Residency · Residency · Neurology

Multiple Sclerosis: Diagnosis and the 2017 McDonald Criteria

Overview

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system and the most common non-traumatic cause of disability in young adults. Its prevalence is approximately 1 million in the United States, with higher rates in temperate latitudes. Peak onset occurs between ages 20 and 40 with a female predominance of approximately 3:1. The pathology involves perivenular inflammatory demyelination with axonal injury, gliosis, and neurodegeneration. The disease course is relapsing-remitting in 85-90% of patients at onset, with primary progressive disease accounting for the remaining 10-15%.

Clinical Presentations (Common Attack Phenotypes)

Optic Neuritis

Optic neuritis presents with unilateral eye pain worsened by eye movement accompanied by subacute visual loss. Examination reveals a relative afferent pupillary defect (RAPD/Marcus Gunn pupil), a central scotoma or diffuse visual field loss, and color desaturation (especially red). It may be the presenting event of MS as a clinically isolated syndrome (CIS). MRI of the orbit with contrast demonstrates enhancement and swelling of the optic nerve.

Transverse Myelitis

Partial transverse myelitis in the MS pattern presents as an asymmetric, incomplete cord syndrome typically spanning fewer than 2 vertebral segments (short segment) with dorsal and lateral cord predilection. The Lhermitte sign is an electric shock-like sensation down the spine with neck flexion. The Uhthoff phenomenon refers to worsening of neurological symptoms with heat or exercise.

Brainstem/Cerebellar Syndromes

Internuclear ophthalmoplegia (INO) manifests as impaired adduction with contralateral abducting nystagmus; bilateral INO in a young adult is highly suggestive of MS. Other presentations include trigeminal neuralgia in a young patient, vertigo, diplopia, facial numbness, cerebellar ataxia, and dysarthria.

Cerebral Hemispheric

Hemispheric involvement produces sensory symptoms (paresthesias, numbness), motor weakness in a pyramidal pattern, and cognitive impairment affecting processing speed and executive function.

2017 McDonald Criteria

Core Concept: Dissemination in Space (DIS) and Dissemination in Time (DIT)

The MS diagnosis requires evidence that lesions are disseminated in space (involving at least 2 of 4 characteristic CNS regions) and disseminated in time (occurring at different time points).

DIS -- MRI Criteria (at least 1 T2 lesion in at least 2 of 4 regions)

The four regions include periventricular (at least 3 periventricular lesions), cortical/juxtacortical (lesions at the cortical-white matter junction or purely cortical), infratentorial (brainstem or cerebellar lesions), and spinal cord (typically short-segment, peripheral, dorsolateral cord lesions).

DIT -- Can Be Demonstrated By

DIT can be established by the simultaneous presence of gadolinium-enhancing and non-enhancing lesions on a single MRI (indicating lesions of different ages), by a new T2 or enhancing lesion on follow-up MRI compared to a baseline scan (regardless of timing), or by a second clinical attack.

Key 2017 Updates

CSF oligoclonal bands (OCBs) can now substitute for DIT in patients with DIS and a single clinical attack (CIS). If OCBs are present in CSF but not serum, the diagnosis of MS can be made without waiting for a second attack or follow-up MRI. This was a major change that allows earlier diagnosis and treatment. Cortical lesions (not just juxtacortical) can contribute to DIS. The criteria apply to both RRMS and PPMS with modifications for the latter.

Diagnosis of PPMS (2017 McDonald)

PPMS requires at least 1 year of clinical progression plus at least 2 of 3 supporting criteria: DIS in the brain (one or more T2 lesions in periventricular, cortical/juxtacortical, or infratentorial regions), DIS in the spinal cord (two or more T2 spinal cord lesions), or positive CSF OCBs.

<image>Flowchart of the 2017 McDonald criteria for MS diagnosis showing the pathways for DIS and DIT demonstration including the role of CSF oligoclonal bands</image>

MRI in MS

Characteristic Lesion Features

MS lesions appear as T2/FLAIR hyperintense lesions in white matter. Periventricular lesions oriented perpendicular to the ventricles form the characteristic "Dawson fingers" pattern, reflecting perivenular inflammation. Lesions typically have an ovoid morphology. Gadolinium enhancement indicates active blood-brain barrier breakdown and typically lasts 2-8 weeks. T1 "black holes" are chronic hypointense lesions representing axonal loss and gliosis.

Spinal Cord MRI

MS spinal cord lesions are characteristically short-segment (fewer than 2 vertebral segments), peripheral, and dorsolateral in location, with partial cord cross-section involvement. It is important to distinguish these from NMOSD lesions, which are long, central cord lesions spanning 3 or more segments.

Emerging MRI Biomarkers

The central vein sign (CVS) reflects the perivenular location of MS lesions visible on T2-weighted or FLAIR sequences and has high specificity for MS versus other white matter diseases; 40% or more of lesions showing CVS strongly supports MS. Paramagnetic rim lesions (PRL) represent chronic active ("smoldering") lesions with iron-laden microglia at the lesion edge, visible on phase/susceptibility-weighted imaging and associated with progressive tissue damage. Cortical lesion detection has improved with 3T and 7T MRI using double inversion recovery (DIR) and phase-sensitive inversion recovery (PSIR) sequences. Brain atrophy measured as accelerated brain volume loss (greater than 0.4% per year) reflects neurodegeneration and is increasingly used as a treatment outcome measure.

<image>Brain MRI showing characteristic MS findings including periventricular Dawson fingers on FLAIR, gadolinium-enhancing lesions on T1 post-contrast, T1 black holes, and the central vein sign on T2*-weighted imaging</image>

CSF Analysis

Oligoclonal bands (OCBs) are present in 95% or more of MS patients and must be present in CSF and absent in serum (type 2 pattern). They are highly sensitive but not specific, as they also occur in NMOSD, neurosarcoidosis, and CNS infections. The IgG index is elevated (above 0.7) in MS, reflecting intrathecal IgG synthesis. Cell count shows mild lymphocytic pleocytosis (fewer than 50 cells per microliter); if above 50, alternative diagnoses should be considered. Kappa free light chains are emerging as a potentially more sensitive and cheaper alternative to OCBs.

Differential Diagnosis

Neuromyelitis optica spectrum disorder (NMOSD) is characterized by AQP4 antibodies, longitudinally extensive transverse myelitis, often severe or bilateral optic neuritis, and area postrema syndrome. MOG antibody-associated disease (MOGAD) presents with bilateral optic neuritis, longitudinal myelitis, and cortical encephalitis with positive MOG-IgG. Neurosarcoidosis shows leptomeningeal enhancement, cranial neuropathies (especially CN VII), and hypothalamic involvement. CNS vasculitis produces multifocal lesions that are often cortical or subcortical, accompanied by headache and encephalopathy. Susac syndrome presents with encephalopathy, branch retinal artery occlusion, and sensorineural hearing loss, with corpus callosum "snowball" lesions. Migraine and small vessel disease produce periventricular and deep white matter lesions without enhancement, cord lesions, or OCBs. CADASIL produces anterior temporal pole and external capsule white matter lesions due to NOTCH3 mutations. Vitamin B12 deficiency myelopathy produces posterior column involvement.

Clinically Isolated Syndrome (CIS)

CIS refers to the first clinical episode suggestive of MS, such as optic neuritis, partial myelitis, or a brainstem syndrome. If McDonald criteria for DIS plus DIT are met, the diagnosis is MS rather than CIS. If only DIS is met without DIT and OCBs are present, the diagnosis can be upgraded to MS under the 2017 criteria. If criteria are not met, the designation remains CIS with follow-up serial MRI. Evidence supports early DMT initiation even at the CIS stage if the risk for MS is high, as demonstrated by the BENEFIT and TOPIC trials.

Radiologically Isolated Syndrome (RIS)

RIS describes incidental MRI findings meeting MS imaging criteria in a patient without clinical symptoms. Approximately 30-45% of these patients convert to clinically definite MS within 5-10 years. Risk factors for conversion include young age, male sex, spinal cord lesions, and CSF OCBs. The ARISE trial (2024) showed that teriflunomide reduced the risk of a first clinical event, supporting treatment consideration in high-risk RIS.

<image>Spinal cord MRI comparison showing short-segment peripheral dorsolateral MS lesion versus long-segment central NMOSD lesion spanning three or more vertebral segments</image>

Clinical Pearls

Bilateral INO in a young adult is MS until proven otherwise. CSF OCBs now allow MS diagnosis at the time of a single clinical attack (with DIS criteria met), eliminating the need to wait for a second event in many cases. The central vein sign (40% or more of lesions with a central vein) can help distinguish MS from its mimics, especially in patients with comorbid vascular risk factors or migraine. MS lesions spare the U-fibers (subcortical arcuate fibers); lesions that predominantly involve U-fibers suggest a different diagnosis such as ADEM or vasculitis. A "tumefactive" MS lesion (greater than 2 cm with mass effect, incomplete ring enhancement, and leading edge of demyelination) can mimic a brain tumor and may require biopsy. In patients over 50 presenting with a first demyelinating event, alternative diagnoses should be considered more seriously because MS is rare as a new diagnosis in this age group. The Lhermitte sign is suggestive of MS but not specific, as it also occurs in cervical spondylotic myelopathy, B12 deficiency, and radiation myelopathy. Both brain and spinal cord MRI should always be ordered in the evaluation of suspected MS, as cord lesions contribute to DIS and help distinguish MS from migraine or vascular white matter disease.

References

• 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.
• Filippi M, Bar-Or A, Bhatt DL, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43.
• Sati P, Oh J, Constable RT, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nat Rev Neurol. 2016;12(12):714-722.
• Lebrun-Frenay C, Kantarci OH, Siva A, et al. Teriflunomide for radiologically isolated syndrome (ARISE). N Engl J Med. 2024;391:1893-1905.
• Solomon AJ, Naismith RT, Cross AH. Misdiagnosis of multiple sclerosis: impact of the 2017 McDonald criteria on clinical practice. Neurology. 2019;92(1):26-33.

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