demyelinating diseases fm brett., md., frcpath
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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 earlyand may be irreversible
~ 85 % RRMS i.e sporadic attacks followed by complete, partialor 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 byprogression from onset with acute relapses
ORPrimary 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 lesionsin time
Dissemination of lesions in space
Clinical history
Paraclinical testsVER, MRI
Less commonly acute mass lesion difficult to distinguish clinically and pathologically from a neoplasm
MS Characteristics1. Immune-mediated CNS
disease2. Characterized by demyelination and axonal loss neurologic impairment and disability
3. Dissemination of lesions in space
Normal white matter
Active demyelination
Inactive plaque
Biopsy
F21 wheelchair bound
F23Ambulant14 yrs later
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
DiseaseStage
Main Clinical Outcome
Early Inflammation and demyelination Relapses(incipient global tissue loss,
altered NAA content)
Late Atrophy, axonal loss, and Disability increasing tissue destruction
(less Gd-defined inflammation, demyelination ongoing)
Main Component
Inflammation and AxonalInflammation and axonal transection
AXONAL TRANSECTION IN ACUTE MS MS Lesions
Reprinted with permission from Trapp BD et al. N Engl J Med. 1998;338:278-285. Copyright 1998 Massachusetts Medical Society. All rights reserved.
64 m 45 mA B
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 BBB
Breakdown
Macrophage activation accumulation
Gliosis
Cytokines, chemokines, excitotoxins
ECEC EC EC
Sinus arachnoid villi
Lymphatics
Lymph node
Lymphatics
Lymph node
Spinal nerves
Dominant parameter governing leukocyte traffic into the CNS
1.1. Activation of the migrating cell type:Activation of the migrating cell type:
T cells
B cells
2. 2. Alteration/activation of the CNS endothelial cellAlteration/activation of the CNS endothelial cell
Neutrophils
Phagocytic macrophages
Memory and naïve T cells
3.3. Physiological (no known alteration/activation required)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
T B
T
BB
stimulus
Cytokines, chemokines, excitotoxins
BBB breakdown
Recruitment of elements for defensive inflammatory reaction
EC ECEC
NAWM and ‘new’ imaging techniques
Away from areas of enhancement
Contralateral NAWM
Location of lesion
Several months
3 mo6 weeks6-8moTime interval between changes and lesion appearance
MTRMTRMean diffusivity
MR diffusion imaging
Technique
Goodkin et al, Neurol
1998
Filippi et
al., Ann Neurol 1998
Rocca et al., Neurol
2000
Werring er al., Brain 2000
Study
NAWM
NAWM
Pathological
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
NAWM
T1, T2
De Groot., Brain 2001
van Waesberghe et al., Ann Neurol 1999
van Walderveen et al., Neurology 1998
NAWM
Diff imaging
MTR
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
BA
A B
ADEM vs MS
Clinical CSF Radiology Pathology
ADEM monophasic Cells ++
OB+
Abn
Symmetric
Cerebrum
Cerebellum
Basal ganglia
Inflam +++
Demyel +
MS monosymptomatic
Cells +
OB +
Multiple lesions Inflam +
Demyel ++++
EDSS: Progression to Disability
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
3.0–3.5 = Disability is mild to moderate
2.0–2.5 = Disability is minimal
1.0–1.5 = No disability
0 = Normal neurologic exam
10.0 = Death due to MS
9.0–9.5 = Completely dependentConfined to a wheelchair or bed
Walking Ability
Walks with aid(<5 yards)
Walks with assistance(22–220 yards or more)
Walks unaided (110–220
yards or more)Walks unaided (330–
550yards or more)
Fully ambulatory
Kurtzke JF. Neurology. 1983;33:1444-1452.
Diagnosis of MS
Dissemination of lesionsin time
Dissemination of lesions in space
Clinical history
Paraclinical testsVER, MRI
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 wherehyponatremia 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