Download Demyelination

Demyelinating diseases
FM Brett., MD., FRCPath
Classification of demyelinating
disorders of the CNS
1. Primary demyelinating diseases – MS, ADEM, AHL
2. Secondary demyelinating diseases CPM, PML, SADC,
3. Leukodystrophies and metabolic disorders e.g sudanophilic
leucodystrophy, metachromatic leucodystrophy,
adrenoleucodystrophy, Krabbes leucodystrophy, Canavans
disease
4. Toxic demyelination - Hexachlorophane, cyanide, carbon
monoxide, chronic solvent vapour abuse.
MS
• Chronic, progressive immune-mediated
CNS disease
• Characterized by demyelination and axonal
loss  neurologic impairment and disability
• Axonal damage and brain atrophy occur early
and may be irreversible
~ 85 % RRMS i.e sporadic attacks followed by complete, partial
or no improvement
~ Within 10 years half of these pts develop secondary-progressive
disease (essentially unrelenting clinical progression with possible
superimposed acute attacks and minor remissions)
~ Remainder primary-relapsing disease – characterised either by
progression from onset with acute relapses
OR
Primary progressive disease progression without relapse or
remission
Epediomology of MS
• ~350,000 affected in US
– ~8,500–10,000 new cases yearly
• Most cases strike between ages 15 and 45
– Women outnumber men 2:1
• 85% present with RRMS
– Within 10 years, 50% of these patients develop
secondary-progressive MS  associated with
significant disability
Presenting features of MS
Limb weakness
50%
Optic neuritis
20%
Diplopia
10%
Parasthesia
10%
Bladder Parasthesia
10%
Vertigo and nystagmus
5%
Diagnosis of MS
Dissemination of lesions
in time
Dissemination of
lesions in space
Paraclinical tests
VER, MRI
Clinical
history
Less commonly acute mass lesion difficult to distinguish
clinically and pathologically from a neoplasm
MS Characteristics
1. Immune-mediated CNS
disease
2. Characterized by demyelination
Axonal
Transection
in acute
acute
Multiple
Axonal
Transection
in
MultipleSclerosis
Sclerosis
and
axonal
loss

neurologic
lesions
lesions
impairment and disability
3. Dissemination of lesions in
space
SMI-32
(non-phosphorylatedneurofilament)
neurofilament) -demyelinated
swellings
SMI-32
(non-phosphorylated
-demyelinatedaxons
axonsand
and
swellings
MBP
intact
axons
MBP intact axons
Bruce
Trapp
et al.,
NEJM
338,278
278(1998)
(1998)
Bruce
Trapp
et al.,
NEJM
338,
Normal white matter
Active demyelination
Inactive plaque
Biopsy
F23
Ambulant
14 yrs later
F21 wheelchair bound
F 36 Died 56 dys after
admission
Normal white matter
Active demyelination
Inactive plaque
Pathological features of acute
demyelination
Hypercellularity – macrophages
+++++
Areas of complete myelin loss
Relative axonal preservation
Perivascular lymphocytic cuffing
Annesley-Williams et al., JNEN
2000;59:477-89
Inflammation
and axonal
Inflammation
andtransection
Axonal
Disease
Stage
Early
Main
Component
Main
Clinical
Outcome
Inflammation and demyelination Relapses
(incipient global tissue loss,
altered NAA content)
Late
Atrophy, axonal loss, and
increasing tissue destruction
(less Gd-defined inflammation,
demyelination ongoing)
Disability
AXONAL
TRANSECTION
IN
ininacute
Axonal Transection
Transection
acuteMultiple
MultipleSclerosis
Sclerosis
lesions
ACUTE MS MS Lesions
A
64 m
B
45 m
Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285. Copyright  1998 Massachusetts Medical S
All rights reserved.
swellings
(non-phosphorylated neurofilament)
SMI-32 (non-phosphorylated
SMI-32
neurofilament)-demyelinated
-demyelinatedaxons
axonsand
and
swellings
axons
intact axons
MBP intact
MBP
Clinical forms of MS
•
•
•
•
•
•
•
•
Charcot triad
Generalised form
Onset with ocular symptoms
Sensory form
Cerebral form
Spinal form
Brainstem forms
Acute multiple sclerosis
BBB
Blood –brain barrier breakdown as initiating
event in demyelination
Endothelial reaction
EC
ECEC
EC
Cytokines, chemokines, excitotoxins
Macrophage
activation
accumulation
Gliosis
BBB
Break
down
Sinus arachnoid villi
Spinal nerves
Lymphatics
Lymphatics
Lymph node
Lymph node
Dominant parameter governing leukocyte traffic into the
CNS
1. Activation of the migrating cell type:
T cells
B cells
2. Alteration/activation of the CNS endothelial cell
Neutrophils
Phagocytic macrophages
Memory and naïve T cells
3. Physiological (no known alteration/activation required)
Perivascular cells
Microglia (during fetal life)
Meningeal macrophages
Choroid plexus macrophages
Mast cells
Parenchymal reaction as the initiating
event in demyelination
Recruitment of elements for
defensive inflammatory reaction
EC
EC
EC
BBB breakdown
stimulus
BB
T
T
B
Cytokines, chemokines, excitotoxins
NAWM and ‘new’ imaging techniques
Study
Werring
er al.,
Brain
2000
Rocca et
al.,
Neurol
2000
Filippi et
al., Ann
Neurol
1998
Goodkin
et al,
Neurol
1998
Technique
MR
diffusion
imaging
Mean
diffusivit
y
MTR
MTR
Time interval
6-8mo
between changes and
lesion appearance
6 weeks
3 mo
Several
months
Location of lesion
Away
from
areas of
enhancem
ent
Contralat
eral
NAWM
NAWM
NAWM
Pathological
NAWM
T1, T2
NAWM
Diff imaging
MTR
Evangelou et al., Ann Neurol 2000
Allen et al., J Neurol Sci 2001
Allen & McKeown., J Neurol Sci 1979
Adams CWM., B Med Bull 1979
De Groot., Brain 2001
van Waesberghe et al., Ann Neurol 1999
van Walderveen et al., Neurology 1998
Werring et al., Brain 2000
Rocca et al., Neurol 2000
Filippi et al ., Ann Neurol 1998
Goodkin et al., Neurol 1998
A
B
A
B
Female aged 36
years
24 weeks
gestation
A
B
A
B
Male aged 38 died 5 mo after presentation
A
B
A
B
ADEM vs MS
Clinical
CSF
Radiology
Pathology
ADEM monophasic Cells
++
OB+
Abn
Symmetric
Cerebrum
Cerebellum
Basal ganglia
Inflam +++
Demyel +
MS
Multiple lesions
Inflam +
Demyel
++++
monosympt Cells +
omatic
OB +
EDSS: Progression to Disability
Walking Ability
10.0 = Death due to MS
9.0–9.5 = Completely dependent
8.0–8.5 = Confined to bed/chair; self-care with
help
7.0–7.5 = Confined to wheelchair
6.0–6.5 = Walking assistance is needed
5.0–5.5 = Increasing limitation in ability to
walk
4.0–4.5 = Disability is moderate
Confined to a
wheelchair or bed
Walks with aid
(<5 yards)
Walks with assistance
(22–220 yards or more)
Walks unaided (110–220
yards or more)
Walks unaided (330–550
yards or more)
3.0–3.5 = Disability is mild to moderate
2.0–2.5 = Disability is minimal
Fully ambulatory
1.0–1.5 = No disability
0 = Normal neurologic exam
Kurtzke JF. Neurology. 1983;33:1444-1452.
Diagnosis of MS
Dissemination of lesions
in time
Dissemination of
lesions in space
Paraclinical tests
VER, MRI
Clinical
history
Less commonly acute mass lesion difficult to distinguish
clinically and pathologically from a neoplasm
Central Pontine Myelinolysis
~ Middle aged or elderly patients who are malnourished
or chronically debilitated
~ Associated with fluid-electrolyte imbalance particularly where
hyponatremia has been treated rapidly with hypo-osmolar saline
~ Mechanism of demyelination is unknown but may relate to
impaired vascular perfusion during the episode of rapid electrolyte
shift
~ Myelin loss usually occurs in the central pons
Progressive Multifocal
leucoencephalopathy
~ Lytic infection of oligodendrocytes by JC virus
~ Usually debilitated or immunosupressed patients
~ well recognised complication of Aids
PML