What are the diagnostic criteria and treatment options for a patient presenting with symptoms suggestive of multiple sclerosis (MS)?

Multiple Sclerosis Diagnosis

Core Diagnostic Principle

MS diagnosis requires demonstrating inflammatory-demyelinating CNS injury disseminated in both space (DIS) and time (DIT), with no better alternative explanation for the clinical presentation. 1

Diagnostic Criteria by Clinical Presentation

Two or More Attacks with Objective Evidence of Two or More Lesions

• No additional testing required for MS diagnosis - clinical evidence alone is sufficient 1
• MRI, CSF, or evoked potentials would typically be abnormal if performed, but are not necessary 2

Two or More Attacks with Objective Evidence of One Lesion

• Requires demonstration of dissemination in space 1
• Achieve DIS through MRI criteria (see below) OR positive CSF analysis combined with at least two brain lesions consistent with MS 2

One Attack with Objective Evidence of Two or More Lesions

• Requires demonstration of dissemination in time 1
• DIT can be shown by: simultaneous gadolinium-enhancing and non-enhancing lesions on any MRI, OR new T2 lesion on follow-up MRI performed ≥3 months after clinical event, OR a second clinical attack 1

One Attack with Objective Evidence of One Lesion (Clinically Isolated Syndrome)

• Requires demonstration of both DIS and DIT 1
• This is the most common diagnostic challenge - typically monosymptomatic presentations like optic neuritis, myelitis, or brainstem syndrome 2
• Apply both MRI criteria for space and time as outlined below 1

Insidious Neurological Progression (Primary Progressive MS)

• Requires positive CSF (essential for this presentation) plus demonstration of DIS and either DIT or continued progression for one year 2, 1
• This presentation requires the most stringent criteria due to absence of discrete relapses 2

MRI Criteria for Dissemination

Dissemination in Space (2016 MAGNIMS/Current Criteria)

Requires lesions in at least 2 of 5 CNS locations: 1

• Periventricular (≥3 lesions required)
• Cortical/juxtacortical (combined into single category)
• Infratentorial (≥1 lesion)
• Spinal cord (≥1 lesion)
• Optic nerve (now counts as additional CNS area)

Key update: No distinction is made between symptomatic and asymptomatic lesions for DIS - both count equally 2, 1

Dissemination in Time

Can be demonstrated by: 1

• Simultaneous presence of gadolinium-enhancing AND non-enhancing lesions on any single MRI (not at site of original clinical event), OR
• New T2 lesion on follow-up MRI compared to baseline scan performed ≥3 months after clinical event, OR
• Second clinical attack

Critical timing consideration: Minimum 3-month interval between clinical event and follow-up MRI reduces risk of misdiagnosing acute disseminated encephalomyelitis 2

Spinal Cord Imaging

• Whole spinal cord imaging is recommended to meet DIS criteria, particularly in patients with non-spinal symptoms not fulfilling brain MRI criteria for DIS 2
• Use at least two MR sequences (T2 and STIR, T2 and DIR, or T2 and post-contrast T1) to increase lesion detection confidence 2
• Approximately 40% of spinal cord lesions occur in thoracolumbar region, necessitating complete cord imaging 2
• Limited role for DIT assessment, as new clinically silent cord lesions are infrequent 2

CSF Analysis

When to Obtain CSF

• Particularly helpful when: imaging criteria fall short, clinical presentation is atypical, or in older patients where MRI findings may lack specificity 1
• Essential for primary progressive MS diagnosis 2

Positive CSF Criteria

Defined as: 1

• Oligoclonal IgG bands (detected by isoelectric focusing) present in CSF but not in serum, OR
• Elevated IgG index
• Lymphocytic pleocytosis should be <50/mm³ 1

Critical caveat: Quality of CSF analysis varies significantly between laboratories - ensure state-of-the-art technology (isoelectric focusing) to avoid misdiagnosis 1

Visual Evoked Potentials

• Abnormal VEP (delayed response with preserved waveform) can provide objective evidence of a second lesion 2
• Particularly useful when only one clinical lesion is apparent and did not affect visual pathways 1
• Most helpful in older patients with vascular risk factors where MRI specificity may be reduced 1

Diagnostic Outcomes

• Criteria fulfilled: Diagnosis is MS 1
• Criteria not completely met: Diagnosis is "possible MS" 1
• Criteria fully explored and not met: Diagnosis is "not MS" 1

Critical Differential Diagnoses to Exclude

High-Priority Mimics

Vascular disorders: 1

• Cerebral ischemia/infarction in young adults (antiphospholipid antibody syndrome, lupus, CADASIL)
• Consider testing: antiphospholipid antibodies, lupus serologies based on clinical context

Infections: 1

• HTLV-1, Lyme disease, syphilis
• Test based on geographic exposure and clinical presentation

Other inflammatory conditions: 1

• Neuromyelitis optica (NMO) - critical to distinguish due to different treatment
• Acute disseminated encephalomyelitis (ADEM) - typically monophasic
• Paraneoplastic disorders

Genetic disorders: 1

• Leukodystrophies in children and teenagers
• Consider genetic testing in appropriate age groups

High-Risk Situations Requiring Extra Caution

Exercise extreme caution when: 1

• Patient age <10 or >59 years (higher risk of alternative diagnoses)
• Progressive onset without relapses
• Unusual presentations: dementia, epilepsy, aphasia
• MRI or CSF tests are negative or atypical for MS 2

If tests are atypical, there must be no better explanation than MS before making the diagnosis 2

Common Diagnostic Pitfalls

Patients with Symptoms but No Objective Findings

• Persistent neurologic symptoms with normal examination, normal MRI, and normal CSF do not lead to MS development 3
• In a 4.4-year follow-up study of 143 such patients, none developed MS 3
• Costly serial investigations should be avoided in patients with persistently normal examinations 3

Quality Control Issues

• Poor quality MRI, CSF analysis, or evoked potentials can lead to misdiagnosis 1
• Ensure state-of-the-art technology for all paraclinical testing 1

Timing Errors

• Insufficient interval between clinical event and follow-up MRI (<3 months) risks misdiagnosing ADEM 2
• Careful documentation of timing between clinical events and imaging is crucial 1

Treatment Considerations

Nine classes of disease-modifying therapies are FDA-approved for relapsing forms of MS (including clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease): 4, 5

• Interferons (including interferon beta-1a)
• Glatiramer acetate
• Teriflunomide
• Sphingosine 1-phosphate receptor modulators
• Fumarates
• Cladribine
• Three types of monoclonal antibodies

Efficacy: These DMTs reduce annualized relapse rates by 29-68% compared with placebo or active comparators 5

For primary progressive MS: Ocrelizumab is the approved disease-modifying therapy 5