Diagnosis of Multiple Sclerosis & 2024 McDonald Criteria
The diagnosis of multiple sclerosis (MS) is built on the hallmark principles of dissemination in space (DIS) and dissemination in time (DIT), demonstrated through clinical features, MRI, and CSF studies. Diagnostic criteria have evolved substantially over the past two decades, culminating in the 2024 McDonald criteria, which introduce a unified diagnostic framework for relapsing and progressive MS, incorporate the optic nerve as a fifth anatomical location, and integrate novel biomarkers including the central vein sign (CVS), paramagnetic rim lesions (PRLs), and kappa free-light chains (kFLC).
Bottom Line
- 2024 McDonald criteria provide a unified approach for diagnosing MS across relapsing and progressive courses and the entire lifespan (pediatric through late-onset)
- Five anatomical locations: The optic nerve joins periventricular, cortical/juxtacortical, infratentorial, and spinal cord regions for DIS
- DIT is no longer mandatory: DIS plus positive CSF (oligoclonal bands or kFLC index) is now sufficient; DIS in ≥4 of 5 locations is also sufficient
- Central vein sign (select 6 method) and paramagnetic rim lesions (≥1 PRL) can be used to diagnose MS in specific situations
- kFLC index is interchangeable with oligoclonal bands as evidence of intrathecal antibody production
- RIS can now fulfill MS criteria when positive CSF, or CVS positivity is demonstrated
- Misdiagnosis remains a significant issue (estimated 10–15%), even at specialty centers
Evolution of the McDonald Criteria
Before paraclinical tests, MS diagnosis required purely clinical demonstration of DIS and DIT (Poser criteria). The McDonald criteria (2001) incorporated MRI for the first time. Subsequent revisions have progressively simplified and improved sensitivity while balancing specificity:
| Revision | Key Changes |
|---|---|
| 2001 | First incorporation of MRI criteria for DIS and DIT |
| 2005 | Refined MRI criteria |
| 2010 | Defined 4 anatomical locations (periventricular, juxtacortical, infratentorial, spinal cord); DIT shown by simultaneous enhancing and non-enhancing lesions |
| 2017 | Added cortical lesions for DIS; symptomatic lesions can count; CSF oligoclonal bands can substitute for DIT |
| 2024 | Optic nerve as 5th location; DIT no longer mandatory; CVS, PRLs, kFLC index incorporated; RIS can fulfill MS criteria; unified relapsing/progressive framework; pediatric/adult unified criteria |
Typical Clinical Presentations
Features suggestive of a first clinical relapse of MS include symptoms lasting a minimum of 24 hours, often persisting for days to weeks:
- Optic neuritis — unilateral visual changes with eye pain (~25% of initial MS presentations)
- Partial myelopathy — unilateral sensory or motor symptoms, with or without bladder/bowel dysfunction
- Infratentorial symptoms — diplopia (INO, sixth nerve palsy), cerebellar ataxia, nystagmus, vertigo
- Sensory symptoms in a CNS pattern, Lhermitte sign
- Facial sensory loss or trigeminal neuralgia (in a young adult <40 years)
- Asymmetric limb weakness
Fatigue, cognitive dysfunction, and mood symptoms commonly accompany MS relapses but in isolation cannot be classified as a typical relapse. The concept of a "cognitive relapse" is gaining recognition but does not yet qualify as a typical presenting symptom.
Red Flags Suggesting Alternative Diagnoses
Clinical Red Flags
Atypical Presentations That Should Raise Concern
- Bilateral optic neuritis or unilateral optic neuritis with poor visual recovery
- Complete gaze palsy or fluctuating ophthalmoparesis
- Intractable nausea, vomiting, or hiccups (consider NMOSD)
- Complete transverse myelopathy with bilateral motor and sensory involvement
- Encephalopathy or subacute cognitive decline
- Headache or meningism
- Isolated fatigue or asthenia
- Constitutional symptoms
- Symptoms lasting <24 hours
MRI Red Flags (MIMICS Mnemonic)
| Letter | Red Flag MRI Features |
|---|---|
| M | Meningeal enhancement |
| I | Indistinct lesions; increasing lesions |
| M | Macrobleeds; microbleeds |
| I | Infarcts |
| C | Cavities; complete ring enhancement |
| S | Symmetric lesions; sparing of U fibers; siderosis; longitudinally extensive spinal cord lesions (≥3 segments) |
CSF Red Flags
- Absence of CSF-specific oligoclonal bands (present in ~90% of MS patients)
- Significant pleocytosis (>50 cells/mm3)
- Significantly elevated CSF protein (>100 mg/dL)
- Atypical cells (neutrophils, eosinophils)
2024 McDonald Criteria: Major Revisions
1. Optic Nerve as a Fifth Anatomical Location
Approximately 25% of MS patients present with optic neuritis as the initial manifestation, and most patients exhibit optic nerve involvement at autopsy. The optic nerve now serves as a fifth DIS location, assessable by:
Methods for Demonstrating Optic Nerve Involvement
- OCT: Inter-eye difference in peripapillary RNFL ≥6 μm or macular GCIPL ≥4 μm (with no better explanation, after rigorous quality control)
- VEP: Delayed latency or asymmetric inter-ocular latencies ≥2.5 SD above the mean (center-specific cutoffs required)
- MRI: One or more intrinsic optic nerve lesions (optic nerve MRI with fat saturation) without prominent chiasmal involvement, perineuritis, or longitudinally extensive lesion
2. Dissemination in Space (2024 Criteria)
DIS is fulfilled when two of five anatomical locations (optic nerve, intracortical/juxtacortical, periventricular, infratentorial, spinal cord) show typical lesions, regardless of whether they are symptomatic.
Key additional pathways to diagnosis:
- DIS + DIT: Sufficient for MS diagnosis (as in 2017)
- DIS + positive CSF (oligoclonal bands or kFLC index): Sufficient for MS diagnosis
- Typical lesions in ≥4 of 5 anatomical locations: Sufficient for MS diagnosis (no DIT or CSF required)
- Lesions in 1 location + select 6 CVS or ≥1 PRL + DIT or positive CSF: Sufficient for diagnosis
3. DIT is No Longer Mandatory
DIT was originally incorporated to differentiate MS from monophasic conditions (ADEM, isolated optic neuritis, isolated myelitis). However, most patients with CIS and typical MRI lesions develop clinical or radiological DIT over time, and other diseases can also exhibit DIT. The 2017 criteria already allowed CSF oligoclonal bands as a substitute for DIT. The 2024 criteria go further — DIT is now not essential but still increases specificity when demonstrated.
| Scenario | Requirements for MS Diagnosis (2024) |
|---|---|
| Typical attack + lesions in ≥2 CNS locations | DIT or positive CSF or select 6 CVS or lesions in ≥4 locations |
| Typical attack + lesions in 1 CNS location | (DIT or positive CSF) plus (select 6 CVS or ≥1 PRL) |
| Progressive course ≥12 months + lesions in ≥2 CNS sites (or ≥2 spinal cord lesions) | DIT or positive CSF or select 6 CVS or lesions in ≥4 locations |
| Progressive course + lesions in 1 CNS site | (DIT or positive CSF) plus (select 6 CVS or ≥1 PRL) |
| RIS with DIS | DIT or positive CSF or select 6 CVS |
4. Central Vein Sign (CVS)
MS plaques characteristically form around venules. CVS detection on susceptibility-based MRI (T2*-weighted or susceptibility-weighted imaging) can increase diagnostic specificity, particularly in differentiating MS from vascular or migraine-related white matter lesions. CVS is not mandatory for diagnosis but can be diagnostic in specific situations.
- Select 6 method: Positive when ≥6 white matter lesions show a central vein; if fewer than 10 white matter lesions are present, CVS-positive lesions should outnumber CVS-negative ones
- CVS prevalence is highest in periventricular (up to 94%) and deep white matter (up to 84%) lesions
- Detection rates: 3T MRI (74–79%) > 1.5T (56–58%); 7T achieves 79–82%
- CVS can discriminate 87% of misdiagnosed MS patients
5. Paramagnetic Rim Lesions (PRLs)
PRLs represent chronic active lesions characterized by an inactive core surrounded by activated iron-laden microglia, detectable on susceptibility-sensitive MRI sequences. They are present even at the earliest stages of MS and rarely found in other MS mimics.
- Composite specificity for MS diagnosis: 98%
- Sensitivity: 10–92% (varies by study)
- Detectable at 3T and 1.5T with appropriate sequences (inter-rater agreement 90–97% at experienced centers)
- One or more PRLs + DIT or positive CSF is sufficient for diagnosis when only one anatomical location is affected
6. Kappa Free-Light Chain (kFLC) Index
The kFLC index is now interchangeable with oligoclonal bands for demonstrating intrathecal antibody production. The kFLC index offers several advantages:
- Measurable by nephelometry/turbidimetry (widely available, cost-effective, rater-independent)
- Concordance with oligoclonal bands: approximately 87% in CIS and 90% in PPMS
- Limitations: can be elevated in NMOSD and MOGAD, though typically with lower values
7. Radiologically Isolated Syndrome (RIS)
RIS — incidental discovery of typical MS-appearing white matter lesions without clinical symptoms — is now formally included in the diagnostic framework. Approximately 51% of individuals with RIS develop clinical symptoms within 10 years.
RIS can fulfill MS criteria when DIS is demonstrated plus any of:
- DIT on MRI
- Positive CSF (oligoclonal bands or kFLC index)
- Select 6 CVS positivity
8. Unified Framework for Relapsing and Progressive MS
Pathological and imaging studies show quantitative — not qualitative — differences between relapsing-onset and progressive-onset MS, supporting a disease continuum. The 2024 criteria apply a single diagnostic framework to both. For progressive-onset MS:
- Clinical progression extending at least 12 months is required
- Two or more spinal cord lesions can serve as evidence of DIS (substituting for a second brain anatomical location)
- Cautious interpretation of isolated spinal cord and CSF findings is encouraged in progressive presentations
9. Pediatric-Onset MS
A single criteria framework applies to both pediatric and adult-onset MS. Key pediatric-specific considerations:
- MOG-IgG testing (cell-based assay) is strongly recommended in all children <12 years with incident CNS demyelination
- MOG-IgG testing is recommended in patients ≥12 years with presentations not specific to MS or suggestive of MOGAD
- In children/adolescents, CVS in >50% of T2 lesions (rather than select 6) strongly supports MS diagnosis
- Criteria should NOT be applied to ADEM presentations; a second attack consistent with typical MS or new T2 lesions >90 days post-ADEM onset is required first
10. Older Patients and Comorbidities
Diagnosis in Patients ≥50 Years or With Vascular Risk Factors
- MS is more likely to be misdiagnosed in patients presenting at age ≥50
- Small vessel ischemic disease, migraine, psychiatric disorders, and some autoimmune diseases increase misdiagnosis risk
- Periventricular lesions are not specific to MS and can be seen in small-vessel ischemia, migraine, infection, and metabolic disorders
- Additional features strongly recommended to confirm diagnosis: a spinal cord lesion, CSF positivity (oligoclonal bands or kFLC index), and/or CVS positivity
Primary Progressive MS Diagnosis
PPMS diagnosis requires:
- One year of disability progression (retrospectively or prospectively determined), independent of clinical relapse
- Plus the DIS criteria described above (unified with relapsing MS framework)
- Two or more spinal cord lesions fulfill DIS for progressive MS
PPMS can be challenging to diagnose early due to subtle symptom onset, subjective perception of progression, and confounders like deconditioning, fatigue, and mood disorders. Diagnosis is often delayed by many years.
Laboratory Workup for Atypical Presentations
| Atypical Presentation | Investigations to Consider |
|---|---|
| Bilateral or severe optic neuritis | AQP4-Ab, MOG-Ab, vitamin B12, copper, infectious screen, autoimmune screen, genetic tests (LHON), OCT |
| Complete gaze palsy | Chest imaging/PET, malignancy screen, autoimmune/infectious screen, vascular and neuromuscular workup |
| Intractable nausea/vomiting/hiccups | AQP4-Ab, MOG-Ab |
| Complete transverse myelopathy | AQP4-Ab, MOG-Ab, autoimmune screen, ACE, infectious screen, spinal MRA/DSA, toxic/metabolic screen |
| Encephalopathy, cognitive decline, meningism | Infectious screen, malignancy screen, autoimmune/vasculitis screen, toxic/metabolic screen, paraneoplastic panel |
Summary: 2024 vs 2017 McDonald Criteria
| Feature | 2017 Criteria | 2024 Criteria |
|---|---|---|
| Anatomical locations for DIS | 4 (periventricular, cortical/juxtacortical, infratentorial, spinal cord) | 5 (adds optic nerve) |
| DIT requirement | Required (OCBs can substitute) | Not mandatory in specific situations |
| Central vein sign | Not included | Select 6 CVS can be diagnostic |
| Paramagnetic rim lesions | Not included | ≥1 PRL can be diagnostic (with DIT or CSF) |
| kFLC index | Not included | Interchangeable with oligoclonal bands |
| RIS | Not part of MS criteria | Can fulfill MS criteria |
| Relapsing vs progressive | Separate diagnostic criteria | Unified framework |
| Pediatric MS | Caution advised; separate considerations | Single framework; MOG-IgG testing recommended |
| Older patients | No specific guidance | Additional confirmatory features recommended for ≥50 years or vascular risk factors |
References
- Montalban X, Lebrun-Frénay C, Oh J, et al. Diagnosis of multiple sclerosis: 2024 revisions of the McDonald criteria. Lancet Neurol. 2025;24:850-865.
- Thompson AJ, Banwell BL, Barkhof F, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018;17(2):162-173.
- Oh J. Diagnosis of multiple sclerosis. Continuum (Minneap Minn). 2022;28(4):1006-1024.
- Brownlee WJ, Hardy TA, Fazekas F, Miller DH. Diagnosis of multiple sclerosis: progress and challenges. Lancet. 2017;389(10076):1336-1346.
- Geraldes R, Ciccarelli O, Barkhof F, et al. The current role of MRI in differentiating multiple sclerosis from its imaging mimics. Nat Rev Neurol. 2018;14(4):199-213.