What are the pathophysiology and investigations for diagnosing multiple sclerosis?

Pathophysiology and Investigations for Multiple Sclerosis

Pathophysiology

Multiple sclerosis is a chronic autoimmune demyelinating disease of the central nervous system characterized by inflammatory lesions, demyelination, axonal loss, and gliosis in the brain and spinal cord. 1 The disease process involves inflammatory-demyelinating injury that becomes disseminated across both time and space within the CNS 2, 3. The causative lesions are inflammatory and demyelinating in nature, resulting in the characteristic neurological disturbances seen clinically 4.

Core Diagnostic Principle

The diagnosis requires objective evidence of CNS lesions disseminated in both space and time, with exclusion of alternative explanations. 4, 5 Historical symptoms alone are insufficient—objective clinical signs are mandatory 4. The diagnosis integrates clinical presentation with paraclinical testing, primarily MRI, with CSF analysis and evoked potentials serving supportive roles 5.

Investigations: Algorithmic Approach

Primary Investigation: MRI

MRI is the most sensitive and specific paraclinical test for MS diagnosis and should be the first-line investigation. 4, 5

Dissemination in Space (DIS) Criteria:

Lesions must be present in at least 2 of 4 locations 5:

• Periventricular (≥3 lesions)
• Cortical/juxtacortical (≥1 lesion)
• Infratentorial (≥1 lesion)
• Spinal cord (≥1 lesion)

Alternatively, DIS can be demonstrated by: one gadolinium-enhancing lesion OR nine T2-hyperintense lesions if no enhancement is present 2.

Dissemination in Time (DIT) Criteria:

DIT is established by either 5, 2:

• Simultaneous presence of gadolinium-enhancing AND non-enhancing lesions on a single MRI
• New T2 or gadolinium-enhancing lesion on follow-up MRI (≥3 months after initial clinical event) compared to baseline

Secondary Investigation: CSF Analysis

CSF analysis provides evidence of inflammation and immunological disturbance, particularly valuable when imaging is atypical or insufficient. 4, 5

Positive CSF Criteria 2:

• Oligoclonal IgG bands (detected by isoelectric focusing) present in CSF but absent in serum
• Elevated IgG index
• Lymphocytic pleocytosis (<50 cells/mm³)

Critical caveat: CSF quality varies significantly between laboratories—ensure state-of-the-art technology is used to avoid misdiagnosis 2. CSF is especially helpful in older patients where MRI findings may lack specificity due to microvascular disease 4, 2.

Tertiary Investigation: Visual Evoked Potentials (VEP)

VEPs showing delayed conduction with preserved waveform provide additional diagnostic support. 4, 5

VEPs are particularly useful when 4, 2:

• MRI abnormalities are few (e.g., primary progressive MS with myelopathy)
• MRI findings have reduced specificity (older patients with vascular risk factors)
• Objective evidence of a second lesion is needed when the clinically expressed lesion did not affect visual pathways

Other evoked potentials contribute little to MS diagnosis. 4

Clinical Criteria Integration

Two or More Attacks + Two or More Objective Lesions:

No additional testing required for diagnosis 2

Two or More Attacks + One Objective Lesion:

Requires MRI or CSF demonstration of dissemination in space 2

One Attack + Two or More Objective Lesions:

Requires MRI demonstration of dissemination in time OR a second clinical attack 2

One Attack + One Objective Lesion:

Requires demonstration of both dissemination in space AND time 2

Insidious Progressive Course:

Requires dissemination in space and time OR continued progression for one year 2

Critical Definitions

An "attack" must last ≥24 hours and represent true neurological dysfunction, not pseudoattacks from fever or infection 5, 6. Single paroxysmal episodes (e.g., one tonic spasm) do not constitute relapse, but multiple episodes over ≥24 hours do 4, 5.

Separate attacks must be ≥30 days apart (measured from onset to onset) 4, 5, 6.

Diagnostic Outcomes

• MS: Criteria fully met 2
• Possible MS: Criteria partially met or evaluation incomplete 4, 2
• Not MS: Criteria explored and not met 2

The outdated terms "clinically definite," "laboratory-supported," "clinically probable," and "laboratory-supported probable MS" are no longer used. 4, 5

Critical Pitfalls to Avoid

Always exclude alternative diagnoses before confirming MS—if MRI or CSF are negative or atypical, exercise extreme caution. 2 Key mimics include 2:

• Cerebral ischemia/infarction (phospholipid antibody syndrome, lupus, CADASIL)
• Infections (HTLV1, Lyme disease)
• Neuromyelitis optica spectrum disorder
• Acute disseminated encephalomyelitis
• Paraneoplastic disorders
• Leukodystrophies (in children/teenagers)

Exercise special caution in 2:

• Patients <10 or >59 years old
• Progressive onset without relapses
• Atypical presentations (dementia, epilepsy, aphasia) 5
• Older individuals where MRI findings may reflect microvascular disease 5, 2

Biopsy is rarely needed but can confirm inflammatory demyelination; however, it cannot alone establish MS diagnosis 5, 2.