Week 1: Neuroimmunolgy
Clinical aspects of MS
Epidemiology:
● More women than men → 2-3:1
● Typical age: 20-40 years. Age at onset is often lower in females.
● A western disease: Further from the equator → less UV light → lower serum Vitamin
D → higher risk of MS. Not yet been proved, but there seems to be an association.
Pathology:
● MS is exclusively in the CNS. A complex interaction between the immune system,
neurons and glia result in inflammation and destruction of the CNS.
● Major pathological process: Demyelination = breakdown myelin + destruction
oligodendrocytes. B and T cell response → inflammatory process which can be
targeted by therapy.
● Demyelinating lesions: located in the periventricular and juxtacortical regions and
spinal cord (brain stem, cerebellum, optic nerve)
● Degeneration: neuronal loss of chronically demyelinated axons, gliosis of astrocytes
and activated microglia.
Cause: MS is familial: increased risk within the family. HLA region in chromosome 6 has
been associated with MS. Over 200 allelic variants in genes have been identified as a risk
factor for MS.
Symptoms:
Most MS patients have symptoms arising from one or more places of inflammation. The
symptoms typically increase in a relapse, and then complete or incompletely stay for some
time.
● Optic neuritis: decreased vision, mainly in the central visual fields. Disturbance of
colour vision. And pain behind the eye. (This manifestation can also be with other
auto-immune diseases. patients presenting this have a 25-72% chance of MS).
● Eye movement: abnormal. most common is double vision and involuntary eye
movement.
● Lhermitte’s symptom: flexion of the neck causes an electrical-like shooting sensation.
● Motor function: weakness of the limbs. Mostly at one side of the brain, and often arm
& leg.
● Bladder function: due to the lower nerves.
● Psychological functions: slowing of processing, attention deficit, disturbance of
memory and language processing.
● Fatigue: most common and high impact. The cause is unknown.
Diagnosis:
Relapsing-remitting MS (RRMS): occurs at the onset. Symptoms come and go. Tissue
damage accumulates and then they move to the secondary progressive phase.
Secondary progressive MS (SPMS): initial relapse remitting and then suddenly begins to
decline without a period of remission.
, Picture:
First RRMS with ups and downs → then
reaching threshold → become SPSM with minimal
ups and downs → then improvements are only
worsening.
The first stage has more inflammation, the second stage is more degeneration
Diagnosing using the McDonald criteria of 2017. Dysfunction of a variable brain or spinal cord
areas on more than one occasion in time.
> Dissemination in space: two of the four places where the lesions can happen. Someone
with optic neuritis only cannot be labelled as an MS patient.
> Dissemination in time: >1 relapse. MRI shows new lesions. Use contrast to see new
versus old lesions. The presence of oligoclonal bands can be seen in the cerebrospinal fluid.
CSF: used in the diagnosis of MS.
● Oligoclonal bands: antibodies. are always present independent of the relapsing
phase. high sensitivity (90%), and lower specificity.
● IgG index: ration CSF and IgG in serum. Not often used because this could indicate
all types of auto-immune diseases.
Treatment:
● The window of opportunity: active white matter demyelination in the relapsing phase.
● First-line therapy: less effective but also has fewer side effects.
● Second-line therapy: more aggressive treatment.
● Early therapy is needed to delay the accumulation of irreversible neurological
damage.
● Effectiveness vs. risks: Natalizumab is very effective, but the chance of opportunistic
viral infection is bigger → possibility of severe disability or death
Histopathology of MS/Practical class of MS pathology
Main aspects revolving around MS:
● Long clinical course → >40 years
● Hallmarks of MS: demyelination, inflammation/immune response and involvement of
both WM and GM.
● Outside-in hypothesis: a primary autoimmune attack causes myelin and axonal
degeneration in the CNS.
● Inside-out hypothesis: a primary cyto-degenerative process causes myelin
degeneration in the CNS and a secondary autoimmune attack against the
fragmented myelin.
● Spotting the basic hallmarks: myelin proteins in the membrane. PLP is often used.
No PLP = lesion. (PLP colours brown).
White matter lesions: classify based on the level of inflammation. Use APC markers like
MHC-II.
● Active: high MHC-II reactivity inside the lesion. A lot of macrophages and active
microglia. This indicates a new lesion.
● Chronic active: high MHC-II reactivity at the rim. Fewer macrophages. Older lesion
than active.
Clinical aspects of MS
Epidemiology:
● More women than men → 2-3:1
● Typical age: 20-40 years. Age at onset is often lower in females.
● A western disease: Further from the equator → less UV light → lower serum Vitamin
D → higher risk of MS. Not yet been proved, but there seems to be an association.
Pathology:
● MS is exclusively in the CNS. A complex interaction between the immune system,
neurons and glia result in inflammation and destruction of the CNS.
● Major pathological process: Demyelination = breakdown myelin + destruction
oligodendrocytes. B and T cell response → inflammatory process which can be
targeted by therapy.
● Demyelinating lesions: located in the periventricular and juxtacortical regions and
spinal cord (brain stem, cerebellum, optic nerve)
● Degeneration: neuronal loss of chronically demyelinated axons, gliosis of astrocytes
and activated microglia.
Cause: MS is familial: increased risk within the family. HLA region in chromosome 6 has
been associated with MS. Over 200 allelic variants in genes have been identified as a risk
factor for MS.
Symptoms:
Most MS patients have symptoms arising from one or more places of inflammation. The
symptoms typically increase in a relapse, and then complete or incompletely stay for some
time.
● Optic neuritis: decreased vision, mainly in the central visual fields. Disturbance of
colour vision. And pain behind the eye. (This manifestation can also be with other
auto-immune diseases. patients presenting this have a 25-72% chance of MS).
● Eye movement: abnormal. most common is double vision and involuntary eye
movement.
● Lhermitte’s symptom: flexion of the neck causes an electrical-like shooting sensation.
● Motor function: weakness of the limbs. Mostly at one side of the brain, and often arm
& leg.
● Bladder function: due to the lower nerves.
● Psychological functions: slowing of processing, attention deficit, disturbance of
memory and language processing.
● Fatigue: most common and high impact. The cause is unknown.
Diagnosis:
Relapsing-remitting MS (RRMS): occurs at the onset. Symptoms come and go. Tissue
damage accumulates and then they move to the secondary progressive phase.
Secondary progressive MS (SPMS): initial relapse remitting and then suddenly begins to
decline without a period of remission.
, Picture:
First RRMS with ups and downs → then
reaching threshold → become SPSM with minimal
ups and downs → then improvements are only
worsening.
The first stage has more inflammation, the second stage is more degeneration
Diagnosing using the McDonald criteria of 2017. Dysfunction of a variable brain or spinal cord
areas on more than one occasion in time.
> Dissemination in space: two of the four places where the lesions can happen. Someone
with optic neuritis only cannot be labelled as an MS patient.
> Dissemination in time: >1 relapse. MRI shows new lesions. Use contrast to see new
versus old lesions. The presence of oligoclonal bands can be seen in the cerebrospinal fluid.
CSF: used in the diagnosis of MS.
● Oligoclonal bands: antibodies. are always present independent of the relapsing
phase. high sensitivity (90%), and lower specificity.
● IgG index: ration CSF and IgG in serum. Not often used because this could indicate
all types of auto-immune diseases.
Treatment:
● The window of opportunity: active white matter demyelination in the relapsing phase.
● First-line therapy: less effective but also has fewer side effects.
● Second-line therapy: more aggressive treatment.
● Early therapy is needed to delay the accumulation of irreversible neurological
damage.
● Effectiveness vs. risks: Natalizumab is very effective, but the chance of opportunistic
viral infection is bigger → possibility of severe disability or death
Histopathology of MS/Practical class of MS pathology
Main aspects revolving around MS:
● Long clinical course → >40 years
● Hallmarks of MS: demyelination, inflammation/immune response and involvement of
both WM and GM.
● Outside-in hypothesis: a primary autoimmune attack causes myelin and axonal
degeneration in the CNS.
● Inside-out hypothesis: a primary cyto-degenerative process causes myelin
degeneration in the CNS and a secondary autoimmune attack against the
fragmented myelin.
● Spotting the basic hallmarks: myelin proteins in the membrane. PLP is often used.
No PLP = lesion. (PLP colours brown).
White matter lesions: classify based on the level of inflammation. Use APC markers like
MHC-II.
● Active: high MHC-II reactivity inside the lesion. A lot of macrophages and active
microglia. This indicates a new lesion.
● Chronic active: high MHC-II reactivity at the rim. Fewer macrophages. Older lesion
than active.
