Revised McDonald Criteria for Multiple Sclerosis: A Big Step Toward Biomarker-Driven Diagnosis

The landscape of multiple sclerosis (MS) diagnosis has undergone its most profound shift in years with the publication of the 2024 revisions to the McDonald diagnostic criteria, moving the field closer to a unified, more biomarker-based approach. These updated criteria — developed by an international committee of experts, finalized in 2025 and formally published in recent weeks (Lancet Neurol.2025;24[10]:850-865) — aim to expedite the diagnosis of MS globally while rigorously maintaining diagnostic specificity.

The driver for this evolution is the success of modern disease-modifying therapies, according to Cleveland Clinic neurologist Daniel Ontaneda, MD, PhD, who served as a co-author of the revised criteria as part of the International Advisory Committee on Clinical Trials sponsored by the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) and the U.S. National Multiple Sclerosis Society (NMSS).

“If treatment, particularly highly effective treatment, is initiated early, patients with relapsing forms of MS can live normal lives and may not accumulate disability,” says Dr. Ontaneda, a staff physician with Cleveland Clinic’s Mellen Center for Multiple Sclerosis.

However, early intervention is frequently hampered by delays in diagnosis (averaging around two years from symptom onset) and significant levels of misdiagnosis. “Approximately 20% of people diagnosed with MS might actually have an incorrect diagnosis,” Dr. Ontaneda notes. “Fortunately, the 2024 McDonald criteria revisions introduce some powerful tools to address these challenges.” He recapped key updates for Consult QD, as outlined below.

Expanding dissemination in space: Optic nerve as a 5th location

The core structure of MS diagnosis still hinges on demonstrating dissemination in space (DIS) and dissemination in time (DIT). However, the 2024 criteria fundamentally change DIS by increasing the potential anatomical locations of lesions from four to five.

For the first time, the optic nerve is officially incorporated as an anatomical site to be used to satisfy DIS requirements. Optic nerve involvement is highly common in MS, presenting as the initial manifestation in about 25% of patients.

Inclusion of the optic nerve increases diagnostic sensitivity without significantly compromising specificity. Optic neuritis is common in MS and could be used under prior criteria, but now asymptomatic optic nerve involvement can also be used. Clinicians now can establish involvement of the optic nerve using several paraclinical tests:

• Optic nerve MRI — presence of a T2-weighted or enhancing short-segment unilateral optic nerve lesion on orbital MRI
• Optical coherence tomography (OCT) — evidence of unilateral optic nerve pathology can be demonstrated by inter-eye differences of the peripapillary retinal nerve fiber layer (≥ 6 µm) or the macular ganglion cell inner plexiform layer (≥ 4 µm)
• Visual evoked potentials (VEPs) — an abnormal VEP, defined as delayed latency or asymmetric inter-ocular latencies (2.5 standard deviations above the mean), supports demyelinating injury

DIS is now fulfilled when typical lesions are found in two of the five regions — optic nerve, intracortical/juxtacortical, periventricular, infratentorial brain, and spinal cord — whether or not these lesions are symptomatic.

Dissemination in time is no longer mandatory

The 2024 criteria mark a dramatic step away from mandatory demonstration of DIT, which was previously needed to distinguish MS from monophasic inflammatory syndromes.

In the setting of a typical attack or neurological progression (12 months or more), the diagnosis of MS can now be established without DIT if at least four of the five anatomical locations are affected by typical lesions.

New alternative to OCBs

One factor recognized as a substitute for DIT since the 2017 McDonald criteria is evidence of intrathecal antibody production, which now includes a new option: the kappa free-light chain (kFLC) index.

Cerebrospinal fluid (CSF) measurement of kFLCs and the kFLC index are now considered interchangeable with CSF-restricted oligoclonal bands (OCBs), which still remain in the criteria. This is an important step toward easier applicability, as kFLC measurement uses automated, cost-effective platforms, potentially making it accessible where traditional OCB testing is challenging.

Harnessing high-specificity imaging biomarkers

The new criteria officially incorporate two novel MRI features — the central vein sign (CVS) and the paramagnetic rim lesion (PRL) — for boosting diagnostic specificity, particularly when diagnostic certainty is low. “These can be critical in avoiding misdiagnosis,” says Dr. Ontaneda, who co-authored recommendations on MRI that were jointly published with the 2024 McDonald criteria revisions (Lancet Neurol.2025;24[10]:866-879).

Central vein sign

CVS detection confirms perivenular inflammatory demyelination, which is a pathological hallmark of MS lesions. Using susceptibility-based imaging sequences, the presence of CVS can differentiate MS lesions from lesions resulting from other conditions, such as vascular disease or migraine.

Development of this imaging tool stemmed from advances in MRI technology that enabled improved resolution, allowing for accurate visualization of these small central veins previously seen only in pathology reports. “CVS is an easy discriminator for clinicians to use,” Dr. Ontaneda notes. For diagnostic purposes, the “Select 6” method is recommended, requiring the presence of six or more white matter lesions to be CVS positive; alternately, if fewer than 10 white matter lesions are present in total, the majority must be CVS positive.

Paramagnetic rim lesions

PRLs identify chronic active MS lesions characterized by an inflammatory rim of iron-laden microglia. Like CVS, PRLs are highly specific to MS and are rarely found in MS mimics. PRLs can be viewed using the same susceptibility sequence as CVS.

The revised criteria state that if a patient presents with a typical clinical attack or progression of neurological disability and has lesions in only one anatomical location, MS can be diagnosed with the presence of one or more PRL in addition to DIT on MRI or positive CSF.

Dr. Ontaneda is particularly enthusiastic about PRLs, calling them a biomarker that “combines diagnosis and prognosis into one.” He explains that these lesions are very specific for MS and that studies indicate that having four or more PRLs substantially raises the likelihood of greater MS disability accumulation.

MS as a single disease, and diagnosis without symptoms

The 2024 revision mandates a single, unified diagnostic framework for relapsing-onset and progressive-onset MS, recognizing that the two forms share similar mechanisms and constitute a continuum. “There is just one remaining difference for primary progressive MS, where evidence of two or more spinal cord lesions is sufficient to fulfill DIS, recognizing the ability to diagnose MS without brain lesions,” Dr. Ontaneda notes.

One of the biggest changes is the formalized inclusion of radiologically isolated syndrome (RIS) and other nonspecific presentations within the MS diagnostic criteria. Patients with RIS — i.e., incidentally found to have MS-typical lesions on MRI without clinical symptoms — can now be diagnosed with MS if they satisfy specific criteria (e.g., DIS plus DIT, or DIS plus positive CSF, or DIS plus CVS positivity).

“Under certain circumstances,” Dr. Ontaneda explains, “you can actually make a diagnosis of MS in an asymptomatic individual and you can potentially start treatment.”

While acknowledging the critical need for early intervention, he notes that this change presents clinical challenges, particularly regarding drug approvals and patient counseling. “Making a diagnosis in an asymptomatic individual is something that may take some getting used to for many neurologists,” he says.

Considerations in older and pediatric patients

Recognizing that vascular risk factors and comorbidities increase the risk of misdiagnosis, especially in older patients, the new criteria provide specific recommendations:

• In individuals aged 50 years or older, or those with significant vascular risk factors (such as hypertension or diabetes), additional features are strongly recommended to confirm an MS diagnosis. These include a spinal cord lesion, positive CSF or CVS positivity. CVS is particularly helpful in this setting, as it can differentiate MS lesions from vascular lesions.
• For pediatric-onset MS, a unified framework with adult-onset MS is now applied, but differential diagnosis remains critical. In view of the prevalence of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) at younger ages, MOG-IgG testing with a cell-based assay is recommended in children younger than 12 years who have an incident CNS demyelinating event and also in those over 12 but under 18 if atypical features exist.

A fully biomarker-based future?

For Dr. Ontaneda, these revisions point to the future of MS diagnosis. “I imagine that we might ultimately be able to have a fully biomarker-based diagnosis of MS,” he says. “The example I think of is cardiologists, who don’t need to wait for a patient to develop symptoms of heart failure from mitral valve insufficiency, for instance. They can do an echocardiogram, find the pathology and make the diagnosis — no questions asked. That’s because they have very specific diagnostic testing. I think we’re heading in that direction with MS.”