is an associate editor for Frontiers in Neurology—Neuro-ophthalmology section; and is on the editorial board for Neurology® and Multiple Sclerosis Journal. O. Ciccarelli is NIHR Research Professor (RP-2017-08-ST2-004); over the last 2 years, member of independent DSMB for Novartis; gave a teaching talk in a Merck local symposium; contributed to an advisory board for Biogen; is deputy editor of Neurology®, for which she receives an honorarium; and has received research grant support from the MS Society of Great Britain and Northern Ireland, the NIHR UCLH Biomedical Research Centre, the Rosetree Trust, the National MS Society, and the NIHR-HTA. Go to Neurology.org/N for full disclosures.

Figures

Figure
Figure. Proposed Algorithm for MS Diagnosis in Patients With a First Demyelinating Event
DIT = dissemination in time; MS = multiple sclerosis; OCB = oligoclonal band.
See this image and copyright information in PMC

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