Pathophysiology
• Pathophysiology of MS is characterized by autoimmune inflammation, demyelination, and
axonal degeneration.
• Most commonly accepted theory: Activation of autoreactive T-lymphocytes → inflammatory
processes → focal demyelination with partial preservation of axons (acute plaques) → loss
of axons and atrophy of oligodendrocytes (chronic plaques) → gliosis → inadequate
remyelination
• B-lymphocyte dysfunction: The following suggests that B-lymphocytes play a role in the
pathogenesis of MS, although the exact mechanism of their involvement is unclear.
• Anti-CD20 agents (ocrelizumab, ofatumumab, rituximab) are effective in preventing exacerbations.
• Presence of tertiary lymphoid organs in the meninges of individuals with secondary progressive MS
• Intrathecal synthesis of IgG (oligoclonal bands)
• Progressive phenotypes (forms) of MS are characterized by
• Chronic inflammation that occurs with an intact blood-brain barrier and is driven by immune cells
compartmentalized in the leptomeninges and perivascular spaces
• Accelerated compared to relapsing-remitting phenotype brain atrophy
Pathophysiology
Etiology
• The etiology of multiple sclerosis is unclear; it is believed to develop in
genetically predisposed people who have been exposed to certain
environmental factors.
• Genetic predisposition
• Presence of HLA-DRB1*15 allele increases the risk of MS.
• Presence of HLA-A*02 allele appears to be protective against MS.
• 30% disease concordance among monozygotic twins
• 3–4% disease concordance among first-degree relatives (age-adjusted risk 4–5% for
siblings and 2–3% for parents or offspring)
• Environmental risk factors
• Low vitamin D levels (insufficient intake, decreased exposure to UV radiation)
• Cigarette smoking
• Pathogens: EBV, HHV 6
• Obesity early in life
Epidemiology
• Sex: ♀ > ♂ (2:1)
• Age of onset: 20–40 years of age, onset before puberty or
after the age of 60 years is rare
• Ethnicity: ↑ prevalence among the white and black
population
• Prevalence:
• 50-300 per 100 000 people (greater among people who live further
from the equator)
• 120 per 100 000 in UK
• The vitamin D hypothesis suggests that increased exposure to
sunlight during childhood might be protective.
Much of the initial acute clinical deficit is caused by the
effect of inflammatory cytokines on transmission of the
nervous impulse rather than structural disruption of myelin,
and may explain the rapid recovery of some deficits and
probably the acute benefit from glucocorticoids.
Clinical pearl!
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Classification
• Exacerbation
• New symptoms or significant worsening of symptoms caused
by CNS demyelination that last at least 24 hours and are not
accompanied by fever or infection
• Also referred to as an attack, relapse, or flare
• Remission:
• A period of recovery after an exacerbation during which
clinical symptoms resolve completely or almost completely
• Pseudorelapse:
• A recurrence or significant worsening of existing symptoms
due to stressors (e.g., infection, heat)
Classification
• Radiologically isolated syndrome (RIS)
• The presence of demyelinating lesions characteristic of MS in
an asymptomatic individual
• Not considered an MS phenotype but may progress to MS
• Clinically isolated syndrome (CIS)
• A single episode of neurological symptoms resulting
from CNS demyelination
• A second episode of such symptoms increases the likelihood
that the symptoms are not clinically isolated and that the
patient meets the diagnostic criteria for MS.
Clinical course
• Relapsing-remitting MS (RR-MS)
• ∼ 90% (most common clinical course)
• Exacerbations occur.
• Symptoms remit almost completely between exacerbations.
• Secondary progressive MS (SP-MS)
• ∼ 50% of patients with RR-MS develop SP-MS.
• A progression of RR-MS characterized by continuous worsening of neurological
function that occurs independently of exacerbation events
• Primary progressive MS (PP-MS)
• ∼ 10%
• Symptoms continuously worsen from the onset of the disease.
• Fulminant MS
• Rare, leads to early death
Clinical features
• Constitutional symptoms: fatigue, headache
• Optic neuritis
• Most often the earliest manifestation
• Typically unilateral
• Can be painful
• Impaired vision and color blindness
• Relative afferent pupillary defect (Marcus Gunn pupil)
• Internuclear ophthalmoplegia (INO) as a result of a lesion in
the medial longitudinal fasciculus (MLF)
• Ipsilateral medial rectus weakness but an intact convergence reflex
• Disconjugate, lateral gaze nystagmus in the contralateral eye
• More frequently bilateral than unilateral
Symptoms and signs of MS
usually evolve
over days or weeks, resolving
over weeks or months
Clinical pearl!
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Clinical features
Clinical features
RAPD
Swing a light back and forth in front of the two
pupils and compare the reaction to stimulation
in both eyes.
When light reaches a pupil there should be a
normal direct and consensual response.
An RAPD is diagnosed by observing paradoxical
dilatation when light is directly shone in the
affected pupil after being shown in the healthy
pupild to be from a pathologic process
This decrease in constriction or widening of the
pupil is due to reduced stimulation of the visual
pathway by the pupil on the affected side. By
not being able to relay the intensity of the light
as accurately as the healthy pupil and visual
pathway, the diseased side causes the visual
pathway to mistakenly respond to the decrease
in stimulation as if the flashlight itself were less
luminous. This explains the healthy eye is able
to undergo both direct and consensual
dilatation seen on the swinging flashlight test.
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Clinical features
Clinical features
Clinical features
Clinical features
Clinical features
MS is a chronic condition that typically
manifests in a relapsing-remitting form
characterized by episodic CNS dysfunction
(exacerbations) with at least partial recovery
between episodes.
Clinical pearl!
26
Diagnostics
• General principles
• Diagnosis of MS depends on a combination of clinical findings (e.g., optic
neuritis, Lhermitte sign, sensory abnormalities, cerebellar signs), imaging,
and laboratory results.
• Consider early specialist (i.e., neurology) consultation for patients with
history and clinical features suggestive of MS.
• The McDonald Criteria for both DIT and DIS must both be met to confirm
a diagnosis of MS:
• Dissemination in time (DIT): the appearance of new CNS lesions over time that
can be confirmed clinically, with imaging, or with CSF analysis
• Dissemination in space (DIS): the presence of lesions in different regions of
the CNS that can be confirmed clinically or in MRI
• In some cases, electrophysiological, CSF, and laboratory studies may be
necessary to support the diagnosis and exclude differential diagnoses.
Diagnostics
Diagnostics
• Imaging
• MRI is the imaging study of choice for the diagnosis and monitoring of MS.
• Indications
• MRI brain (with and without gadolinium): all patients with suspected MS
• MRI spinal cord (with and without gadolinium): to increase diagnostic yield (e.g., in
patients with nondiagnostic brain MRI or symptoms of partial myelitis )
• Typical findings on MRI
• Multiple sclerotic plaques (most commonly found in the periventricular white
matter) with finger-like radial extensions (Dawson fingers) related
to demyelination and reactive gliosis
• In T1: hypointense or isointense lesions (i.e., black hole lesions) due to severe demyelination and
axonal destruction
• In T2 and FLAIR: hyperintense lesions, typically round or oval in shape and found in both
hemispheres
• Contrast-enhancement of active lesions; usually resolves after 2–8 weeks
Diagnostics
• CSF examination:
• commonly performed to support MS diagnosis and rule out other
conditions
• Oligoclonal bands
• Oligoclonal bands in the CSF but not in blood support diagnosis of MS.
• Oligoclonal bands manifest due to increased production of multiple
nonspecific IgG sub-fractions in the CSF, which are caused by intrathecal
inflammation.
• Detected using electrophoresis or isoelectric focusing of CSF
• Found 70–90% of patients between attacks
• Not specific for MS and denote only intrathecal inflammation, provided they are
unique for the CSF
• Other common findings: moderate lymphocytic pleocytosis,
increased myelin basic protein
Diagnostics
Treatment
• Management of acute exacerbations
• If an acute exacerbation of MS is suspected, a specialist
should be consulted immediately for management.
• Preferred therapy:
• High-dose glucocorticoid pulse therapy (e.g., methylprednisolone)
• Start measures to prevent complications of glucocorticoid therapy
(e.g., PPIs, monitoring for hyperglycemia).
• Prolonged administration of glucocorticoids does not alter the long-
term outcome and is associated with severe adverse effects; it
should therefore be avoided.
• Alternatives: plasmapheresis, ACTH gel
Treatment
Phenotype Drugs commonly used
Clinically isolated syndrome Interferon therapy (IFN-β)
Glatiramer acetate
Teriflunomide
Relapsing-remitting MS Interferon therapy (IFN-β)
Glatiramer acetate
Fumarates (e.g., dimethyl fumarate)
Teriflunomide
Sphingosine 1-phosphate receptor modulators
(e.g., fingolimod, siponimod)
Monoclonal antibodies (e.g., natalizumab,
ocrelizumab, alemtuzumab, ofatumumab)
Mitoxantrone
Secondary progressive MS All disease-modifying therapies may be used for active SP-
MS.
Primary progressive MS Ocrelizumab
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