Contents
Part 1: Summary............................................................................................................................................ 1
Part 2: Background........................................................................................................................................ 3
Part 3: Pathogenesis of MS........................................................................................................................... 6
Part 4: Treatment......................................................................................................................................... 13
Treatment options.................................................................................................................................... 15
Proposed Mechanism of Action................................................................................................................ 15
Disease modifying treatment is neuroprotective.......................................................................................16
Strategies of restoring myelination........................................................................................................... 16
Maximising future success....................................................................................................................... 17
New drugs in trial..................................................................................................................................... 17
Part 1: Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelination disease of the central nervous system
(CNS). In MS, the immune system is thought to attack the myelinated axons in the CNS, impairing the
ability of the CNS to transmit its neuronal signals. This results in a range of symptoms including muscle
weakness, loss of coordination, and blindness. While the exact cause of the disease remains relatively up
for debate, the mechanism by which such demyelination occurs is fairly well understood. Activation of
immune cells drive and trigger MS by targeting the oligodendrocytes and myelin of the CNS. This results in
the pathological hallmark of demyelinated plaques and lesions concomitant with degeneration,
inflammation, and reactive astrocytosis. Interestingly, the location of these lesions is thought to reflect a
specific set of symptoms. While it was traditionally though that these plaques would primarly affect the CNS
white matter, more recent evidence based on pathological and imaging studies propose that demyelination
of the cortex is also present.
There are two underlying views as to how these immune cells are activated. The ‘outside-in’ model
proposes that autoimmunity is generated in the periphery and enters the CNS, while the ‘inside-out’ model
suggests that neurodegeneration is initiated in the CNS, subsequently triggering the immune system as a
secondary phenomenon. Moreover, there are several factors that are thought to increase the risk of
developing MS, such as a history Epstein-Barr virus (EBV).
Pathogenesis
,Main pathological lesions: multiple sclerotic plaques showing demyelination of white and gray matter in
the brain and spinal cord caused by immune cell infiltration across the BBB that promotes
inflammation, demyelination, gliosis, and neuroaxonal degeneration leads to disruption of neuronal
signalling
Consist of well-demarcated hypocellular area
Characterised by loss of myelin, relative preservation of axons, and formation of astrocytic scars
In the lesions, myelin, oligodendrocytes and axons are destroyed axonal dysfunction results from
nerve conduction disorders following demyelination
Accumulation of demyelinated lesions may lead to neurological features of MS
During early stages of MS, spontaneous remyelination (where oligodendrocyte progenitor cells re-
ensheath demyelinated axons) will help to restore axonal conduction
o Over time, remyelination fails to compensate for progression of inflammation-drivedn
demyelination
o Consequence axonal damage = permanent, irreversible neurological decline
Pathology
1. Myelin sheaths and oligodendrocytes are destroyed after myeline protien components are
recognised by cells of the immune system
a. Inflammatory reaction includes activation of myelin-specific CD4+ autoreactive T cells and
differentiation into pro-inflammatory Th1-like phenotype + CD8+ T cells, B cells secreting
myelin-directed antibodies
2. Activated lymphocytes recruited from periphery to CNS cross the CSF barrier and BBB
3. Presence of activated immune cells + immunoglobins and cytokines in CSF in patients with MS
suggests participation of immune system in pathogenesis
, Part 2: Background
Multiple sclerosis (MS) is a chronic (auto)immune-mediated CNS confined demyelinating disease
affecting 3 million people worldwide and about 130,000 people in the United Kingdom
Disease onset is usually between 20 and 40 years of age (F:M ratio, 2:1)
MS is clinically characterized by a relapsing-remitting course usually followed by a progressive
phase
MS is pathologically heterogeneous – inflammation, demyelination and neurodegeneration (axonal
loss and neuronal damage)
Spontaneous repair occurs but MS invariably progresses (ambulatory problems in 70-80% patients
at 25 years from onset)
Society views the Late Stages of MS to be Worse than Death
Characterisation of MS
Confluent demyelinated areas in white and grey matter of brain and spinal cord plaques/lesions
Plaques/lesions indicate loss of myelin sheath and oligodendrocytes
Ongoing disease = gradual neuroaxonal loss that correlates with patient disability Brain atrophy
o Accompanied by ventricular enlargement
Astrocytes form multiple sclerotic glial scars in white matter lesions
Demyelinated areas in white matter can be partially repaired by remyelination
Inflammation is more pronounced in acute phases than in chronic phases
Clinical Spectrum
Part 1: Summary............................................................................................................................................ 1
Part 2: Background........................................................................................................................................ 3
Part 3: Pathogenesis of MS........................................................................................................................... 6
Part 4: Treatment......................................................................................................................................... 13
Treatment options.................................................................................................................................... 15
Proposed Mechanism of Action................................................................................................................ 15
Disease modifying treatment is neuroprotective.......................................................................................16
Strategies of restoring myelination........................................................................................................... 16
Maximising future success....................................................................................................................... 17
New drugs in trial..................................................................................................................................... 17
Part 1: Summary
Multiple sclerosis (MS) is a chronic inflammatory demyelination disease of the central nervous system
(CNS). In MS, the immune system is thought to attack the myelinated axons in the CNS, impairing the
ability of the CNS to transmit its neuronal signals. This results in a range of symptoms including muscle
weakness, loss of coordination, and blindness. While the exact cause of the disease remains relatively up
for debate, the mechanism by which such demyelination occurs is fairly well understood. Activation of
immune cells drive and trigger MS by targeting the oligodendrocytes and myelin of the CNS. This results in
the pathological hallmark of demyelinated plaques and lesions concomitant with degeneration,
inflammation, and reactive astrocytosis. Interestingly, the location of these lesions is thought to reflect a
specific set of symptoms. While it was traditionally though that these plaques would primarly affect the CNS
white matter, more recent evidence based on pathological and imaging studies propose that demyelination
of the cortex is also present.
There are two underlying views as to how these immune cells are activated. The ‘outside-in’ model
proposes that autoimmunity is generated in the periphery and enters the CNS, while the ‘inside-out’ model
suggests that neurodegeneration is initiated in the CNS, subsequently triggering the immune system as a
secondary phenomenon. Moreover, there are several factors that are thought to increase the risk of
developing MS, such as a history Epstein-Barr virus (EBV).
Pathogenesis
,Main pathological lesions: multiple sclerotic plaques showing demyelination of white and gray matter in
the brain and spinal cord caused by immune cell infiltration across the BBB that promotes
inflammation, demyelination, gliosis, and neuroaxonal degeneration leads to disruption of neuronal
signalling
Consist of well-demarcated hypocellular area
Characterised by loss of myelin, relative preservation of axons, and formation of astrocytic scars
In the lesions, myelin, oligodendrocytes and axons are destroyed axonal dysfunction results from
nerve conduction disorders following demyelination
Accumulation of demyelinated lesions may lead to neurological features of MS
During early stages of MS, spontaneous remyelination (where oligodendrocyte progenitor cells re-
ensheath demyelinated axons) will help to restore axonal conduction
o Over time, remyelination fails to compensate for progression of inflammation-drivedn
demyelination
o Consequence axonal damage = permanent, irreversible neurological decline
Pathology
1. Myelin sheaths and oligodendrocytes are destroyed after myeline protien components are
recognised by cells of the immune system
a. Inflammatory reaction includes activation of myelin-specific CD4+ autoreactive T cells and
differentiation into pro-inflammatory Th1-like phenotype + CD8+ T cells, B cells secreting
myelin-directed antibodies
2. Activated lymphocytes recruited from periphery to CNS cross the CSF barrier and BBB
3. Presence of activated immune cells + immunoglobins and cytokines in CSF in patients with MS
suggests participation of immune system in pathogenesis
, Part 2: Background
Multiple sclerosis (MS) is a chronic (auto)immune-mediated CNS confined demyelinating disease
affecting 3 million people worldwide and about 130,000 people in the United Kingdom
Disease onset is usually between 20 and 40 years of age (F:M ratio, 2:1)
MS is clinically characterized by a relapsing-remitting course usually followed by a progressive
phase
MS is pathologically heterogeneous – inflammation, demyelination and neurodegeneration (axonal
loss and neuronal damage)
Spontaneous repair occurs but MS invariably progresses (ambulatory problems in 70-80% patients
at 25 years from onset)
Society views the Late Stages of MS to be Worse than Death
Characterisation of MS
Confluent demyelinated areas in white and grey matter of brain and spinal cord plaques/lesions
Plaques/lesions indicate loss of myelin sheath and oligodendrocytes
Ongoing disease = gradual neuroaxonal loss that correlates with patient disability Brain atrophy
o Accompanied by ventricular enlargement
Astrocytes form multiple sclerotic glial scars in white matter lesions
Demyelinated areas in white matter can be partially repaired by remyelination
Inflammation is more pronounced in acute phases than in chronic phases
Clinical Spectrum
