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