Workup for Suspected Multiple Sclerosis
Brain MRI with gadolinium is the single most important diagnostic test and should be performed immediately in all patients with suspected MS, using a standardized protocol that includes axial T1-weighted sequences, axial T2-weighted and proton-density sequences, and sagittal T2-FLAIR sequences. 1, 2
Initial Clinical Assessment
Obtain objective neurological examination findings—historical symptoms alone are insufficient for diagnosis. 3 Focus specifically on:
- Prior episodes of optic neuritis, sensory disturbances, motor weakness, brainstem symptoms (particularly internuclear ophthalmoplegia), or myelopathy 4
- An "attack" must last at least 24 hours with objective clinical findings, not just subjective symptoms 5
- Separate attacks must be separated by at least 30 days from onset to onset 3
Critical caveat: Patients with persistent neurologic symptoms but normal examinations, normal brain MRI, and normal CSF do not develop MS—costly serial investigations should be avoided in this scenario. 6
MRI Protocol Requirements
Brain MRI (Mandatory for All Patients)
Use minimum 1.5T field strength with maximum 3mm slice thickness and 1×1mm in-plane spatial resolution. 5 Required sequences include:
- Axial T2-weighted and proton-density (or T2-FLAIR) sequences 5
- Sagittal T2-FLAIR to evaluate corpus callosum 5
- Gadolinium-enhanced T1-weighted sequences 5
Look for lesions in at least 2 of 5 CNS locations to establish dissemination in space (DIS): 3, 5
- Periventricular (at least 3 lesions required) 5
- Cortical/juxtacortical 5
- Infratentorial 5
- Spinal cord 5
- Optic nerve 5
Key imaging characteristics that confirm MS lesions: 5
- Lesions affecting inferior corpus callosum asymmetrically 5
- Perivenular orientation (central vein sign)—highly specific for MS 5
- Ovoid lesions 7
Spinal Cord MRI (Mandatory in Specific Situations)
Spinal cord MRI is mandatory in patients with spinal cord symptoms at disease onset, primarily to exclude non-demyelinating pathology. 1 It is also indicated when:
- Brain MRI results are equivocal or show only 1-2 lesions 1
- Clinical presentation is atypical 2
- Patient is older with vascular risk factors 5
Even without spinal symptoms, consider spinal cord MRI as 30-40% of clinically isolated syndrome patients have asymptomatic cord lesions. 2, 3
Required spinal cord sequences: 2
- Sagittal dual-echo sequences 2
- Sagittal STIR sequences 2
- Contrast-enhanced T1-weighted spin-echo sequences 2
Establishing Dissemination in Time (DIT)
DIT can be demonstrated on a single MRI by the presence of simultaneous gadolinium-enhancing and non-enhancing lesions. 3, 5 Alternatively:
- New T2 or gadolinium-enhancing lesions on follow-up MRI performed ≥3 months after baseline 5
- A second clinical attack 3
If baseline MRI shows lesions but doesn't fulfill DIS/DIT criteria, repeat brain MRI at 3-6 months; if inconclusive, obtain a third scan at 6-12 months. 5
Cerebrospinal Fluid Analysis
CSF examination is indicated when: 3, 5
- Imaging criteria are not fully satisfied 3
- Clinical presentation is atypical 3
- Patient is older (>50 years) or has vascular risk factors 5
- To exclude alternative diagnoses 2
Positive CSF findings include: 5
- Oligoclonal IgG bands detected by isoelectric focusing (different from serum bands) 5
- Elevated IgG index 2, 5
- Albumino-cytological dissociation 2
- Lymphocytic pleocytosis <50/mm³ 5
Important: CSF quality varies between laboratories—ensure state-of-the-art technology is used to avoid misdiagnosis. 5
Additional Diagnostic Tests
Visual Evoked Potentials (VEP)
VEP provides objective evidence of a second lesion when only one clinical lesion is apparent, particularly useful in older patients with vascular risk factors or when MRI abnormalities are few. 5, 4
Blood Tests (To Exclude MS Mimics)
Obtain the following based on clinical context: 3, 5
- Complete blood count and comprehensive metabolic panel 3
- Anti-aquaporin-4 (AQP4-IgG) antibodies to exclude neuromyelitis optica spectrum disorder 5
- Antiphospholipid antibodies, lupus serologies 5
- HTLV-1, Lyme serology, syphilis testing (based on epidemiology) 5
Applying the 2017 McDonald Criteria
Two or More Attacks + Two or More Objective Lesions
No additional tests required for MS diagnosis, though MRI/CSF would typically be abnormal if performed. 5
Two or More Attacks + One Objective Lesion
Demonstrate DIS through MRI criteria or positive CSF. 5
One Attack + Two or More Objective Lesions
Demonstrate DIT through MRI showing simultaneous enhancing and non-enhancing lesions, new lesions on follow-up MRI, or a second clinical attack. 5
One Attack + One Objective Lesion
Demonstrate both DIS and DIT. 5
Primary Progressive MS (Insidious Neurological Progression)
Requires stringent criteria: 5
- Abnormal CSF with evidence of inflammation 5
- Demonstration of DIS using MRI criteria 5
- Demonstration of DIT through continued progression for 1 year or new MRI lesions 5
Critical Differential Diagnoses to Exclude
Always exclude neuromyelitis optica spectrum disorder (NMOSD) by checking AQP4-IgG antibodies—NMOSD shows longitudinally extensive transverse myelitis and different brain lesion patterns. 5
Other important mimics include: 5
- Vascular disorders (phospholipid antibody syndrome, lupus, CADASIL) 5
- Infections (HTLV-1, Lyme disease, syphilis) 5
- Paraneoplastic disorders 5
- Monophasic demyelinating diseases (acute disseminated encephalomyelitis) 5
- Genetic disorders of myelin (leukodystrophies in children/teenagers) 5
Red Flags Suggesting Non-MS Diagnosis
Exercise extreme caution if: 5
- Patient is younger than 10 or older than 59 years 5
- Progressive onset without relapses 5
- Unusual presentations (dementia, epilepsy, aphasia) 5
- Bilateral sudden hearing loss 5
- Isolated cranial nerve involvement (rare in MS at 10.4%; isolated eighth nerve palsy <1%) 5
- Persistent gadolinium enhancement >3 months 7
- Lesions with mass effect 7
- Meningeal enhancement 7
Common Diagnostic Pitfalls
Never diagnose MS on MRI alone—MRI lesions are pathologically nonspecific and must be interpreted in the appropriate clinical context. 5, 7, 8
Misinterpreting MRI in patients with few lesions carries high risk of misdiagnosis—evaluate both individual lesion characteristics and overall lesion patterns. 5
In patients over age 50 with vascular risk factors, require more stringent criteria including a higher number of periventricular lesions to distinguish from age-related white matter changes. 5
For children under 11 years, require at least one T1 hypointense lesion and at least one periventricular lesion to distinguish MS from monophasic demyelination. 3, 5
If tests (MRI, CSF) are negative or atypical, exercise extreme caution before making an MS diagnosis—alternative diagnoses must be thoroughly excluded. 5