Multiple Sclerosis

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Introduction

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease characterized by distinct episodes of neurologic deficits. It is the most common demyelinating disorder, affecting 1:1000.

 

 

 

The Case of...

a simple case introducing clincial presentation and calling for a differential diagnosis. To get students thinking.

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Causes and Risk Factors

MS can occur at any age, though onset during childhood and over the age of 50 is relatively rare.

women are affected twice as often as men.

Genetic factors are linked to MS; the risk is 15x higher in people with first-degree relatives with MS, and even higher for monozygotic twins. Linkage has been established to the DR2 extended haplotype, though other loci can also be involved.

 

Environmental factors are also involved, though latitude effects appear to be linked primarily to genes.

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Pathophysiology

MS is characterized by multiple white matter lesions caused by an immune response against the myelin sheath. Current evidence suggests CD4+ Th1 cells react against myelin components and secrete cytokines such as IFN-γ that activates macrophages.

CD4+, CD8+ cells, and macrophages are all present, along with antibodies, though their role is less clear.

 

It is unclear how the autoimmune reaction begins, though microbial triggers and genetic factors are thought to play a role. Initially, there is relative preservation of axons with loss of oligodendrocytes. Over time, astrocytes become reactive and proliferate.

 

MS Plaques

While plaques can occur throughout the CNS, certain patterns are commonly observed. Plaques usually occur throughout CNS white matter, though can also be found on the brainstem surface and along the spinal cord.

They often present alongside the ventricles and can follow the course of paraventricular veins. They frequently develop in the optic nerves and chiasm, brain stem ascending and descending tracts, cerebellum, and spinal cord

Plaques can range in size from microscopic to involving large portions of the centrum semiovale.

At the microscopic level, plaques have sharply defined borders.

In active plaques, there is evidence of ongoing myelin breakdown, with many macrophages containing lipid-rich PAS-positive debris. Quiescent plaques have little to no myelin, few oligodendrocytes, an abundance of glial cells, and decreased axons number.

 

In shadow plaques, there is a blurring between healthy and diseased tissue.

 

Plaques can be well demarcated and centred on blood vessels, with or without immunoglobulin and complement deposition, or they can be less well demarcated and not centred on vessels. This suggests distinct mechanisms at work, as the same type of plaques is normally found within the same individual

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Signs and Symptoms

Some plaques can be clinically silent in people with or without MS.

Cognitive Assessment

 

cognitive impairment

speed is thought to be one of the primary impairments, but these can be difficult to assess.

• inattention
• slowed information processing
• memory loss
• difficulties with abstract concepts and complex reasoning

 

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Investigations

Lab Tests

 

Increased protein in CSF

Oligobanding on CSF protein electrophoresis due to B cell proliferation within the CNS. Epitopes are widely variable

Moderate pleocytosis in the CSF in 1/3 of cases

Diagnostic Criteria

The 2005 Revised MacDonald criteria (Polman et al, 2005):

clinical attacks	objective lesions	additional requirements
2 or more	2 or more	none
2 or more	1	dissemination is space by MRI, or 2 or more lesions on MRI consistent with MS plus +CSF, or await further attack implicating other site
1	2 or more	dissemination is space by MRI, or second clinical attack
1	1	dissemination is space by MRI, or 2 or more lesions on MRI consistent with MS plus +CSF, AND dissemination is time by MRI, or second clinical attack
0	1 or more	disease progression for one year, AND 2/3 of the following: positive brain MRI positive spinal cord MRI positive CSF

 

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Differential Diagnosis

Inflammatory diseases:

• acute disseminated encephalomyelitis
• SLE
• PAN
• Sjogren's
• Behcet's disease
• granulomatosis angitis
• paraneoplastic encepalomyelopathies

Infections

• Lyme neuroborreliosis
• neurosyphilis
• HIV
• HLTV-1
• PML

granulomatous diseases

• sarcoidosis
• Wegener's granulomatosis
• lymphomatoid granulomatosis

myelin diseases

• adult metachromatic leukodystrophy
• adrenomyeloleukodystrophy

other

• vitamin B12 deficiency
• Arnold-Chiari malformation
• spinocerebellar disorders

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Treatments

Medications

Steroids can be used in acute situations

 

Interferon beta: immunomodulating; shots daily or weekly

 

Tysabri (natalizumab) antibody against integrin α4; appears to prevent crossing of immune cells across the blood brain barrier

 

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Consequences and Course

There are a number of patterns of MS

 

relapsing-remitting (about 85% at presentation): Half of people will have more progression after some years, with an average of one attack per year.

primary progressive (about 15% at presentation)

secondary progressive: Occurs after a period of relapsing-remitting

progressive-relapsing: relapsing course, but with overall progression

 

Exacerbations are new/worsening neurological deficits that lasts longer than 24 hours and is not due to fever or other systemic processes.

Pseudo-exacerbations ae transient neurological signs and symptoms due to illness (ie UTI), heat, or exertion. They typically resolve with removal of trigger.

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The Case of...

Case #2 - a small story wrapping it all up and asking about esp management.

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Additional Resources

Polman CH et al. 2005. Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Annals of Neurology. 58(6):840-6.

Tintore et al, 2000. Am J Radiography 21:702-706.

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