A fourth revision of the McDonald diagnostic criteria is currently underway to address some of the conceptual and practical difficulties in the diagnosis of multiple sclerosis, according to Dr. Jeffrey Cohen, Cleveland Clinic, Cleveland, Ohio. His remarks were made at the 43rd International Neuroscience Symposium of the Université de Montréal, held May 3-5, 2022, in Montreal.
The McDonald criteria were last revised in 2017. Key changes included allowing oligoclonal bands to substitute for MRI evidence of dissemination in time (DIT) in patients with clinically isolated syndrome (Thompson et al. Lancet Neurol 2018;17:162-173). Symptomatic lesions were also included to show dissemination in space (DIS) or DIT; and cortical lesions were added to demonstrate DIS.
While the McDonald criteria have allowed for earlier diagnosis, an ongoing concern is misdiagnosis, reported to be 17-19% at some U.S. centres and as high as 30% elsewhere (Kaisey et al. Mult Scler Relat Disord 2019;30:51-56. Yamout et al. Mult Scler Relat Disord 2017;18:85-89). Another area of criticism is the emphasis on the dissemination of CNS lesions rather than their pathology.
The proposed revisions will provide an update on the epidemiology of MS, with particular emphasis on under-represented populations in regions where MS is common. Also in review is the concept of MS phenotypes based on clinical course, formalized a quarter-century ago and now recognized as artificial distinctions, Dr. Cohen said (Lublin & Reingold. Neurology 1996;46:907-911). The underlying pathological processes of relapsing and progressive MS differ quantitatively but not qualitatively, he noted.
Two key MRI findings are expected to be added in the upcoming revision of the McDonald criteria.
Central vein sign (CVS) and/or paramagnetic rim lesions (PRL). The use of CVS as an MRI biomarker for MS diagnosis is being evaluated in the ongoing CAVS-MS study by the North American Imaging in MS (NAIMS) Cooperative (Ontaneda et al. Neuroimage Clin 2021;32:102834). A previous study reported that a 35% CVS proportion cut-off (3T MRI) yielded a high specificity (82.9%) and a moderate sensitivity (68.1%) in differentiating MS from other conditions (Sinnecker et al. JAMA Neurol 2019;76:1446-1456).
PRLs are lesions with a hypointense rim on susceptibility-weighted imaging. The rim is iron deposition at the lesion edge by macrophages/microglia and indicates chronic inflammatory demyelination (Kwong et al. PLoS One 2021;16:e0256845). PRLs are highly specific to MS and useful in the differential diagnosis (Maggi et al. Ann Neurol 2020;88:1034-1042). A recent report found that >1 PRL had high specificity and sensitivity (88%, 80%) for MS (Renner et al. ACTRIMS Forum 2022). The study also found that 29% of individuals with radiologically isolated syndrome (RIS) had PRLs versus 5% with other diagnoses.
Asymptomatic optic nerve lesions. The McDonald 2017 panel felt that there was insufficient evidence to use optic nerve lesions to show DIS in patients presenting with optic neuritis (Thompson 2017). However, a MAGNIMS-CMSC-NAIMS consensus paper subsequently suggested that optic nerve imaging may be useful in some circumstances (Wattjes et al. Lancet Neurol 2021;20:653-670).
While the focus has been on optic nerve lesions in patients with optic neuritis, the VWIMS study showed that one-half of RRMS without optic neuritis had asymptomatic optic nerve lesions on MRI (3D double inversion recovery sequence) (Davion et al. Neurology 2020;94:e2468-e2478). These asymptomatic lesions were associated with thinner inner retinal layers and lower contrast visual acuity.
A German study also reported that a diagnosis of MS was four-fold more likely in CIS patients with asymptomatic thinning of the ganglion cell and inner plexiform layer (GCIPL) and peripapillary retinal nerve fibre layer on optical coherence tomography (OCT) (Zimmermann et al. JAMA Neurol 2018;75:1071-1079).
While imaging biomarkers have seen progress, fluid biomarkers are not expected to be included in the McDonald criteria revisions. Neurofilament-light chain (NfL) level does not appear to be a useful diagnostic biomarker, Dr. Cohen said, although it may help in determining treatment response.