What is the appropriate workup and treatment approach for a patient presenting with new onset symptoms suggestive of multiple sclerosis (MS)?

New Onset Multiple Sclerosis Workup

For a patient with new onset symptoms suggestive of MS, immediately obtain brain and spinal cord MRI with gadolinium and refer to a neurologist experienced in MS diagnosis—MRI is the most sensitive and specific test, and diagnosis requires objective clinical evidence of CNS lesions disseminated in space and time with no better alternative explanation. 1

Initial Clinical Assessment

Obtain objective neurological findings—symptoms alone are insufficient for diagnosis. 1, 2 Focus your history on:

• Unilateral optic neuritis (painful vision loss with color vision impairment developing over days) 3, 4
• Partial myelitis (incomplete transverse myelitis with sensory level, weakness, or bladder dysfunction) 3
• Brainstem syndromes (diplopia, internuclear ophthalmoplegia) 3, 4
• Sensory disturbances or motor weakness 4
• Prior episodes separated by at least 30 days from onset to onset 1

An "attack" must last at least 24 hours with objective clinical findings, not just subjective symptoms. 1 Multiple paroxysmal episodes occurring over 24 hours count as one attack. 1

Essential Diagnostic Testing

MRI Protocol (First-Line Test)

Obtain brain and spinal cord MRI with gadolinium using at least 1.5T field strength, 3mm maximum slice thickness, completed in 25-30 minutes. 1 Required sequences include:

• Axial T2-weighted and T2-FLAIR 1
• Sagittal T2-FLAIR (to evaluate corpus callosum) 1
• Gadolinium-enhanced T1-weighted sequences 1

MRI Diagnostic Criteria

Dissemination in space (DIS) requires lesions in ≥2 of 5 CNS locations: 1

• Periventricular (≥3 lesions required) 1
• Cortical/juxtacortical 1
• Infratentorial 1
• Spinal cord 1
• Optic nerve 1

Dissemination in time (DIT) is demonstrated by: 1

• Simultaneous gadolinium-enhancing and non-enhancing lesions, OR 1
• New T2 lesions or gadolinium-enhancing lesions on follow-up MRI ≥3 months after baseline 1

Critical imaging characteristics confirming MS lesions include periventricular location affecting the inferior corpus callosum asymmetrically and perivenular orientation (central vein sign), which is highly specific for MS. 1

CSF Analysis (When Indicated)

Obtain lumbar puncture for CSF analysis in atypical presentations, progressive onset, when imaging criteria fall short, or in patients >50 years where MRI findings may lack specificity. 1, 2

Positive CSF is defined as: 1

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

Visual Evoked Potentials

Consider VEP when MRI abnormalities are few (especially in primary progressive MS with myelopathy), in older patients with vascular risk factors, or when only one clinical lesion is apparent and you need objective evidence of a second lesion. 1, 2

Diagnostic Algorithm by Clinical Scenario

Two or more attacks + objective evidence of ≥2 lesions: No additional tests required for MS diagnosis (though MRI/CSF would typically be abnormal if performed). 1

Two or more attacks + objective evidence of 1 lesion: Demonstrate DIS through MRI criteria or positive CSF. 1

One attack + objective evidence of ≥2 lesions: Demonstrate DIT through MRI showing simultaneous enhancing and non-enhancing lesions, new lesions on follow-up MRI, or a second clinical attack. 1

One attack + objective evidence of 1 lesion: Demonstrate both DIS and DIT using MRI criteria. 1

Insidious neurological progression (primary progressive MS): Requires abnormal CSF with evidence of inflammation, demonstration of DIS using MRI criteria, and demonstration of DIT through continued progression for 1 year or new MRI lesions. 1, 3

Critical Differential Diagnoses to Exclude

You cannot diagnose MS if there is a better explanation for the clinical and paraclinical abnormalities. 5, 2 Exclude:

• Neuromyelitis optica spectrum disorder (NMOSD): Check AQP4-IgG antibodies; NMOSD shows longitudinally extensive transverse myelitis (≥3 contiguous segments) and different brain lesion patterns 5
• MOG-antibody disease 1
• Cerebrovascular disease: Consider in patients with vascular risk factors, especially phospholipid antibody syndrome, lupus, CADASIL 1, 2
• CNS infections: HTLV-1, Lyme disease, syphilis, HIV 1, 2, 6
• Vitamin B12 deficiency 6
• Sarcoidosis, systemic lupus erythematosus, Sjögren's syndrome 6
• Spinal cord compression 6
• Leukodystrophies (in children and teenagers) 1

Consider antiphospholipid antibodies, lupus serologies, HTLV-1, Lyme serology, and syphilis testing based on clinical context. 1

Red Flags Suggesting Non-MS Diagnosis

Immediately reconsider the diagnosis if you encounter: 1, 2

• Bilateral sudden hearing loss 2
• Sudden onset focal neurologic symptoms (suggesting stroke) 2
• Isolated cranial nerve involvement (rare in MS at 10.4%; isolated eighth nerve palsy <1%) 1
• Gaze-evoked or downbeat nystagmus 1
• Concurrent severe bilateral vestibular loss 1

Age-Specific Considerations

Diagnostic criteria apply best to individuals aged 10-59 years. 1, 2

For patients <11 years: Require at least one T1 hypointense lesion ("black hole") and at least one periventricular lesion to distinguish MS from monophasic demyelination. 1, 3

For patients >50 years or with vascular risk factors: Apply more stringent criteria with a higher number of periventricular lesions to distinguish from age-related white matter changes. 1

Follow-Up Imaging Strategy

If baseline MRI shows lesions but doesn't fulfill DIS/DIT criteria, repeat brain MRI at 3-6 months. 1 If the second scan is inconclusive, obtain a third scan at 6-12 months. 1

Critical Diagnostic Pitfalls to Avoid

Never diagnose MS on MRI alone—at least one clinical event consistent with acute demyelination is mandatory. 5, 3

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

Ensure state-of-the-art technology for MRI, CSF analysis, and evoked potentials, as poor quality leads to misdiagnosis. 1

If tests are negative or atypical, exercise extreme caution before making an MS diagnosis. 1

Diagnostic Outcomes

If criteria are fulfilled: Diagnosis is MS 1

If criteria are not completely met: Diagnosis is "possible MS" 1

If criteria are fully explored and not met: Diagnosis is "not MS" 1

Specialist Referral

Diagnosis should be made by a neurologist experienced in MS, its differential diagnoses, and interpretation of paraclinical assessments. 2 Neurology consultation is essential for definitive diagnosis and treatment initiation. 2