How to diagnose multiple sclerosis (MS) in a young to middle-aged adult presenting with optic neuritis, sensory disturbances, motor weakness, or balance and gait dysfunction?

Diagnosing Multiple Sclerosis

Diagnose MS by demonstrating inflammatory-demyelinating CNS lesions disseminated in both space and time using the McDonald criteria, which integrate clinical attacks with MRI findings and CSF analysis, while systematically excluding alternative diagnoses. 1

Core Diagnostic Framework

The diagnosis requires three fundamental elements: 1

• Evidence of CNS lesions separated in space (multiple anatomic locations)
• Evidence of CNS lesions separated in time (occurring at different time points)
• No better explanation for the clinical presentation

Obtain objective clinical evidence through neurological examination—symptoms alone are insufficient for diagnosis. 1 Focus your history on prior episodes of optic neuritis, sensory disturbances, motor weakness, brainstem symptoms (internuclear ophthalmoplegia), or myelopathy. 1, 2

Diagnostic Algorithm by Clinical Scenario

Two or More Attacks + Two or More Objective Lesions

No additional testing required for diagnosis, though MRI, CSF, or other tests would typically be abnormal if performed. 1 This represents the most straightforward diagnostic scenario.

Two or More Attacks + One Objective Lesion

Demonstrate dissemination in space through: 1

• MRI criteria (see below), OR
• Positive CSF (oligoclonal IgG bands by isoelectric focusing different from serum, or elevated IgG index) 1

One Attack + Two or More Objective Lesions

Demonstrate dissemination in time through: 1

• MRI showing simultaneous gadolinium-enhancing and non-enhancing lesions, OR
• New T2 lesions or gadolinium-enhancing lesions on follow-up MRI ≥3 months after baseline, OR
• A second clinical attack 1

One Attack + One Objective Lesion

Demonstrate both dissemination in space AND time using the criteria above. 1 This requires the most comprehensive workup.

Progressive Onset (Primary Progressive MS)

Requires stringent criteria: 1

• Abnormal CSF with evidence of inflammation
• Demonstration of dissemination in space using MRI criteria
• Demonstration of dissemination in time through continued progression for 1 year OR new MRI lesions 1

MRI Diagnostic Criteria

Brain and spinal cord MRI with gadolinium is the most sensitive and specific test for MS diagnosis. 1 Use minimum technical requirements of 1.5T field strength, maximum 3mm slice thickness, and 1×1mm in-plane spatial resolution. 1

Dissemination in Space (DIS)

Requires lesions in ≥2 of 5 CNS locations: 1

• Periventricular (at least 3 lesions required)
• Cortical/juxtacortical (combined category)
• Infratentorial
• Spinal cord
• Optic nerve 1

Critical lesion characteristics that confirm MS: 1

• Perivenular orientation (highly specific for MS)
• Lesions affecting inferior corpus callosum asymmetrically
• Sharp edges, ovoid shape
• Orientation perpendicular to ventricles 1, 3

Dissemination in Time (DIT)

Demonstrated by: 1

• Simultaneous presence of gadolinium-enhancing AND non-enhancing lesions (not at site of original event), OR
• New T2 lesions on follow-up scan ≥3 months after baseline 1

No distinction is made between symptomatic and asymptomatic MRI lesions for both DIS and DIT. 1

CSF Analysis

Perform lumbar puncture in atypical presentations, progressive onset, or when diagnosis is uncertain. 4 CSF is particularly helpful when imaging criteria fall short or in older patients where MRI findings may lack specificity. 1

Positive CSF defined as: 1

• Oligoclonal IgG bands by isoelectric focusing (different from serum bands), OR
• Elevated IgG index
• Lymphocytic pleocytosis should be <50/mm³ 1

Ensure state-of-the-art laboratory technology—quality varies between laboratories and poor testing can lead to misdiagnosis. 1

Visual Evoked Potentials (VEP)

Consider VEP when MRI abnormalities are few or have lesser specificity, particularly in: 1

• Primary progressive MS with progressive myelopathy
• Older patients with vascular risk factors
• When the only clinically expressed lesion did not affect visual pathways 1

VEP provides objective evidence of a second lesion when only one clinical lesion is apparent. 1, 4

Defining an "Attack"

An attack must: 1

• Last at least 24 hours
• Represent objective clinical findings, not just subjective symptoms
• Multiple paroxysmal episodes occurring over 24 hours count as one attack

Separate attacks must be separated by at least 30 days from onset to onset. 1

Critical Differential Diagnoses to Exclude

Always exclude alternative diagnoses—if tests are negative or atypical, extreme caution is required before diagnosing MS. 1

High-Priority Mimics to Rule Out

Neuromyelitis optica spectrum disorder (NMOSD): 1

• Check AQP4-IgG antibodies
• Look for longitudinally extensive transverse myelitis
• Different brain lesion patterns than MS

Cerebrovascular disease in young adults: 1

• Antiphospholipid antibody syndrome
• Lupus (check ANA, lupus serologies)
• CADASIL

Infectious diseases: 1

• HTLV-1
• Lyme disease (Lyme serology)
• Syphilis testing

MOG-antibody disease: 1

• Check MOG antibodies
• Distinct from MS and NMOSD

Paraneoplastic disorders: 1

• Consider in atypical presentations

Monophasic demyelinating diseases: 1

• Acute disseminated encephalomyelitis (ADEM)
• Devic's syndrome

Special Populations Requiring Extra Caution

Apply more stringent diagnostic criteria in: 1, 4

• Patients younger than 10 years (consider leukodystrophies; require ≥1 T1 hypointense lesion and ≥1 periventricular lesion to distinguish from monophasic demyelination) 1
• Patients older than 59 years or with vascular risk factors (require higher number of periventricular lesions to distinguish from age-related white matter changes) 1
• Progressive onset from the beginning
• Unusual presentations: dementia, epilepsy, aphasia 1, 3

Red Flags Suggesting Non-MS Diagnosis

Be highly suspicious of alternative diagnoses with: 1, 4

• Bilateral sudden hearing loss
• Sudden onset of focal neurologic symptoms (headache, confusion, diplopia, dysarthria, focal weakness)
• Gaze-evoked or downbeat nystagmus
• Concurrent severe bilateral vestibular loss
• Isolated cranial nerve involvement (rare in MS at 10.4%; isolated eighth nerve palsy <1%) 1

Follow-Up Imaging Strategy

If baseline MRI shows lesions but doesn't fulfill DIS/DIT criteria: 1

• Repeat brain MRI at 3-6 months
• If second scan is inconclusive, obtain third scan at 6-12 months 1

Diagnostic Outcomes

Based on criteria fulfillment: 1

• Criteria fulfilled: Diagnosis is MS
• Criteria not completely met: Diagnosis is "possible MS"
• Criteria fully explored and not met: Diagnosis is "not MS"

Critical Pitfalls to Avoid

Never diagnose MS on MRI alone—at least one clinical event consistent with acute demyelination is mandatory. 4 Confirm lesions on multiple planes for quality control. 1

Misinterpreting MRI in patients with few lesions carries high risk of misdiagnosis—evaluate both individual lesion characteristics and overall lesion patterns. 1

A positive test for a putative MS mimic does not automatically exclude MS—some patients may have both conditions. 5

Diagnosis should be made by a specialist familiar with MS, its differential diagnoses, and interpretation of paraclinical assessments. 4 Neurology consultation is essential for definitive diagnosis and treatment initiation. 4